Cancer Biology Research

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The Importance of Cancer Biology Research

Research on the biology of cancer starts with the simplest of questions: What is—and isn’t—normal? To understand how cancer develops and progresses, researchers first need to investigate the biological differences between normal cells and cancer cells. This work focuses on the mechanisms that underlie fundamental processes such as cell growth, the transformation of normal cells to cancer cells, and the spread ( metastasis ) of cancer cells.

Virtually all major advances against cancer originated with discoveries in basic science . Basic research can reveal new ideas about the causes of cancer and how it develops, progresses, and responds to therapy.

Knowledge gained from such studies deepens our understanding of cancer and produces insights that could lead to new clinical interventions. For example, studies of cell signaling pathways  in normal cells and cancer cells have contributed greatly to our knowledge about the disease, revealing molecular alterations that are shared among different types of cancer and pointing to possible treatment strategies.

Decades of basic research in cancer biology have created a broad base of knowledge that has been critical to progress against the disease.

Selected NCI Activities in Cancer Biology Research

National Cancer Plan

NCI Research and the National Cancer Plan

NCI supports a broad variety of research that aligns with the goals of the National Cancer Plan. Read about the plan and explore each goal.

Federal funding for cancer biology is essential because this area of research receives relatively little funding from entities that are driven by profit. NCI supports and directs cancer biology research through a variety of programs and approaches. For example:

  • The Metastasis Research Network (MetNet) supports research to improve our understanding of how cancer spreads. Cancer metastasis is a complex, dynamic, nonlinear process. The network supports several specialized centers working collaboratively on multidisciplinary projects focused on several themes of the metastatic process, including mechanisms of early dissemination, cellular and physical microenvironment crosstalk, dormancy, and mechanisms of responses to therapy by metastatic cells.
  • The Translational and Basic Science Research in Early Lesions (TBEL) Program is advancing the understanding of the mechanisms driving, or restraining, the development of precancers and early cancers, as well as informing the development of precision prevention approaches. The program supports multidisciplinary research centers that are integrating basic and translational research to investigate the interactions of an early lesion, its microenvironment, and host factors as “co-organizers” of tumor initiation and the development of cancer.
  • The Human Tumor Atlas Network is constructing 3-dimensional atlases of the cellular, morphological, and molecular features of human cancers as they evolve from precancerous lesions to advanced disease. The atlases, which represent a diverse patient population, will also be used to study how tumors respond to treatment and develop resistance to drugs.
  • The Cancer Tissue Engineering Collaborative (TEC) supports the development and characterization of state-of-the-art biomimetic tissue-engineered technologies for cancer research. This program advances innovative, well-characterized in vitro and ex vivo systems available for cancer research, expands the breadth of these systems to several cancer types, and promotes investigations of cancer with tissue-engineered systems.

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NCI Fiscal Year 2025 Professional Judgment Budget Proposal

Each year, NCI prepares a professional judgment budget to lead progress against cancer.

  • The consortium of tumor glycomics laboratories and their research partners that make up the Alliance of Glycobiologists for Cancer Research are investigating the cancer-related dynamics of complex carbohydrates. The alliance, which NCI sponsors with the National Institute of General Medical Sciences and the National Heart, Lung, and Blood Institute, aims to study the structure and function of glycans in relation to cancer.
  • The NCI RNA Biology Initiative facilitates the exchange of information and expertise among investigator studying the structure, function, and biological roles of RNA for the purpose of developing new cancer diagnostics and therapies.
  • NCI’s Centers of Excellence bring together the institute’s intramural researchers to collaborate on new projects and initiatives in various areas of cancer biology, including Chromosome Biology and Genitourinary Malignancies .

Recent Research Findings in Cancer Biology

  • Loss of Y Chromosome in Men Makes Bladder Cancer More Aggressive
  • Cells’ decision to divide is reversible
  • How Fatty Liver Disease Helps Cancer Thrive in the Liver
  • No Glucose? Pancreatic Cancer May Have a Ready Energy Alternative
  • How Some Brain Tumors Hijack the Mind to Grow
  • Researchers discover the multiple shapes of RNA, a boon for drug design
  • Vulnerability in Brain Tumors May Open Door to New Treatments
  • Preventing Chemo Brain? Study Identifies Potential Approach for Common Problem

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Cancer Biology

Focus areas.

The mission of the Department of Cancer Biology is to identify and understand the causes of cancer, to develop innovative approaches to reduce cancer incidence, to create and test novel and more effective therapies, and to translate these findings into clinical care for the benefit of patients.

Research in our department is highly collaborative and is potentiated through close interactions with other basic science departments and translated through clinical collaborations.

Our faculty members are aligned into eight research focus areas that address cancer development, progression and treatment.

Cancer disparities

While cancer affects everyone, certain groups have higher rates of cancer cases, deaths and health complications. These differences can be associated with genetics, sex, racial and ethnic populations, socioeconomic status, or specific geographic areas. Studying the factors that lead to cancer disparities leads to more-effective prevention and treatment approaches for the affected populations.

  • Read more about the cancer disparities focus area .

Cancer stem cells

The stem cell theory of cancer proposes that among the many different types of cells within a cancer, there exists a subpopulation of cells called cancer stem cells that multiply indefinitely, are resistant to chemotherapy, and are thought to be responsible for relapse after therapy. Cancer stem cells also give rise to highly metastatic cells that spread to other organs and tissues within the body. A deeper understanding of cancer stem cells is leading to better implementation of existing anti-cancer therapies and identification of new approaches that target the cancer stem cells specifically.

  • Read more about the cancer stem cells focus area .

Cancer systems biology

Cancer is a complex disease with many molecular, genetic and cellular causes. Considering these causes as a system of interactions can lead to a better understanding of the processes involved in the development of cancer and response to therapies. Cancer systems biology integrates advanced experimental models, insights from genome sequencing and other large-scale data projects, and computational models to create unified models of cancer behavior.

  • Read more about the cancer systems biology focus area .

Oncogenic gene dysregulation and carcinogenesis

Cancer initiates from genetic alterations, including mutations, deletions and copy number gains, that function to activate cancer-promoting pathways or to block processes that normally inhibit cancer development. Through better understanding of pro- and anti-cancer signaling processes and how they become dysregulated in carcinogenesis and tumor progression, our team can improve biological tools for clinicians and devise molecularly targeted therapies to intervene.

  • Read more about the oncogenic gene dysregulation and carcinogenesis focus area .

Precision cancer medicine and translational therapeutics

Cancers develop and respond to therapies differently from one patient to the next. A better understanding of the specific processes driving cancer growth and spread in an individual patient allows for tailored therapeutic strategies that are more effective with minimal side effects. Profiling the mutations and abnormalities that drive a tumor, in combination with development of experimental models that assess the specific responses of cancer cells to therapeutics that target those abnormalities, has dramatically improved outcomes in many cancer types.

  • Read more about the precision cancer medicine and translational therapeutics focus area .

Tumor immunology and immunotherapy

Therapeutic strategies that stimulate the immune system to target cancer cells can lead to long-lasting tumor regression and minimize relapse. Integrated efforts of laboratory researchers and clinicians are leading to improved knowledge of how the immune system interacts with cancer cells and how immune processes can be intentionally manipulated for therapeutic effect.

  • Read more about the tumor immunology and immunotherapy focus area .

Tumor invasion and metastasis

A fundamental property of malignant tumor cells is the ability to invade surrounding tissues and to metastasize to other organs. These abilities underlie the majority of cancer-associated deaths. While invasion and metastasis are often thought of as the final stages of tumor development, recent studies have shown that tumor spread can occur even at early stages of tumor development, sometimes even before the primary tumor has been identified. Development of therapies targeting invasion and metastasis has the promise to significantly reduce cancer mortality.

  • Read more about the tumor invasion and metastasis focus area .

Tumor microenvironment

Tumors require complex interactions with surrounding blood vessels, immune cells, supportive tissue structures and cell types that are distinct to the tumor site in order to grow, become invasive and metastasize. Tumors influence their microenvironment by releasing soluble signals that lead to degradation and remodeling of the tissue structures that constrain their growth. Targeting the interactions of tumors with the microenvironment is an important and developing area of study.

  • Read more about the tumor microenvironment focus area .

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Recent developments in cancer research: Expectations for a new remedy

1 Department of Surgery and Science, Kyushu University, Fukuoka Japan

Qingjiang Hu

Yuta kasagi, masaki mori.

Cancer research has made remarkable progress and new discoveries are beginning to be made. For example, the discovery of immune checkpoint inhibition mechanisms in cancer cells has led to the development of immune checkpoint inhibitors that have benefited many cancer patients. In this review, we will introduce and describe the latest novel areas of cancer research: exosomes, microbiome, immunotherapy. and organoids. Exosomes research will lead to further understanding of the mechanisms governing cancer proliferation, invasion, and metastasis, as well as the development of cancer detection and therapeutic methods. Microbiome are important in understanding the disease. Immunotherapy is the fourth treatment in cancer therapy. Organoid biology will further develop with a goal of translating the research into personalized therapy. These research areas may result in the creation of new cancer treatments in the future.

Cancer research has made remarkable progress and new discoveries are beginning to be made. In this review, we will introduce and describe the latest novel areas of cancer research: exosomes, microbiomes, immunotherapy, and organoids.

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1. INTRODUCTION

The cancer research field has developed significantly through use of new equipment and technology. One example of new technology is Next‐Generation Sequencing (NGS). Also known as high‐throughput sequencing, NGS is the catch‐all term used to describe a number of different modern nucleic acid sequencing technologies. These methods allow for much quicker and cheaper sequencing of DNA and RNA compared with the previously used Sanger sequencing, and as such have revolutionized the study of genomics and molecular biology. NGS also allows for easier detection of mutations in cancer samples, leading to development of many new agents that can be used to treat patients. For example, if the RAS gene status is detected as wild type in a colorectal cancer patient, then an anti‐EGFR antibody, such as cetuximab or panitumumab, can be used for treatment.

A liquid biopsy, also known as fluid biopsy or fluid phase biopsy, is the sampling and analysis of non‐solid biological tissue, primarily blood. 1 It is being used as a novel way to detect cancer. Like a traditional biopsy, this type of technique is mainly used as a diagnostic and monitoring tool for diseases, and also has the added benefit of being largely noninvasive. Therefore, liquid biopsies can be performed more frequently, allowing for better tracking of tumors and mutations over a duration of time. This technique may also be used to validate the effectiveness of a cancer treatment drug by taking multiple liquid biopsy samples in the span of a few weeks. It may also prove to be beneficial for monitoring relapse in patients after treatment.

Novel devices and drugs have also been developed and used for cancer treatment. For surgery procedures, robotic‐assisted laparoscopic surgery has evolved and made it possible to visualize the fine movement of the forceps in three dimensions. This method is now used in esophageal, gastric, and rectal cancer surgeries in Japan. 2 , 3 , 4

Recently, immunotherapy became an additional method for treating cancer patients. The discovery of the immune checkpoint by Dr Honjo led to the development of immune checkpoint inhibitors. 5 Despite these developments, gastrointestinal cancers are still a major problem in need of new treatment methods. In this review, we introduce and describe four new areas of cancer research that may contribute to cancer treatment in the future: exosomes, microbiome, immunotherapy, and organoids.

2. AN APPLICATION OF EXOSOME RESEARCH IN CANCER THERAPY

An exosome is a small particle that is secreted by cells. Its size can range from 50 to 150 nm and has a surface consisting of proteins and lipids that originate from the cell membrane. Additionally, proteins and nucleic acids, such as DNA, microRNAs, and mRNAs, can be found inside the exosome as its “cargo.” 6 Recently, many researchers have discovered that exosomes are involved in the mechanisms of various diseases. As mentioned above, various functional compounds, such as microRNAs, mRNAs, and proteins, can be contained within exosomes. 7 , 8 Many cells use secretion of exosomes to communicate with one another, and these exosomes can even reach distant cells. Cancer cells can also secrete exosomes that contain molecules beneficial to cancer growth. For example, microRNAs found in cancer exosomes can modulate gene expression to induce angiogenesis in the tumor microenvironment, which supports metastasis. 9 Exosomes released from cancer cells can also reportedly break the blood‐brain barrier, which makes it contribute to brain metastasis. 10 , 11 Cancer cells themselves are similarly affected by the exosomes secreted by the surrounding normal cells. 12 In one case, the exosomes secreted by bone marrow‐delivered mesenchymal stem cells can force cancer cells into a dormant state. 13 These dormant cancer cells become resistant to chemotherapy and are involved in long‐term disease recurrence. Thus, exosomes are deeply involved in cancer proliferation, invasion, and metastasis, as well as in the formation of the tumor microenvironment and pre‐metastatic niche. 13 Further research on cancer‐related exosomes is ongoing.

Knowledge of exosomes can be applied to cancer treatment. If the secretion of exosomes from cancer cells can be prevented, then signal transduction supporting the formation of the tumor microenvironment and pre‐metastatic niche can be blocked. Work focusing on the removal of cancer exosomes is now ongoing. 14

Exosomes can also be utilized for cancer diagnosis. Exosomes secreted by many cell types are found in various body fluids, such as blood and urine. Capturing and analyzing exosomes from cancer cells can be used to detect the presence of disease. 15 Obtaining blood or urine from patients is not very invasive or painful. Since many molecules, such as various proteins, DNA, and microRNAs, can be found in exosomes from normal cells, it is important to distinguish them from cancer‐related ones. If exosomes are to be used for cancer diagnosis, then specific biomarkers need to be discovered. Additionally, the development of a method to detect these exosomes must be done. Currently, exosome detection methods for exosomes abundantly found in the serum of colorectal and pancreatic cancer patients, as well as exosomes found in the urine of bladder cancer patients, are being developed. 16 , 17 Thus, further understanding of the mechanisms governing cancer proliferation, invasion, and metastasis, as well as the development of cancer detection and therapeutic methods, is significantly affected by exosome research.

3. MICROBIOME IN CANCER RESEARCH

A large number of microorganisms inhabit the human body. These microorganisms include bacteria, viruses, and fungi. Among them, bacteria have the most important relationship with the human body. Bacteria can live anywhere within the human body, including the digestive tract, respiratory system, and oral cavity. 18 , 19 , 20 In particular, bacteria in the digestive tract are rich in type and number, 21 with possibly 1000 types and more than 100 trillion individual bacterial cells present. 22 , 23 The overall population of various bacteria found in the human intestine is referred to as the “intestinal flora.” Recently, the terms “microbiota” or “microbiome” have also been widely used.

Recent advancements with NGS have led to a much more precise understanding of the intestinal microbiome. 24 The bacteria in the human microbiome mainly belong to four phyla: Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteri. Of these, Firmicutes and Bacteroidetes are the most dominant species. It is reported that microbiome vary depending on age and race. 25 , 26 Dysbiosis is a condition in which the diversity of the microbiome is reduced. Dysbiosis is reportedly involved in various diseases such as inflammatory bowel disease, colorectal cancer, obesity, diabetes, and allergic diseases. 27 , 28 , 29 For example, bacteria such as Atopobium parvulum and Actinomyces odontolyticus increase in number during the early stages of colorectal cancer (adenomas or intramucosal cancers) and decrease in number during cancer progression. 30 This suggests that a specific microbiome is associated with early stages of colorectal cancer development, which may be useful knowledge for early cancer detection.

Various studies have also been conducted to elucidate the relationship between the microbiome and the human immune system. 31 The IgA antibody, which is one of the most important elements in the intestinal immune system, is believed to play a role in the elimination of pathogens and maintenance of the intestinal environment. The IgA antibody recognizes, eliminates, and neutralizes pathogenic bacteria and toxins. It also maintains a symbiotic relationship by recognizing and binding to the normal microbiome of the host. 32 Mice lacking a microbiome have reduced production of the IgA antibody. A microbiome is required for IgA antibody differentiation. Recent studies have identified W27IgA antibodies that have the ability to bind to various bacteria. 33 Oral administration of a W27IgA antibody to enteritis model mice suppressed enteritis by altering the microbiome. This W27IgA antibody can recognize a part of the amino acid sequence of serine hydroxymethyl transferase, which is a metabolic enzyme involved in bacterial growth. The W27IgA antibody can suppress the growth of E coli by binding to them. However, the W27IgA antibody does not bind to bacteria that suppress enteritis, such as bifidobacteria and lactic acid bacteria. 33 Thus, the microbiome is deeply involved in human intestinal immunity. Recently, it is having been established that the microbiome is not only involved in intestinal immunity, but also in the systemic immune system.

As the analysis of the microbiome progresses, the pathophysiology of various diseases, such as cancers, and its relationship with the regulatory function of the human immune system will be further elucidated. It has been demonstrated that F nucleatum plays a role in the development and progression of colon adenomas and colorectal cancer. It is also related to lymph node metastases and distant metastasis. 34 , 35 Also, microbiome is associated with hepatocellular carcinoma. 36 Studying microbiome will give us some clue in the development and remedy for gastrointestinal cancers (Table  1 ).

Gastrointestinal cancer and their related microbiome

4. THE RISE OF IMMUNOTHERAPY IN CANCER TREATMENT

For many years, surgery, chemotherapy, and radiation therapy were the main methods of cancer treatment. In addition to these therapies, immunotherapy has recently attracted great attention worldwide (Table  2 ). 37 , 38 Under normal circumstances, a cancer antigen will activate the patient's immune system to attack the cancer cells. However, sometimes the immune system does not recognize the cancer cells as non‐self, or it simply fails to attack them. This can result in the development and progression of cancer.

Immune checkpoint inhibitors

Although therapies that activate the immune system against cancer cells have been studied for a long time, the use of the patient's own immune system for cancer treatment was not established. Recently, the effectiveness of both immune checkpoint inhibition therapy and chimeric antigen receptor (CAR)‐T cell therapy has proved to be promising. 39 , 40 Immunotherapy has moved to the forefront of cancer treatment strategies.

There are two major reasons why proving the efficacy of cancer immunotherapies was difficult for some time. First, cancer immunity is strongly suppressed. Signal transduction from immune checkpoint compounds, such as PD‐1 and CTLA4, strongly inhibits cytotoxic T cells (CTLs). 38 This checkpoint mechanism can prevent the immune system from attacking cancer cells. The development of immune checkpoint inhibitors has arisen from the discovery of this mechanism. Inhibition of immune checkpoint molecules with neutralizing antibodies can release the suppression of cancer‐specific CTLs, activate immunity, and promote cancer elimination. The effectiveness of immune checkpoint antibodies has been confirmed and clinically applied to many solid cancers such as melanoma, 41 lung cancer, 42 urothelial cancer, 43 gastric cancer, 44 and esophageal cancer. 45 In addition to PD‐1 and CTLA4, new immune checkpoint molecules, such as LAG3, TIGIT, and SIRPA, are also being actively studied. 46 , 47 , 48 Although this therapy is promising, the cancer cases who respond to these therapies are limited. This is because use of this therapy requires the presence of cancer‐specific CTLs in the patient's body. To maximize the therapeutic effect, it is desirable to select appropriate cases and develop useful biomarkers.

The second difficulty for immunotherapy is that T cells do not recognize specific cancer cell antigens and immune accelerators are too weak. One goal of CAR‐T cell therapy is to strengthen the immune accelerator by administering CTLs to the patient's body that recognize specific cancer cell‐specific antigens. A CAR is prepared by fusing a single chain Fv (scFv), derived from a monoclonal antibody that recognizes a specific antigen expressed by cancer cells, with CD3z and costimulatory molecules (CD28, 4‐1BB, and others). Next, the CAR is introduced to the T cells obtained from a cancer patient and CAR‐T cells are made. CAR‐T cells recognize the specific antigen of the cancer cells and are activated to damage these cells. CAR‐T cells recognize cancer‐specific antigens with high antibody specificity and attack the respective cancer cells with strong cytotoxic activity and high proliferative activity. CAR‐T therapy is effective in blood cancers such as B‐cell acute lymphoblastic leukemia and myeloma. 49 , 50 While CAR‐T cell therapy has a high therapeutic effect, a frequent and serious adverse event called cytokine release syndrome has been observed in some patients. 51 , 52 The development of a technique for suppressing the occurrence of cytokine release syndrome is anticipated. In addition, the development of CAR‐T cell therapies for solid tumors is ongoing.

Recently, there was new progress made in treating gastrointestinal cancer patients. For MSI‐H colorectal cancer, the combination therapy with nivolumab and ipilimumab was approved. From the nivolumab plus ipilimumab cohort of CheckMate‐142, progression‐free survival rates were 76% (9 months) and 71% (12 months); respective overall survival rates were 87% and 85% which were quite high. This new treatment will benefit MSI‐H colorectal cancer patients. 53

Thus, it is expected that further understanding of cancer immune mechanisms and the development of various immunotherapies will contribute to great progress in cancer treatment.

One problem for immunotherapy is that there is no certain predictive biomarker. It was thought that the expression of PD‐1 or PD‐L1 would predict the effect. However, this was not the case. To find a new biomarker, we assessed the cytolytic activity (CYT) score. The CYT score is a new index of cancer immunity calculated from the mRNA expression levels of GZMA and PRF1. We are now evaluating CYT score in gastric cancer patients (data not published). The development in the biomarker search will benefit many gastrointestinal cancer patients.

5. ADVANTAGES FOR USING ORGANOIDS IN CANCER RESEARCH

The three‐dimensional (3D) organoid system is a cell culture‐based, novel, and physiologically relevant biologic platform. 54 An organoid is a miniaturized and simplified version of an organ that is produced in vitro in 3D and shows realistic microanatomy. With only one to a few cells isolated from tissue or cultured cells as the starting material, organoids are grown and passaged in a basement membrane matrix, which contributes to their self‐renewal and differentiation capacities. 54 , 55 The technique used for growing organoids has rapidly improved since the early 2010s with the advent of the field of stem cell biology. The characteristics of stem, embryonic stem cells (ES cells), or induced pluripotent stem cells (iPS cells) that allow them to form an organoid in vitro are also found in multiple types of carcinoma tissues and cells. Therefore, cancer researchers have applied ES cells or iPS cells in their field. 56 , 57 , 58

Organoid formation generally requires culturing stem cells or their progenitor cells in 3D. 54 , 55 The morphological and functional characteristics of various types of carcinoma tissue have been recapitulated in organoids that were generated from single‐cell suspensions or cell aggregates. These suspensions or aggregates were isolated from murine and human tissues or cultured cells, as well as from cancer stem cells propagated in culture. The structures of the organoids show the potential of cancer stem cell self‐renewal, proliferation, and differentiation abilities, and also provide insights into the roles of molecular pathways and niche factors that are essential in cancer tissues. 56 , 57 , 59 , 60 , 61 , 62 The organoid system also has been utilized for studying multiple biological processes, including motility, stress response, cell‐cell communications, and cellular interactions that involve a variety of cell types such as fibroblasts, endothelial cells, and inflammatory cells. These interactions are mediated via cell surface molecules, extracellular matrix proteins, and receptors in the microenvironment under homeostatic and pathologic conditions.

Although the organoid system is a complex and not effortless procedure that requires specific media, supplements, and many tricky techniques, 58 , 63 application of this system has been extended to a variety of cell types from different carcinomas (colorectal, pancreatic, prostate, breast, ovary, and esophageal cancers). 56 , 57 , 59 , 60 , 61 An organoid is generally induced within a few days to weeks, and is faster and less costly than the murine xenograft assay. Furthermore, applying novel genetic manipulations (e.g. CRISPR‐Cas9) can be carried out in the organoid system. 64 , 65

Kasagi et al modified keratinocyte serum‐free medium to grow 3D organoids from endoscopic esophageal biopsies, immortalized human esophageal epithelial cells, and murine esophagi. Esophageal 3D organoids serve as a novel platform to investigate regulatory mechanisms in squamous epithelial homeostasis in the context of esophageal cancers. 64

We anticipate that many experimental results that utilize the organoid system will be published in the future.

The 3D organoid system has emerged in the past several years as a robust tool in basic research with the potential to be used for personalized medicine. 66 By passaging dissociated primary structures to generate secondary 3D organoids, this system can be performed using live tissue pieces obtained from biopsies, operative‐resected specimens, or even frozen tissues. This method has the potential to transform personalized therapy. For example, in the case of cancer recurrence, an effective chemotherapy can be selected by testing the chemotherapeutic sensitivity of cancer‐derived organoids from an individual patient's tissue stocks. In many cases, a patient's organoid accumulation is helpful for testing the sensitivity of novel therapeutic agents for treating carcinoma. 66 Hence, it appears that organoid biology will further develop with a goal of translating the research into personalized therapy.

6. SUMMARY AND FUTURE DIRECTIONS

This review describes four new cancer‐related studies: exosomes, microbiome, immunotherapy, and organoids (Figure  1 ).

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The summary of the four cancer research areas. In this figure the summary of the four cancer research areas is shown: exosome, microbiome, immunotherapy, and organoid research

Since exosomes are released in blood or urine, if the capturing system is established, it will be a less invasive test to diagnose cancer. In the present, the presence of circulating tumor DNA (ctDNA) is one of the tools to detect the minimal residual disease. However, since ctDNA is only DNA, it is difficult to spread to cancer research. In that respect, as exosomes include not only DNA but also other nucleic acids and proteins, this will be a new tool for cancer research such as the diagnosis of early cancer.

Microbiome may lead to improved cancer diagnosis and treatment. Detecting a specific microbiome in a gastrointestinal tract may predict a specific cancer. And changing microbiome in some way may result in preventing cancer development.

Organoids may help address the problem of drug resistance, and also lead to the development of personalized therapy. However, producing organoids takes time and testing the drug resistance may take more time. If we could overcome these problems, the research into organoids can contribute to overcoming cancer.

As shown in Table  3 , many new studies and findings are reported into this field of research. These four novel cancer research areas will make many contributions to the diagnosis and treatment of cancer.

Recent studies on exosome, microbiome, immunotherapy, and organoids

Conflict of Interest: All the authors have no conflict of interest to disclose.

ACKNOWLEDGMENTS

We thank Dr Hirofumi Hasuda and Dr Naomichi Koga for their help in preparing this manuscript. We also thank J. Iacona, PhD, from Edanz Group for editing a draft of this manuscript.

Ando K, Hu Q, Kasagi Y, Oki E, Mori M. Recent developments in cancer research: Expectations for a new remedy . Ann Gastroenterol Surg . 2021; 5 :419–426. 10.1002/ags3.12440 [ CrossRef ] [ Google Scholar ]

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  • Review Article
  • Published: 02 March 2023

Autophagy and autophagy-related pathways in cancer

  • Jayanta Debnath   ORCID: orcid.org/0000-0002-8745-4069 1 ,
  • Noor Gammoh 2 &
  • Kevin M. Ryan   ORCID: orcid.org/0000-0002-1059-9681 3 , 4  

Nature Reviews Molecular Cell Biology volume  24 ,  pages 560–575 ( 2023 ) Cite this article

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  • Tumour-suppressor proteins

Maintenance of protein homeostasis and organelle integrity and function is critical for cellular homeostasis and cell viability. Autophagy is the principal mechanism that mediates the delivery of various cellular cargoes to lysosomes for degradation and recycling. A myriad of studies demonstrate important protective roles for autophagy against disease. However, in cancer, seemingly opposing roles of autophagy are observed in the prevention of early tumour development versus the maintenance and metabolic adaptation of established and metastasizing tumours. Recent studies have addressed not only the tumour cell intrinsic functions of autophagy, but also the roles of autophagy in the tumour microenvironment and associated immune cells. In addition, various autophagy-related pathways have been described, which are distinct from classical autophagy, that utilize parts of the autophagic machinery and can potentially contribute to malignant disease. Growing evidence on how autophagy and related processes affect cancer development and progression has helped guide efforts to design anticancer treatments based on inhibition or promotion of autophagy. In this Review, we discuss and dissect these different functions of autophagy and autophagy-related processes during tumour development, maintenance and progression. We outline recent findings regarding the role of these processes in both the tumour cells and the tumour microenvironment and describe advances in therapy aimed at autophagy processes in cancer.

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Introduction

Macroautophagy (herein referred to as autophagy) is a key homeostatic pathway that facilitates the degradation and recycling of cellular material 1 . The benefits of stimulating autophagy in disease have received increasing interest, for example, in the removal of protein aggregates contributing to neurodegeneration. In cancer, however, the role of autophagy appears to be more complex and depends on tumour stage, biology and the surrounding microenvironment.

During autophagy, a panel of autophagy-related (ATG) gene products orchestrates the formation of a double-membrane vesicle, known as the autophagosome, which encapsulates cellular cargo and fuses with lysosomes, resulting in the degradation of its contents through the activities of lysosomal hydrolases 2 (Fig.  1 ). The ULK complex, which includes UNC-51-like kinase 1 (ULK1) and ULK2, FIP200, ATG13 and ATG101, initiates autophagosome formation and relays cues from cellular signalling hubs involved in nutrient and energy sensing, such as through mechanistic target of rapamycin complex 1 (mTORC1) signalling. Downstream of the ULK complex is the autophagy-specific VPS34 complex I (comprising VPS34, beclin-1, ATG14 and VPS15), which catalyses the production of  phosphatidylinositol-3-phosphate (PI3P) on autophagic membranes. PI3P triggers the recruitment of the autophagy conjugation machinery, including the ATG16L1–ATG5–ATG12 complex, ATG3 and ATG7. These proteins facilitate the lipid conjugation of the ATG8 family members (consisting of the microtubule-associated protein 1A/1B-light chain 3 (LC3) and GABARAP subfamilies), which are important during cargo recruitment and autophagosome maturation 3 , 4 (Fig.  1 ), as well as other processes that involve ATG8–lipid conjugation (see below and Supplementary Box  1 ). Although cargo recruitment can be non-selective, for example in nutrient-depleted cells where autophagosomes take up different cargoes to recycle crucial nutrients such as amino acids or lipids, autophagy is largely highly selective. This selectivity is facilitated by autophagy cargo receptors (ACRs) (Fig.  1 and Supplementary Box  2 ), which bind to specific cargoes that have been tagged for degradation via ubiquitin-dependent or ubiquitin-independent processes 5 . To add further to this complexity, recent studies have unravelled additional roles of ATG proteins beyond autophagosome formation, thereby expanding their functions and implications in disease 6 (Box  1 ). Two additional lysosomal degradation processes exist that are related to (macro)autophagy but do not require the activities of ATG proteins. These include chaperone-mediated autophagy and microautophagy, in which cargo delivery to the lysosome relies on chaperone activity and invagination of the lysosomal membrane to encapsulate cellular material, respectively 1 .

figure 1

Autophagy is initiated when nascent double membranes are formed from the endoplasmic reticulum and other sources forming the phagophore. The process is regulated by a complex containing the kinase UNC-51-like kinase 1 (ULK1), which works together with the class III PI3K kinase complex, containing beclin-1 and VPS34, to generate phosphatidylinositol-3-phosphate, thus facilitating expansion of the autophagosome membrane. ATG8 family members, including MAP1LC3 (microtubule-associated protein 1A/1B-light chain 3), commonly referred to as LC3, are converted to a lipidated form (LC3-II) by conjugation to phosphatidylethanolamine, via a complex containing ATG5, ATG12 and ATG16L1. They are then tethered in the phagophore membrane and regulate various steps of autophagosome biogenesis. During selective autophagy, lipidated ATG8 proteins also function in cargo selection, by associating with autophagy cargo receptors (ACRs; also known as selective autophagy receptors (SARs)) that recognize ubiquitylated cargo. The membranous structures grow to form an organelle termed an autophagosome, which ultimately fuses with lysosomes. Cargoes are then degraded by lysosomal hydrolases and the resulting constituent parts such as amino acids, lipids or sugars are transported into the cytosol for de novo biosynthesis or energy production. Autophagy serves to remove misfolded proteins and damaged organelles, which would otherwise lead to aberrant cellular functions, reactive oxygen species (ROS) imbalances, inflammation or defective antigen presentation, thus predisposing the cell to malignant transformation. In some cases, autophagy can facilitate tumour suppression by removing specific factors such as the ACR p62, elevated levels of which are found in many cancers and are thought to be tumour-promoting. Several cancer-associated factors, including the RAS oncoproteins and p53 tumour suppressor, have been shown to regulate autophagy and influence tumour initiation and development. For example, the nutrient-sensing mechanistic target of rapamycin complex 1 (mTORC1) is a repressor of autophagy, whereas the AMP-activated protein kinase (AMPK), which is activated in situations of energetic stress, is a promoter of autophagy. The regulation of autophagy by p53 is complex: at basal, unstimulated levels the tumour suppressor p53 has been reported to repress autophagy; however, when elevated and activated by cellular stress, p53 activates a panel of target genes (including those encoding damage-regulated autophagy modulator 1 (DRAM1) and AMPK through its subunit PRKAB1) that promote autophagy. Conversely, mutant RAS protein is considered to promote autophagy, but its inhibition can also promote autophagy, indicating that the control of autophagy by RAS is complex and probably context specific.

Early findings indicated a dual role of autophagy in cancer, and ongoing studies are contributing to our growing understanding of the underlying mechanisms through which autophagy influences cancer initiation and progression 7 . It is now widely accepted that autophagy suppresses tumour initiation, but evidence suggests that autophagy processes in established tumours are required to support uncontrolled cell growth and increased metabolic activities, leading to autophagy dependency for tumour maintenance. Moreover, autophagy has important functions within tumour cells themselves (intrinsic) and in the surrounding stroma (extrinsic), both of which have consequences for tumour growth and drug resistance. Overall, the effects of autophagy appear to depend on tumour stage, specific oncogenic mutations and cellular context.

In this Review, we discuss the current understanding and recent developments regarding the role of autophagy during cancer initiation, development and treatment. Also addressed in this Review are the role of autophagy in the tumour environment and recent findings investigating how autophagy in stromal cells can impact various aspects of tumour biology. Furthermore, we present growing evidence that ATG proteins are used for a number of alternative processes that are distinct from classical autophagy and have been broadly termed “autophagy-related” pathways. We discuss these additional functions of ATG proteins and their potential contribution to malignant disease progression. Finally, we describe and discuss the current therapeutic advances that are being investigated and developed to target autophagy to treat tumour development.

Box 1 ATG proteins beyond autophagosome formation

Since their discovery in yeast cells, many ATG gene products have been ascribed functions beyond autophagosome formation or ATG8–lipid conjugation (outlined in Supplementary Box  1 ). Additionally, VPS34 and its binding partners beclin-1 and VPS15 are frequently targeted to regulate autophagy, but also have vital roles during PI3P production on various membranes and their inhibition can thus perturb the endocytic pathway 142 .

The activities of many ATG proteins have been shown to influence cell cycle progression through both autophagy-dependent and autophagy-independent mechanisms 158 . ATG7 appears to regulate p53-mediated cell cycle arrest independently of autophagy in a manner that does not involve ATG5 or its enzymatic activity required for microtubule-associated protein 1A/1B-light chain 3 (LC3) lipidation 159 . By binding to p53, ATG7 was shown to aid the expression of the cell cycle inhibitor p21 (also known as CDKN1A) and subsequently cell cycle progression during nutrient starvation 159 . How this regulation of p53 activity by autophagy-independent roles of ATG7 affects tumour progression remains to be investigated. Interestingly, recent findings show that hemizygous deletion of ATG7 does not affect autophagy levels in cells but appears to enhance the initiation and progression of pancreatic tumours expressing mutant p53 (ref. 160 ). Tumours with reduced ATG7 expression also appear to have reduced metastatic potential 160 . Together, these findings highlight non-autophagy-related roles of ATG7 that can impact tumorigenesis.

In addition, a complex relationship between ATG proteins and cell death exists. This occurs through both autophagosome-dependent and autophagosome-independent mechanisms (previously reviewed elsewhere 6 ). For example, UNC-51-like kinase 1 (ULK1) has been shown to translocate to the nucleus where it can bind to and activate PARP1, which is required for maintaining DNA integrity 161 . This autophagy-independent activity of ULK1 is required during oxidative stress-induced cell death. How the non-autophagic activities of ATG proteins that influence cell death affect tumour progression remains unclear.

Finally, a number of ATG proteins can influence the immune response in a manner independent of their role in autophagy 6 . During bacterial infection, ATG16L1 can suppress cytokine production mediated by the pattern recognition receptors NOD1 and NOD2 (refs.  162 , 163 ). Interestingly, an ATG16L1 variant associated with Crohn’s disease, ATG16L1 T300A , has also been associated with lung cancer metastasis to the brain 164 . This mutation of ATG16L1 lies within the C-terminal half of the protein that has been previously shown to be dispensable for canonical autophagy; however, the precise contribution of this variant to Crohn’s disease development remains to be investigated 163 .

Altogether, the multifaceted roles of ATG proteins in cells highlight the need to conduct studies that employ genetic and/or chemical inhibition of different autophagy players in order to specifically address the contribution of their autophagy-dependent and autophagy-independent activities in cells.

Suppression of tumour development

In line with the initial investigations of autophagy in yeast, it is generally accepted that this process functions as a mechanism to promote cell survival 8 . Seminal studies showed that autophagy was activated to degrade cellular components for the provision of nutrients during periods of nutrient deprivation, and this response was found to be conserved in higher eukaryotes 9 . It has also become clear that autophagy is highly adaptable to respond to and mitigate different forms of cellular stress including protein and organelle damage and redox imbalance. Autophagy not only contributes to nutrient availability and provides a means for metabolic adaptation, but is also a major homeostatic mechanism within cells that promotes cellular integrity, redox balance and proteostasis 1 (Fig.  1 ). In light of these functions, it is not surprising that autophagy has roles that protect against cancer. In the following subsections we first briefly summarize work on the roles of autophagy as a tumour suppressor mechanism that has been discussed in greater detail elsewhere 10 , 11 , 12 , 13 , 14 , to provide essential background understanding for our more detailed discussion of recent developments in the field.

Evidence for autophagy in tumour suppression

The first indication for a tumour-suppressive role of autophagy came from studies of the BECN1 gene, which encodes beclin-1. Analysis of breast cancer cell lines and primary mammary tumour material revealed frequent allelic loss of BECN1 and that mice hemizygous for BECN1 are tumour-prone 15 , 16 , 17 . Subsequent studies have questioned these findings, suggesting that allelic loss of BECN1 may be a result of linkage to the BRCA1 tumour suppressor on chromosome 17q21 (ref. 18 ). Although the consequences of the loss of the region containing BECN1 remain to be conclusively dissected, it is established that autophagy genes are often perturbed in early tumorigenesis and that autophagy functions in tumour suppression 19 .

The impacts of autophagy perturbation on tumour formation are both tissue-specific and autophagy gene-specific. Early studies of the Becn1 gene in mice found that whole-body hemizygosity of Becn1 led to tumour formation in lung, liver and lymphatic tissue, but not in other organs and tissues 17 , 20 . In addition, deletion of Atg7 alone, without other genetic events, led to the formation of tumours only in the liver 21 . Subsequent work demonstrated that loss of autophagy in the liver results in cycles of tissue destruction and regeneration, which causes the emergence of hepatocyte-derived progenitor cells that drive early stages of liver tumour initiation 22 . In other tissues, the role of autophagy is only evident in combination with other genetic lesions. This raises the question as to whether autophagy is an active tumour-suppressive process or whether its complete loss simply results in a microenvironment that is tumour-promoting. Nevertheless, most studies argue for a direct role of autophagy in tumour suppression. Several studies have shown that autophagy itself can be regulated by tumour-suppressive pathways. In particular, the major tumour-suppressive transcription factor p53 has been shown to modulate autophagy in multiple ways (Fig.  1 ). At basal levels, cytoplasmic p53 can act as a repressor of autophagy 23 , but when activated by cellular stress such as DNA damage, p53 levels become elevated, resulting in activation of a myriad of genes involved in the promotion of autophagy including DRAM1 (encoding  damage-regulated autophagy modulator 1 (DRAM1)) and PRKAB1 (encoding a regulatory subunit of AMP-activated protein kinase (AMPK)) 24 , 25 . The relationship between p53 and autophagy is somewhat reciprocal, with studies showing that ATG7 represses p53 activation and that chaperone-mediated autophagy elicits the degradation of mutant p53 (refs. 26 , 27 ). Other studies describe a selection for cells harbouring inactivation of specific autophagy proteins during disease progression, thus supporting the theory of autophagy pathways as active tumour suppressors. The above-described studies on allelic loss of BECN1 in breast and ovarian cancers provide an example of this. Although they did not establish a definitive link between autophagy and tumour suppression in human cancer, further studies have reported allelic loss or decreased expression of BECN1 in other cancer types 28 , 29 . Moreover, recent findings have shown that other autophagy genes, or factors that regulate ATG proteins, are mutated or inactivated to evade the tumour-suppressive effects of autophagy as tumour development progresses. For example, several ATG genes — ATG2B , ATG5 , ATG9B and ATG12 — have been reported to contain frameshift mutations in gastrointestinal and liver cancers, and ATG5 and ATG7 have also been shown to be down-regulated in melanoma 30 , 31 . Moreover, studies in mouse models found that deletion of the mitophagy receptors BNIP3 or BNIP3L (also known as NIX) in the context of otherwise functional autophagy promoted the development of breast and pancreatic cancer 32 , 33 . Effects observed following perturbation of autophagy need to be evaluated carefully to distinguish between effects stemming from total loss of autophagy and those caused by specific components or pathways.

Selective autophagy in tumour suppression

Recent work has implicated selective forms of autophagy in various diseases, including cancer. The multiple forms of selective autophagy have been reviewed extensively elsewhere 34 , 35 , 36 , 37 . Of these, two forms are particularly relevant to tumour suppression, both of which are involved in mitigating cellular stress caused by reactive oxygen species (ROS), which can cause damage to DNA resulting in mutagenesis and transformation.

Mitophagy, the selective removal of mitochondria, was one of the first forms of selective autophagy to be described and remains the best characterized. As the mechanisms to repair mitochondrial DNA and proteins are less complex and efficient than those active in the nucleus and cytoplasm, mitochondrial fidelity is preserved predominantly by autophagic degradation of damaged mitochondria and replacement by de novo biogenesis 38 . The importance of mitophagy in tumour suppression is evidenced by accumulation of damaged mitochondria in cells in which key autophagy genes are deleted, leading to accumulation of ROS and DNA damage 39 , 40 .

The second form of selective autophagy that is intrinsically connected to the balance of ROS is pexophagy, which mediates the selective removal of peroxisomes 41 , 42 . Although it is clear that fatty acid β-oxidation is important in cancer and that pexophagy has an important role in maintaining the balance of ROS 42 , in comparison with mitophagy, the involvement and importance of pexophagy in cancer are less well defined.

As detailed in Supplementary Box  2 , several ACRs are known to function in selective autophagy. The first ACR to be identified was p62 (also known as SQSTM1). Aside from functioning as an ACR, p62 has multiple roles in cancer that are outlined below, including activation of the NF-κB and NRF2 pathways . Activation of either of these pathways is considered tumour-promoting, or, at least, tumour-supporting. Hence, maintaining appropriate levels of p62 through autophagy-mediated degradation is a key tumour-suppressive effect of autophagy. This is best exemplified by studies of liver cancer in mice, in which tumour development caused by deletion of key autophagy genes is reversed upon concomitant deletion of p62 (ref. 21 ) (see below).

Roles in tumour progression

Initial evidence supporting a role for autophagy in the maintenance of established cancers was based on the finding that some tumour tissues exhibit high levels of LC3 puncta and lipidated LC3 (LC3-II), indicative of accumulated autophagosomes 43 . However, these static tissue-based readouts strictly show only the levels of autophagosomes, hence they are largely unable to distinguish between induction of autophagy or impairment of autophagosome turnover. This inability to analyse autophagic flux in tissue remains a major limitation of studying autophagy in human cancer. Nevertheless, multiple preclinical studies have demonstrated that autophagy supports the growth and metabolism of advanced tumours downstream of the activation of various oncogenes and/or inactivation of tumour suppressors 39 , 44 (Fig.  2 ).

figure 2

Autophagy can support tumour growth and survival through various paths. For example, autophagy has important roles during metabolic adaptation of tumour cells (for example, through the clearance of dysfunctional mitochondria) and escaping immune detection (for example, through NBR1-mediated degradation of major histocompatibility complex class I (MHC-I)). During metastasis, opposing roles have been described for autophagy. Autophagy can support resistance to detachment-induced cell death (anoikis) in delaminating or circulating tumour cells and can promote adaptation to nutrient limitations. However, autophagy has also been shown to be required to maintain tumour dormancy (for example, through the autophagic degradation of the glycolysis mediator PFKFB3) and genomic stability, leading to an increase in polyploid tumour cells following inactivation of autophagy 148 . Thus, inhibition of autophagy can result in enhanced metastatic growth. Although the mechanisms underlying this tumour-suppressive activity of autophagy are largely unknown, they probably involve multiple autophagic targets, such as NBR1. In epithelial–mesenchymal transition, autophagy has both metastasis-promoting and metastasis-inhibitory effects (through degradation of the epithelial–mesenchymal transition master regulator TWIST1, not shown). ECM, extracellular matrix.

Autophagy promotes cancer following oncogenic activation

Studies using genetically engineered mouse models of cancer driven by oncogenic Ras revealed a requirement for functional autophagy pathways in tumour development. RAS genes are often mutated in certain cancers: for example, 90% of pancreatic ductal adenocarcinomas involve mutation of the KRAS gene 45 . In its activated state, RAS promotes tumour proliferation and survival and can alone drive tumour development. However, this causes increased demand on cellular energy and anabolic precursors, and, through self-digestion, autophagy serves to mitigate the limited availability of external nutrients and thus to sustain and promote tumour development. Studies have shown that this role leads to autophagy dependency in the progression of certain RAS-driven cancers, and such tumours progress only to a certain degree in the absence of autophagy. In some cases, because autophagy has tumour-suppressive effects in normal cells, the absence of autophagy may even enhance the early stages of tumour development, but in RAS-driven cancers, further progression to cancer was blocked in the absence of other genetic lesions 46 , 47 , 48 .

Progression to cancer is driven not only by the activation of oncogenic factors such as RAS that promote tumour development, but also by the loss of factors that restrict tumour development. These tumour suppressor genes can be activated by oncogenic factors such as RAS 49 , and they have also been studied in the context of autophagy in tumour development. Two important tumour suppressor genes in cancer are p53 (also known as Trp53 in mice, TP53 in humans) and Pten , the latter encoding  phosphatase and tensin homologue (PTEN). Studies in mice have shown that deletion of either of these genes can alleviate this block of tumour development in the absence of autophagy, although this does not always lead to fully established cancers 46 , 48 , 50 , 51 , 52 . The progression of pancreatic cancer appears to depend on the p53 status, with total loss of p53 promoting tumour development 46 , whereas hemizygous deletion or the presence of mutant p53 alone did not 48 . Moreover, in the case of lung cancer, deletion of p53 in combination with mutant KRAS permits tumour development beyond the state reached with KRAS mutation alone, but only leads to benign tumours (termed oncocytomas) that contain excessive dysfunctional mitochondria 52 . The loss of a tumour suppressor does not, however, always circumvent autophagy dependency. Mouse models of lung tumours driven by loss of the AMPK activator and tumour suppressor LKB1 (also known as STK11) showed a decreased capacity to adapt to nutrient and energy depletion. In line with this deficiency, it was shown that some tumours depend on autophagy to maintain lipid and amino acid reserves, so much so that deletion of both LKB1 and ATG7 was synthetically lethal 53 . These different examples indicate that the role of autophagy in cancer can be dependent on the type of oncogenic lesion driving transformation. Further studies are therefore required in other tumour types and in additional models to ascertain where and when autophagy contributes to or inhibits tumour development. These studies are fundamental to target the pathway therapeutically in different cancer types.

Autophagy and tumour metabolism

A common function of autophagy in normal development and tumour progression is to mitigate cellular stress and thus maintain homeostasis and cell survival 8 , 9 . This homeostatic role ranges from the provision of nutrients during limited periods of exogenous nutrient deprivation, as occurs in poorly vascularized regions of developing tumours, to the balance of ROS, which if uncontrolled may lead to cell death.

One key difference between tumours and normal tissues lies in their metabolism. Tumours commonly rewire their metabolism to become more anabolic, including a switch from oxidative phosphorylation to glycolysis and the subsequent redirection of glycolytic intermediates into biosynthetic pathways such as the pentose phosphate pathway (required for nucleotide synthesis) 54 . In such contexts, despite a decreased requirement for ATP production, mitochondrial function is still required for certain anabolic reactions, and autophagy preserves mitochondrial integrity as evidenced by the fact that loss of autophagy leads to an accumulation of defective mitochondria in KRAS -driven cancers 52 . Furthermore, the deletion of Atg7 in BRAF V600E -driven lung cancer results in deficiency of glutamine, which is crucial to support mitochondrial respiration and survival of tumour cells driven by BRAF V600E (ref. 55 ). Interestingly, these effects of autophagy inhibition on primary tumour metabolism may result in metabolic and redox adaptations that favour metastatic outgrowth (Fig.  2 ). For example, mammary cancer cells with impaired mitophagy display enhanced metastatic capacity 32 . These phenotypes probably arise from the accumulation of damaged mitochondria in mitophagy-deficient cancer cells, resulting in increased ROS levels and consequently a shift from oxidative to glycolytic metabolism, which is proposed to favour both primary tumour growth and metastatic progression.

Beyond mitophagy, the accumulation of the ACR p62 in autophagy-deficient breast cancer cells prevents the proteasomal degradation of a critical glycolysis mediator, PFKFB3, which promotes proliferation and outgrowth of otherwise dormant metastatic tumour cells 56 . Excessive ROS concentrations in autophagy-deficient cells are frequently mitigated by the induction of NRF2-mediated antioxidant transcriptional programmes secondary to accumulation of p62 (ref. 57 ). Importantly, NRF2 induction has been implicated in the promotion of metastasis in diverse cancer models 58 , 59 . Together, these results show that autophagy deficiency can promote both glycolytic metabolism and NRF2-driven antioxidant programmes, which ultimately activate metabolic programmes that facilitate the dissemination of tumour cells.

Dual roles of autophagy in metastasis

Currently, the role of autophagy on cancer metastasis, the primary cause of mortality in cancer patients, remains controversial. Initial work provided evidence that autophagy promotes several biological pathways crucial for efficient metastasis including migration and invasion 60 , 61 , 62 , modulation of  epithelial–mesenchymal transition 63 , 64 , resistance to detachment-induced cell death (anoikis) 65 , adaptation to nutrient deprivation and hypoxia 66 , and survival in foreign tissue microenvironments 44 (Fig.  2 ). These pro-metastatic effects spurred interest in autophagy inhibition as a potential therapeutic strategy to prevent metastatic disease and late recurrent disease in various cancers 44 . Preclinical studies using mouse models indeed demonstrated reduced metastasis upon loss or inhibition of autophagy. For example, an in vivo model of hepatocellular carcinoma determined that autophagy promoted both anoikis resistance and metastatic dissemination 67 . These findings support the hypothesis that autophagy confers a survival advantage to tumour cells lacking contact to extracellular matrix as they disseminate to secondary organs 65 . Furthermore, early studies using the polyoma middle T oncogene-driven (PyMT) mammary tumour model demonstrated that the genetic deletion of Fip200  (also known as Rb1cc1 ), a critical regulator of autophagy induction, resulted in reduced primary tumour growth and a concomitant reduction in metastasis to the lung 64 . However, these initial studies did not examine the specific effects of autophagy on primary tumour versus metastatic phenotypes 68 .

By contrast, more recent work in multiple models demonstrates that autophagy may restrict key rate-limiting steps in the metastatic cascade (Fig.  2 ). Many cancers, such as melanoma and carcinomas of the breast and prostate, have been shown to disseminate tumour cells that remain dormant, and clinically undetectable, in the metastatic organ for extended periods of time. Ultimately, these cells undergo proliferative growth, resulting in macro-metastatic lesions that frequently result in the death of the patient. This process of outgrowth of disseminated tumour cells into lethal metastasis is termed ‘metastatic colonization’ and is considered to be a key rate-limiting step in metastatic progression 69 , 70 . In recent years, several studies have illuminated important roles for the autophagy pathway in controlling emergence from dormancy and more specifically in suppressing metastatic colonization and outgrowth. For example, transplanted D2.OR mammary cancer cells exhibit dormant behaviour and fail to progress into active metastasis in syngeneic hosts 71 . Knockdown of Atg3 in these cells causes them to exit dormancy, resulting in proliferative metastatic cells with increased cancer stem-like properties, indicating that autophagy inhibition gives rise to aggressive subpopulations in vivo 56 . Similarly, in dormant breast cancer models induced via  doxorubicin treatment, stable autophagy inhibition by Atg5 knockdown resulted in both escape from dormancy and metastatic recurrence earlier than in autophagy-proficient control cells 72 . In this study, it is noteworthy that autophagy-deficient metastases exhibited higher frequencies of proliferating polyploid-like cells, suggesting that loss of autophagy may promote genomic instability; however, it remains uncertain how autophagy protects tumour cells from genomic instability or whether such events functionally contribute to metastatic recurrence in these models.

Finally, consistent with the original work on Fip200 in the PyMT model 68 , PyMT cells genetically deficient for either Atg12 or Atg5 displayed reduced primary tumour growth when orthotopically transplanted into mammary glands 73 . Yet, upon excision of primary tumours, autophagy-deficient tumours displayed profound increases in spontaneous metastatic recurrence compared to autophagy-competent counterparts. Follow-up experiments demonstrated that the conditional genetic deletion of Atg5 or Atg12 in tumour cells after their dissemination to the lungs resulted in a highly proliferative subpopulation capable of enhanced metastatic outgrowth 73 . Similar results were found upon Atg12 knockdown in experimental metastasis models based on 4T1 mammary cancer cells 73 . By contrast, stimulating autophagy by genetic depletion of Rubcn , an established negative regulator of autophagy, was sufficient to attenuate macro-metastatic outgrowth 73 . Remarkably, autophagy inhibition resulted in the expansion of tumour cell subpopulations exhibiting basal epithelial differentiation, marked by the upregulation of the transcription factor TP63 (p63) and keratin type I cytoskeletal 14 (also known as cytokeratin-14 (CK-14)) 73 . Basal differentiation has been implicated in aggressive, pro-metastatic phenotypes in breast cancer 74 , yet how autophagy modulates these subpopulations during the metastatic cascade remains an important unanswered question. Overall, these studies implicate autophagy as a stage-specific suppressor of metastatic colonization.

The exact mechanisms through which autophagy inhibition enhances metastatic colonization and outgrowth remains an active area of investigation. In recent years, specific scrutiny has turned to the impaired turnover of ACRs, which mediate selective autophagy and function as multidomain signalling hubs (Supplementary Box  2 ). The accumulation of ACRs, most notably p62, promotes oncogenic progression and therapeutic resistance in autophagy-deficient cells via diverse, non-mutually exclusive signalling pathways 7 , 75 . The most well-characterized role for p62 as a signalling scaffold is its ability to potentiate pro-tumorigenic NF-κB signalling, which has been linked to increased primary tumour growth in the setting of autophagy deficiency 64 , 76 . Whether p62-mediated activation of NF-κB pathways similarly promote metastases remains unclear. In addition, p62 has been shown to suppress the degradation of the transcription factor TWIST1, a master regulator of EMT. Accordingly, p62 overexpression promotes mesenchymal differentiation and enhances metastatic tumour growth in vivo 77 . The accumulation of NBR1, an ACR closely related to p62, has similarly been implicated in metastasis. In mouse mammary cancer models, impaired autophagy results in the accumulation of NBR1, resulting in the development of aggressive subpopulations of tumour cells exhibiting pro-metastatic basal differentiation 73 . Functional studies support that increased levels of NBR1 are both necessary and sufficient for pulmonary metastatic colonization and the acquisition of these basal differentiation traits 73 . Overall, these studies implicate accumulation of the ACRs p62 and NBR1 in autophagy-deficient backgrounds as key mediators of the metastatic phenotype.

Roles in the tumour microenvironment

Although most studies of autophagy in cancer have focused on the genetic deletion of ATG genes in tumour cells, a key consideration when employing autophagy modulators in vivo is that such agents invariably regulate autophagy in tumour cells along with the surrounding and distant stromal cells throughout the host. Studies in model organisms have begun to illuminate the effects of systemic genetic autophagy inhibition in various host cells. One elegant, groundbreaking study investigated a role for host autophagy in promoting tumour growth using systemic Atg7 deletion in mice 78 . The resultant loss of autophagy throughout the animal led to a significantly greater regression of KRAS -driven tumours when compared to inhibiting autophagy only in tumour cells 78 , 79 . Importantly, these beneficial effects on tumour regression occurred more rapidly than the lethal metabolic and neurological deteriorations that developed upon conditional Atg7 deletion in adult mice. These results indicate the presence of an optimal therapeutic window for systemic autophagy inhibition as anticancer therapy. As most mice succumbed to neurodegenerative disease, it was proposed that the potential toxicity of autophagy inhibitors could be mitigated by developing agents unable to cross the blood–brain barrier 78 . In addition, in a model of systemic autophagy inhibition achieved via the inducible expression of a dominant-negative Atg4b mutant, acute autophagy inhibition in established Kras -driven pancreatic tumours resulted in profound tumour regression, implying that both host and tumour cell autophagy contributed to tumorigenesis 80 .

Autophagy supports host–tumour metabolic cooperation

Tumours are not independent entities but are connected to and develop in concert with host stromal and immune cells. Growing evidence shows that autophagy in host cells contributes to the anabolic rate of tumours. In transplantation models of pancreatic ductal adenocarcinoma (PDAC), autophagy in  pancreatic stellate cells , a key constituent of the tumour stroma, is crucial to both generate and extracellularly secrete the nonessential amino acid alanine, which is then used by pancreatic tumour cells for growth and survival in adverse microenvironments 81 . Systemically, autophagy in one organ may support the growth of a tumour at a distant site. Although arginine is a non-essential amino acid, the enhanced anabolic state associated with tumour development creates a high demand for this amino acid that effectively renders tumour cells auxotrophic for this amino acid 82 . Whole-body or liver-specific deletion of autophagy results in the release of the arginine-degrading enzyme arginase I from the liver into the blood, which in turn causes decreased levels of circulating arginine and an inability to sustain the growth of a distant primary tumour in the lung 79 . This may be particularly relevant in tumours with reduced argininosuccinate synthase activity, which is required for de novo arginine synthesis 83 . This causes tumours to become auxotrophic for arginine and therefore potentially excellent targets for autophagy inhibition in the liver.

These results were further reinforced using a model of autophagy inhibition achieved via the inducible expression of a dominant-negative Atg4b mutant. In this model, acute, whole-body autophagy inhibition in established Kras -driven pancreatic tumours resulted in tumour regression 80 . Moreover, by inhibiting autophagy in various combinations of host and tumour cells, this study revealed that both host and tumour cell autophagy contributed to tumour growth. Studies in the Drosophila Ras V12 ; scrib −/− tumour model demonstrated that these tumours develop non-cell autonomously and systemically induce autophagy throughout host tissues 84 , 85 . Autophagy in the host stromal cells thereby promotes the aggressive growth and invasion of Ras V12 ; scrib −/− tumours throughout the fly. Similar to studies of adult systemic autophagy deletion in mice, the genetic loss of host autophagy in Ras V12 ; scrib −/− tumour-bearing flies has stronger effects on inhibiting tumour growth and proliferation than the loss of autophagy only in the tumour compartment 84 . Notably, systemic autophagy inhibition achieved via transient Atg5 knockdown has recently been demonstrated to suppress the uptake of glucose and lactate into Kras G12D /+ ; p53 −/− lung tumours in mice, which resulted in impaired tumour growth, adding a new example of how stromal cell autophagy may more broadly influence host–tumour metabolite transfer 86 .

Taken together, these studies demonstrate important roles for autophagy in different host cells in providing key metabolites, most importantly amino acids, that are employed by proliferating tumour cells to sustain the core metabolic functions of the proliferating tumour. These studies also show that although systemic therapeutic targeting of autophagy may have unwanted side effects in normal tissues such as neurons, autophagy inhibition in the host improves the therapeutic response against the tumour compared to tumour cell-specific targeting of autophagy (Fig.  3 ).

figure 3

Studies of autophagy inhibition in host stromal cells, including cancer-associated fibroblasts (CAFs), have illuminated three principal non-cell-autonomous functions through which host cell autophagy impacts the tumour microenvironment. First, autophagy facilitates the production of diverse metabolites such as amino acids, which are released by stromal cells and subsequently used by the tumour cell compartment for growth and proliferation (centre). This metabolic exchange is particularly crucial for tumour cells as these often switch to a largely anabolic state and require high levels of essential amino acids, most notably alanine and asparagine, and non-essential amino acids (NEAA). Second, autophagy supports secretion of pro-inflammatory cytokines from CAFs, including IL-6, IL-8 and IL-1β. These promote tumorigenesis by directly facilitating tumour cell proliferation and modulating innate and adaptive immune cells to create a tumour-permissive immune microenvironment (left). In addition to cytokine secretion, autophagy-related processes, such as microtubule-associated protein 1A/1B-light chain 3 (LC3)-dependent extracellular vesicle (EV) loading and secretion (LDELS) and conjugation of ATG8 to single membrane (CASM), may promote biogenesis and secretion of EVs from both tumour cells and associated stromal cells. How such ATG-dependent EV subpopulations communicate with stromal elements to influence the tumour microenvironment remains unclear. Third, autophagy promotes procollagen proteostasis, which is necessary for type I collagen deposition and creates a stiff, desmoplastic extracellular matrix (ECM) that promotes neo-angiogenesis and primary tumour growth (right).

Autophagy supports the function of cancer-associated fibroblasts

Additional roles for stromal cell autophagy have been implicated in tumorigenesis, including, most notably, the control of protein secretion. These new roles for stromal autophagy have largely been illuminated through studies in cancer-associated fibroblasts (CAFs), the fibroblasts residing within most solid tumours that modulate tumour cell proliferation and behaviour through diverse mechanisms 87 . CAFs secrete a spectrum of growth and angiogenic factors, inflammatory cytokines, extracellular matrix components and proteases. In head and neck cancer, increased autophagy in fibroblasts correlated with poor patient outcome 87 . Accordingly, inhibiting fibroblast autophagy was associated with reduced tumour progression in in vitro co-culture models owing to the attenuated secretion of multiple pro-tumorigenic factors, including IL-6, IL-8 and basic fibroblast growth factor (FGF) 88 .

Autophagy in CAFs has also been implicated in key secretory events required for the desmoplastic stromal response (Fig.  3 ). Tumour desmoplasia refers to the fibrotic and inflammatory microenvironment associated with poor prognosis in different human solid tumours. Histologically, desmoplasia is marked by evidence of fibroblast activation and type I collagen deposition along with increased tissue stiffness and inflammation 89 . Autophagy in pancreatic stellate cells, the cells that give rise to the desmoplastic fibrotic stroma commonly observed in PDACs, has been shown to promote the secretion of both extracellular matrix components and inflammatory cytokines from CAFs 90 . Recent work further provides important mechanistic insight into how fibroblast autophagy promotes this desmoplastic response: in both  autochthonous and orthotopic transplant mammary tumour models driven by the PyMT oncogene, the genetic loss of autophagy in CAFs is sufficient to profoundly attenuate primary tumour growth and improve survival of the tumour-bearing host 91 . Furthermore, the genetic loss of autophagy in fibroblasts causes specific defects in procollagen proteostasis, resulting in impaired type I collagen secretion both in vitro and in vivo 91 , 92 . Atomic force microscopic analysis confirmed that these reductions in type I collagen deposition in stroma derived from autophagy-deficient fibroblasts results in reduced tissue stiffness, a biophysical promoter of cancer progression 93 . In addition to these effects on type I collagen secretion and tissue stiffness, autophagy deficiency in fibroblasts results in reduced secretion of multiple pro-inflammatory cytokines and neo-angiogenesis factors, thereby supporting a role for fibroblast autophagy in directing multiple secretory events that orchestrate the tumour desmoplastic response 91 . Overall, these studies point to the critical role of stromal autophagy in primary tumour progression and illuminate important mechanisms that may contribute to the potentially beneficial impact of autophagy inhibition in all constituent parts of the tumour for anticancer therapy.

Secretory autophagy

The studies above illustrating the importance of autophagy in the host stroma have coincided with a growing appreciation in the field that autophagy controls extracellular secretion. In addition to its role in lysosomal degradation, the core autophagy machinery has now been implicated in both conventional and unconventional secretory pathways (Fig.  3 ). Most of the mechanistic work to understand autophagy-dependent secretion has focused on the unconventional secretion of proteins lacking an N-terminal signal peptide using diverse mechanisms collectively termed secretory autophagy 94 , 95 . In contrast to proteins that utilize the canonical endoplasmic reticulum–Golgi pathway, these so-called leaderless proteins follow multiple divergent mechanisms that bypass the Golgi on their way to the plasma membrane for secretion outside the cell. ATG proteins were first implicated in the unconventional secretion of acyl-CoA-binding protein (Acb1) in yeast 96 , 97 . Multiple targets of secretory autophagy have now been identified in mammals, including IL-1β and IL-18, the  high mobility group protein B1 (HMGB1), the integral membrane protein CFTR, cathepsins and insulin-degrading enzymes 95 . Among these targets, analysis of IL-1β, an important mediator of the inflammatory response, has yielded mechanistic insights. A seminal study demonstrated that mature IL-1β is incorporated into autophagosomes, but subsequently trafficked to the plasma membrane for secretion rather than degraded by lysosomal fusion 98 . Follow-up studies proposed that IL-1β is incorporated into the space between the outer and inner membrane of double-membrane autophagosome intermediates 99 . Recent work has suggested that this vesicular structure may in part correspond to the  endoplasmic reticulum–Golgi intermediate compartment , and that IL-1β is transported into this compartment through the protein channel TMED10 (ref. 100 ). During inflammasome activation, IL-1β is released through gasdermin D pores at the plasma membrane, suggesting that autophagy-independent pathways are probably the principal mode of IL-1β secretion in physiological settings 101 , 102 . IL-1β directs pleotropic functions in the tumour microenvironment, including effects on inflammation and angiogenesis that promote tumour progression and metastasis 103 . Hence, clarifying the relative contribution between secretory autophagy and gasdermin D-mediated IL-1β secretion remains an important topic for future study.

More recently, research has implicated autophagy regulators in the unconventional secretion of proteins via small extracellular vesicles (EVs), also known as exosomes (Fig.  3 ). The ATG8 conjugation machinery was shown to mediate the cargo loading of multiple RNA-binding proteins into EVs through a process termed LC3‐dependent EV loading and secretion (LDELS) 104 . LDELS also requires LC3-dependent activation of  neutral sphingomyelinase (nSMase-2, also known as SMPD3), which has been proposed to mediate intraluminal budding at the  multivesicular body during EV biogenesis 104 . Although the precise roles of LDELS in cancer still remain unknown, it is noteworthy that the ATG8 family protein GABARAPL1 facilitates both cargo loading and the biogenesis of pro-angiogenic EVs in hypoxic tumour cells 105 . In addition to LDELS, ATG8 family proteins have been implicated in the release of extracellular DNA and histones independently of EVs, although the genetic role of ATG proteins involved in such processes remains obscure 106 . Recent work has revealed another secretory autophagy pathway activated upon lysosomal inhibition such as treatment with hydroxychloroquine (HCQ), an agent used to inhibit autophagy during anticancer therapy by increasing lysosomal pH 11 . Several independent studies have demonstrated that pharmacological lysosome inhibition elicits robust extracellular release of both LC3-II and autophagic cargo via EVs and EV-associated secretory intermediates 107 , 108 , 109 . Specifically, lysosomal blockade promotes the extracellular secretion of ACRs, including p62, that are released as EV-associated nanoparticles in a fraction of extracellular vesicles termed extracellular vesicles and particles (EVPs) 107 . This pathway, termed secretory autophagy during lysosome inhibition (SALI), requires multiple ATG proteins for the progressive steps in autophagosome formation as well as RAB27A, which mediates the release of vesicles outside the cells. Importantly, the ACRs secreted via SALI are detected in vivo in EVPs isolated from blood plasma following HCQ treatment. Accordingly, measuring the autophagy-dependent EVP secretome in human plasma may be a powerful biomarker for non-invasively monitoring the efficacy of next-generation lysosomal inhibitors in cancer treatment 110 . Overall, these studies highlight potential connections between autophagy regulators and endolysosomal acidification in the control of unconventional secretion mediated by EVs and EVPs. Increasing evidence shows that EVPs facilitate intracellular communication between tumour, stromal and immune cells in the tumour microenvironment and support pre-metastatic niches that favour metastatic growth 111 . An important unanswered question is how autophagic control of specific EVP cargoes influences cancer progression and the response to therapy.

Despite an abundance of genetic evidence supporting a functional role for ATG proteins in modulating the secretion of cytokines and growth factors in diverse cancer models, our understanding of the cell biological mechanisms through which the autophagy machinery governs conventional secretion is still rudimentary. As detailed above, studies of cancer fibroblasts have revealed a genetic role for autophagy in the secretion of IL-6, IL-8 and other inflammatory cytokines that promote tumorigenesis 88 , 90 , 91 (Fig.  3 ). Moreover, multiple ATG players have been implicated in the efficient production and secretion of pro-tumorigenic factors during oncogene-induced  senescence and RAS-driven cancer cell invasion in 3D culture models 62 , 112 . Nevertheless, to date, it remains uncertain whether autophagy pathways play any direct role in mediating the extracellular release of pro-tumorigenic mediators. Overall, delineating the functions of autophagy-dependent secretion, not only in cancer but also in other disease pathologies, remains an important area for future study.

Autophagy and tumour immunity

Based on its degradative and trafficking functions, it is unsurprising that important immunomodulatory roles for autophagy have been described, including the degradation and presentation of externally derived antigens on MHC-II, as well as  cross-presentation of these antigens on MHC-I 113 , 114 . In light of the surging interest in the role of tumour-associated immunity in both tumour development and anticancer therapy, particularly  immune checkpoint blockade therapy, a large number of recent studies have investigated these immunomodulatory roles of autophagy. A recent review has covered the topic comprehensively, so we refer the reader there for further information 115 and restrict our discussion here to a few studies of particular interest. In a study in PDAC, the authors discovered an unexpected role for autophagy in the evasion of immune attacks by targeting MHC-I in cancer cells for autophagic degradation via selective mechanisms involving NBR1 (ref. 116 ).This process must be intricately controlled, as total loss of MHC-I would lead to an immune attack by  natural killer (NK) cells . Encouragingly, blocking autophagy led to the restoration of MHC-I, which reversed the immune evasion seen in PDAC and led to a synergistic enhancement of immune checkpoint blockade therapy 116 .

Additional genome-wide screening studies have showed that autophagy is important for modulating host immune responses that regulate tumour development 117 . Furthermore, it was reported that autophagy in the liver represses antitumour T cell responses by stimulation of regulatory T cells. In the lung, enhanced autophagy caused by loss of LKB1 was associated with decreased antigen processing and presentation, thereby compromising immune checkpoint blockade therapy 118 , 119 . This seems in contrast to previous reports showing a positive role for autophagy in antigen presentation, whereby, as highlighted above, autophagy mediates degradation of cargoes to produce antigens, which are subsequently presented on the cell surface for recognition by immune cells 120 , 121 . Despite these conflicting results, the authors were able to show that inhibition of autophagy by targeting ULK1 restored antigen presentation and synergized with blockade of PD1 (ref. 119 ). In addition to antigen presentation, autophagy controls immune trafficking into tumours via altering chemokine and cytokine expression in the tumour microenvironment. One of the first examples of increased immune trafficking in response to autophagy inhibition was observed upon FIP200 deletion in PyMT mammary tumours, which led to elevated production of CXCL9 and CXCL10, chemokines that promote the recruitment of antitumour CD8 + cytotoxic T cells into tumours 68 . Similarly, the genetic or pharmacological ablation of autophagy in B16-F10 melanoma cells results in the increased expression and secretion of CCL5, which enhances NK cell infiltration into tumours 122 . Because cytotoxic T cells and NK cells play important roles in antitumour immunity and the efficacy of immune checkpoint blockade 115 , further understanding how tumour cell autophagy influences the infiltration and function of these cytotoxic immune cell populations remains an important area of active investigation.

ATG proteins in alternative pathways

In addition to autophagy, several ATG proteins play critical roles in alternative cellular pathways 6 . As a result, genetic modulation of ATG regulators affects not only canonical degradative autophagy but also additional processes. Below, we discuss the current state of knowledge and speculate how such processes may be important in cancer.

LC3-associated processes in tumour development

The observation that some phagocytic vesicles are decorated with LC3 led to the identification of a non-classical role of ATG proteins beyond autophagosome formation 123 . Subsequent studies further expanded this process of LC3-associated phagocytosis (LAP) and identified LAP-like LC3 conjugation on endosomes 124 , LC3-associated endocytosis (LANDO) 125 and LDELS (mentioned above) 104 . These processes share the conjugation of ATG8 proteins on single membranes, recently referred to as CASM 126 . CASM processes can be distinguished by the requirement of specific ATG complexes 127 (Supplementary Box  1 ).

During LAP, LC3 conjugation requires the activities of a distinct VPS34 complex (containing VPS34, UVRAG, beclin-1 and VPS15) and Rubicon (encoded by RUBCN ), an inhibitor of autophagosome formation 123 . LAP enhances lysosomal recruitment to phagosomes and phagosome content degradation, thereby suppressing pro-inflammatory signals by facilitating the clearance of phagocytosed substrates. Inhibiting LAP by RUBCN deletion in myeloid cells was shown to enhance  type I interferon signalling in tumour-associated macrophages, resulting in T cell-mediated suppression of tumour growth 128 . Interestingly, elevated expression of Rubicon, required for LAP but not canonical autophagy 128 , 129 , 130 , is observed in a number of cancers, including stomach, liver and breast, and is associated with poor prognosis in patients 131 . Whether LAP has exclusively tumour-promoting activities across various types and stages of cancer remains to be further studied. It is possible that, similar to canonical autophagy, LAP-mediated suppression of immune cells may have opposing effects during tumour initiation and maintenance.

In addition to LAP, LC3 lipidation on other endocytic compartments has also been observed. These processes are collectively referred to as LAP-like LC3 lipidation, and their relevance in cancer is beginning to emerge. LAP-like LC3 lipidation can be induced by  lysosomotropic agents , including high doses of HCQ, and ionophores 124 (Fig.  4 ). Given that HCQ is used as an agent to inhibit autophagy during anticancer therapy, it will be interesting to investigate the contribution of LAP-like LC3 lipidation to the antitumour activity of HCQ. In addition, the process of  entosis (cell-in-cell invasion) has been shown to induce LC3 lipidation on the entotic vacuole surrounding the internalized cell, akin to LAP 132 . This LC3 lipidation promotes the death and lysosomal digestion of the internalized cell and may provide macromolecules to support host cell growth 133 . Entosis can therefore be pro-tumorigenic by supporting tumour evolution and killing of neighbouring normal cells, thus providing another role of LC3-associated processes during tumour growth 134 .

figure 4

The autophagy pathway is a major contributor to tumour cell survival and as a result is considered a target for cancer therapy. To date, only a small number of autophagy modulators have been described, with the majority of studies focused on inhibition of the lysosomal degradation stage of autophagy, using agents such as hydroxychloroquine (HCQ) or the lysosomal autophagy inhibitor Lys05. Additional inhibitors targeting other stages of the process such as autophagosomal membrane elongation and closure as well as lysosomal fusion are currently largely lacking. Inhibitors against UNC-51-like kinase 1 (ULK1) and VPS34, which act on the initiation stage of autophagy, are showing promise in preclinical studies 149 , 150 , 151 , 152 . Alternatively, autophagy can be targeted in cancer backgrounds that are particularly dependent on autophagy owing to oncogenic activation of signalling pathways. For example, the RAS–mitogen-associated kinase (MAPK) pathway is activated in a large proportion of cancers through overexpression or mutation of receptor tyrosine kinases (RTKs) and/or mutation of the downstream effectors RAS and RAF 153 . Inhibitors of this pathway were designed to promote cell death in cases in which the pathway was activated. It was found that inhibition of RAS signalling pathway components causes activation of the kinase LKB1, resulting in the activation of AMP-activated protein kinase (AMPK) and leading to activation of autophagy, which in turn represses cell death and promotes cell survival 154 , 155 , 156 . This has motivated interest in combining autophagy inhibitors with RAS–MAPK pathway inhibitors. Given the opposing roles of autophagy in cancer, a few studies have also indicated that promotion of autophagy may be beneficial for cancer therapy. For example, combination of the tricyclic antidepressant imipramine with the purinergic receptor inhibitor ticlopidine was found to cause excessive autophagy and cell death dependent on autophagy 157 . The combination showed promising results in preclinical models of glioma. ACR, autophagy cargo receptor; ERK, extracellular signal-regulated kinase; LC3-II, lipidated microtubule-associated protein 1A/1B-light chain 3; MEK, mitogen-activated protein kinase kinase; ULK1i, inhibitor against ULK1; VPS34i, inhibitor against VPS34.

LC3-associated processes can also perform non-degradative roles. LANDO was found to regulate the recycling of cell surface receptors, and inhibition of LANDO in myeloid cells prevented the recycling of receptors involved in the uptake of Aβ amyloid (associated with Alzheimer disease pathogenesis), including CD36, TLR4 and TREM2 (ref. 125 ). Thus, LANDO inhibition results in increased extracellular levels of Aβ amyloids and an inflammatory response in mouse brains. Interestingly, the expression of TREM2 was recently shown to correlate with poor cancer prognosis 135 . Whether LANDO-mediated recycling of TREM2 or other receptors can regulate tumour growth and response to immune therapy remains to be investigated.

Autophagic membranes as signalling platforms

Accumulating evidence suggests that tissue and tumour cells derived from autophagy-deficient mice show reduced oncogenic signalling through pathways such as the AKT–PI3K and mitogen-associated kinase (MAPK)–extracellular signal-regulated kinase (ERK) signalling pathways 78 , 136 , 137 . This could simply be a result of the tumour-promoting roles of autophagy discussed throughout this Review, but direct interactions between autophagy players and growth factor signalling have also been reported. Autophagy proteins such as LC3B can co-localize with the  receptor tyrosine kinase (RTK) MET (also known as HGFR) and phosphorylated ERK during hepatocyte growth factor stimulation, and the LC3 lipidation machinery is required for optimal MET activation and downstream signalling 138 , 139 . The ULK1 complex component ATG13, however, is dispensable for MET activation, indicating that autophagy proteins associate with signalling hubs, termed autophagy-related endomembranes, which are distinct from canonical autophagosomes 139 . Similarly, epithelial growth factor (EGF)-induced ERK signalling also appears to rely on core ATG players, including ATG5 and ATG7, and phosphorylated ERK colocalizes with LC3 and the ATG16L1–ATG5–ATG12 complex, but not with ULK1 or VPS34 (ref. 137 ). These results suggest that during the activation of some RTKs, autophagy-related membranes may be used for efficient signalling. It remains unclear, however, whether these signalling hubs are located on double or single membranes within cells and more detailed analyses (for example, using electron microscopy) are required to distinguish their nature.

Growth factor-mediated signalling can also be regulated by ATG players through additional mechanisms. For example, EGFR signalling can be controlled by autophagy-mediated degradation of a pool of perturbed early endosomes that are enlarged and marked by galectin-8 (ref. 140 ). In the absence of autophagy, EGFR can accumulate on early endosomes, disrupting their endocytic recycling and compromising signalling. As another example, the ATG8 family member LC3C directly binds MET, resulting in its autophagic degradation and thereby negatively regulating MET signalling 141 . Altogether, these findings suggest a complex interplay between autophagic machinery and oncogenic signalling pathways and warrant further investigation to carefully dissect their role during tumour initiation and/or during later stages of cancer development.

Autophagy-independent roles of ATG proteins in tumorigenesis

The existence of non-autophagy-related activities of ATG proteins that can influence tumorigenesis is important to consider when targeting autophagy in cancer. For example, chemical inhibition of VPS34 lipid kinase activity or genetic ablation of its binding partner beclin-1 are commonly used to suppress autophagy. VPS34, however, is required to generate PI3P on various membranes, including endosomes 142 . Therefore, the phenotypes observed during VPS34 suppression can result from inhibiting autophagy, inhibiting endocytosis, or both.

As mentioned above, autophagy proteins have documented roles in the secretion of EVs 143 . This is likely to occur through both autophagy-dependent and autophagy-independent mechanisms. The formation of a non-canonical conjugate between ATG12 and ATG3 (ATG12–ATG3) was shown to be dispensable for LC3 lipidation. By contrast, ATG12–ATG3 can bind to Alix, a component of the endosomal sorting complexes required for transport (ESCRT) complex, to regulate late endosome trafficking and EV secretion 144 . ATG5 and ATG16L1, but not ATG7, are required for EV secretion through a lipidation-independent recruitment of LC3 that stimulates the de-acidification of multivesicular bodies 145 . Intriguingly, EV secretion in this model enhances breast cancer cell migration and metastasis, suggesting an autophagy-independent role of ATG proteins in cancer.

FIP200 was shown to suppress the activity of TBK1, a central regulator of both innate immune response and autophagic cargo binding. This regulation of TBK1 activity by FIP200 may occur through autophagy-dependent and autophagy-independent functions of FIP200 (ref. 146 ). An initial study showed that FIP200 and autophagy facilitate mammary gland tumorigenesis by regulating cancer cell growth and T cell infiltration 68 . Recent findings from the same group demonstrated that the tumour-supporting function of FIP200 can also be attributed to its autophagy-independent activities 147 . By expressing an autophagy-deficient mutant of FIP200, the authors showed that whereas autophagy-dependent activities of FIP200 are required during tumour growth and metastasis, its autophagy-independent roles suppress antitumour immune responses potentially by regulating TBK1 activity 147 .

Multiple additional autophagy-independent activities have been ascribed to ATG proteins with various implications in immune response, vesicular trafficking, cell death and p53 regulation 6 (Box  1 ). Whether and how these functions can impact tumour development remain to be dissected in future studies.

Conclusions and perspectives

Over the last 15 to 20 years, studies delineating the role of autophagy in cancer and its potential as a target for therapy have gathered momentum (Fig.  4 and Box  2 ). First, from a scientific perspective, it is critical to fully re-evaluate observations based on mice lacking individual ATG genes, such as Atg5 or Atg7 , as to whether the resultant cancer phenotypes are directly connected to autophagy or instead involve other processes, including those related to CASM. Second, as detailed above in the sections on autophagy in tumour suppression and tumour progression, it has been known for some time that autophagy has dual roles in cancer. Thus, we need a clearer understanding of how tumours overcome the growth-suppressive effects of autophagy in order to progress, but also to retain or perhaps reinstate autophagy for the survival and maintenance of established tumours. To this end, it is essential to select models that allow us to inhibit or activate autophagy in various tissues and at the different stages of tumour development. From a clinical perspective, it is clear that we need more potent and specific autophagy-targeting drugs. These can be designed to target (i) the turnover stage of autophagy by targeting lysosome activity, (ii) autophagy initiation by targeting factors such as VPS34 or ULK1, or (iii) the promotion of excessive autophagy (Fig.  4 ). In addition, it is important to consider the genetic background or mutational signatures of individual tumours — for example, by combining autophagy inhibition with RAS–MAPK pathway inhibitors in KRAS -driven cancers, or with therapeutics targeting immune checkpoints. Finally, it will be important to identify strategies to modulate autophagy in cancer that avoid unwanted side effects of autophagy inhibition on metastatic recurrence or potentially neurodegeneration. To achieve this, it is critical to better define the role of autophagy in different cancers and at different stages (for example, primary tumour vs. metastasis) to elucidate how different tumours depend on autophagy — in other words, how effective targeting autophagy will be in individual patients. In addition, understanding the different outcomes resulting from complete genetic inhibition of autophagy, as employed by most studies, and partial autophagy inhibition, as expected from its chemical targeting, may be beneficial when considering deleterious outcomes expected during anticancer treatment. To date, most approaches rely on evaluation of steady-state levels of autophagosomes or LC3-II, which fail to distinguish between autophagosome maturation arrest and enhanced induction of autophagy. Despite the rapid progress made to date in understanding how autophagy influences cancer, only when these issues have been resolved can we successfully leverage both existing and forthcoming novel strategies to inhibit autophagy for the benefit of cancer patients. Encouragingly, however, as detailed above, these approaches could be used in combination with classical chemotherapy, with novel agents that enhance autophagic dependency in tumours or tumour-supporting stroma, or with strategies to engage the antitumour immune response.

Box 2 Challenges in targeting autophagy in cancer

Two key considerations in developing targeted therapies are when to target and how. Given the fundamental roles of autophagy in homeostasis as well as its benefits for preventing disease in diverse normal tissues, the timing of intervention is particularly crucial. As such, we should perhaps only consider autophagy inhibition for cancer therapy in a pulsatile nature, and only in contexts in which there is a clear heightened dependence on autophagy in the tumour compared to the rest of the body. A persistent theme in targeting autophagy lies in the dependence of autophagy on functional lysosomes, leading to the hypothesis that lysosomotropic agents may serve as effective autophagy inhibitors. In particular, it was found that the antimalarial drug hydroxychloroquine (HCQ), which raises the lysosomal pH, may be quickly repurposed as an agent to treat cancer by inhibition of autophagy 165 . As a result, a series of clinical trials was established to examine the potential for the use of HCQ to treat malignant disease. Despite reports of individual patient success, overall, the trials were not transformative 166 . At the same time, studies also indicated that HCQ may not be an effective autophagy inhibitor at clinically permitted doses and that even in cases in which an effective response was found, the therapeutic effects of HCQ may not be through autophagy inhibition 167 , 168 . It is therefore clear that further studies are required to determine when to apply HCQ and other more recently developed derivatives for autophagy inhibition in various treatment contexts 169 . Clinical trials may also have been hampered by the current inability to determine which tumours are truly autophagy-dependent and which simply exhibit accumulation of autophagosomes or lipidated microtubule-associated protein 1A/1B-light chain 3 (LC3-II). In this regard, a flurry of reports has indicated that inhibition of the RAS–mitogen-associated kinase (MAPK) pathways in tumours driven by RAS or RAF results in activation of pro-survival autophagy 154 , 155 , 156 (Fig.  4 ). These results contrast previous reports, as outlined above, showing that activation of KRAS by mutation also promotes autophagy 47 . This may indicate that either too little or too much activation of RAS–MAPK results in induction of autophagy. Future studies should aim to address this apparent discrepancy, which is particularly relevant given the current development of multiple RAS and RAF inhibitors for the treatment of cancer 170 , 171 . Recent focus has also turned to targeting the initiation of autophagy, with UNC-51-like kinase 1 (ULK1) and VPS34 inhibitors showing success in preclinical studies 152 , 172 , 173 .

Tumour relapse and resistance to therapy pose additional challenges during anticancer treatment. The observation that some cancer cells can grow or adapt in the absence of autophagy suggests that understanding resistance mechanisms to autophagy inhibition is clinically relevant 174 . Bypassing the need for autophagy in cells may result from additional mutations acquired during cancer evolution or upregulation of compensatory cellular pathways. For instance, the upregulation of NRF2 in autophagy-deficient cells was shown to confer resistance to autophagy inhibition 174 . NRF2 stabilization and protection from proteasomal degradation can occur as a result of p62 accumulation in the absence of autophagy 175 . NRF2 acts to simulate the expression of antioxidant response genes to help cells adapt to increased reactive oxygen species 174 . These findings are supported by previous studies showing a requirement for p62 during the growth of autophagy-deficient tumours 64 , 76 . In addition, acquired mutations may enhance tumour growth in the absence of autophagy as seen in pancreatic cancers with p53 mutations 46 . A recent study has shown that alternative mechanisms can compensate for the loss of organelle quality control when autophagy is inhibited in cells that are sensitive to the accumulation of aberrant mitochondria 176 . In the absence of autophagosome biogenesis, mitochondrial-derived vesicles can be targeted to lysosomes 176 , thereby maintaining mitochondrial metabolism required for optimal cancer cell growth 177 . Whether this upregulated mitochondrial quality control is necessary for most cancer cells to survive autophagy inhibition remains to be determined. Similar alternative lysosomal delivery processes that can occur in the absence of the core autophagy machinery may support potential mechanisms that underlie cancer resistance to autophagy inhibition 178 , 179 .

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Acknowledgements

Work in the Tumour Cell Death and Autophagy Laboratory (K.R.) is supported by Cancer Research UK (A17196 and A22903). J.D. receives support from the US National Institutes of Health (CA201849, CA126792, CA213775 and AG057462), the Congressionally Directed Medical Research Program (W81XWH-22-2-0007), the Samuel Waxman Cancer Research Foundation and a Mark Foundation for Cancer Research (Endeavor Award). N.G. is supported by a Cancer Research UK fellowship (C52370/A21586). We would also like to acknowledge all researchers whose studies we have been unable to cite and discuss due to the wide nature of the field.

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Jayanta Debnath

MRC Institute of Genetics & Cancer, The University of Edinburgh, Edinburgh, UK

Noor Gammoh

Cancer Research UK Beatson Institute, Glasgow, UK

Kevin M. Ryan

School of Cancer Sciences, University of Glasgow, Glasgow, UK

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Correspondence to Jayanta Debnath , Noor Gammoh or Kevin M. Ryan .

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Supplementary information.

The transplantation of cells into the origin tissue from where they were derived.

Enzymes that cause protein breakdown, principally within lysosomes.

The ability of antigen-presenting cells to present extracellular antigens, which are normally presented on MHC-II, on MHC-I; MHC-I and MHC-II are cell membrane proteins that typically present internal or externally derived antigens, respectively, to immune cells.

(DRAM1). A p53-inducible, inflammation-inducible lysosomal membrane protein linked to autophagy and mechanistic target of rapamycin complex 1 (mTORC1) activation.

(Anoikis) A form of programmed cell death by which cells die following detachment from the extracellular matrix.

A chemotherapeutic drug that intercalates with DNA and is used to treat a variety of cancers.

An organelle that mediates traffic from the endoplasmic reticulum to the Golgi complex.

(ESCRT). A complex important in membrane remodelling during scission and budding and crucial for endosomal sorting.

A form of cell death whereby one cell inserts itself into the cytoplasm of a neighbouring cell.

A change in cell shape and structure from a polarized epithelial cell to one with mesenchymal characteristics, thus gaining migratory and invasive properties.

A caspase substrate involved in the release of inflammatory cytokines in a form of cell death termed pyroptosis.

(HMGB1). A chromatin protein that facilitates transcription factor function and alters chromatin structure. Release of HMGB1 from dying cells is engaged by immune cells, leading to inflammation.

(ICB). Cancer therapies that are designed to interfere with the immune checkpoints that tumour cells establish to evade attack by cytotoxic T cells.

Compounds that bind specific ions and facilitate their transport across membranes.

Weak bases that can accumulate in lysosomes and disrupt lysosomal function.

A cellular organelle involved in trafficking of material to lysosomes and the recycling of factors via the endocytic pathway.

Specialized cytotoxic lymphocytes that function in the innate immune response, particularly in the removal of cells lacking surface expression of MHC-I.

A hydrolase involved in the breakdown of sphingomyelin into the smaller lipids phosphocholine and ceramide.

A pathway leading to the activation of the NF-κB family of transcription factors, which control inflammatory responses and cell viability.

An antioxidant defence pathway driven by the transcription factor NRF2.

The grafting or implantation of cells or tissue into their natural site of origin.

Fibroblast-like cells in the pancreas that generate matrix components that can lead to fibrosis.

(PTEN). A tumour suppressor that dephosphorylates phosphorylated lipids involved in cellular signalling downstream of RAS.

(PI3P). A phospholipid found in membranes that acts as a critical signalling molecule.

A family of tyrosine kinases resident on the cell membrane and involved in cell-to-cell communication.

A viable cell state induced by ageing or oncogene activation in which cells are permanently cell-cycle arrested.

A cellular response pathway triggered as a defence mechanism to pathogen infection.

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Debnath, J., Gammoh, N. & Ryan, K.M. Autophagy and autophagy-related pathways in cancer. Nat Rev Mol Cell Biol 24 , 560–575 (2023). https://doi.org/10.1038/s41580-023-00585-z

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Accepted : 01 February 2023

Published : 02 March 2023

Issue Date : August 2023

DOI : https://doi.org/10.1038/s41580-023-00585-z

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