Abstract
Autophagy is a highly conserved, finely regulated and lysosome-dependent biological process through which eukaryotic cells mobilize metabolites in response to nutrient deprivation and dispose of supernumerary or toxic cytoplasmic entities to ensure cellular quality control. In line with the notion that autophagy globally preserves cellular homeostasis, defects in the molecular machinery for autophagy generally favour malignant transformation. Conversely, proficient autophagic responses are often beneficial to developing tumours as they support the survival of malignant cells facing harsh microenvironmental conditions. Finally, the ability of neoplastic cells to undergo autophagy influences their susceptibility to anticancer immune responses in a context-dependent manner. Thus, although autophagy stands out as a major target to intercept cancer at multiple inflection points of the disease, one-size-fits-all approaches are inherently incapable of capturing the complex influence of autophagy on the cancer cell (immuno)biology as a whole. Further complicating this scenario, healthy cells, including tumour-targeting immune effectors, rely on autophagy for their maturation, survival and functions, and pharmacological autophagy inhibitors currently available for use in humans are intrinsically nonspecific. Here, we discuss the promise and limitations of targeting autophagy to limit malignant transformation, exacerbate cancer cell death as driven by conventional therapeutics and restore immunosurveillance in support of superior disease responses to immunotherapy.
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Acknowledgements
E.G., D.R.G. and L.G. are grateful to the William Guy Forbeck Research Foundation (Carbondale, CO, USA) for fostering the dissemination of knowledge, promoting scientific collaboration and supporting the training of the next generation of leaders in cancer research. E.G. is supported by the 2025 AACR-Incyte Immuno-oncology Research Fellowship (grant no. 25-40-46-GUIL), and donations from The Eileen Stein Jacoby Fund (Philadelphia, USA). D.R.G. is supported (as a PI unless otherwise indicated) by two R01 grants from the NIH/NCI (nos CA231620 and AI44828). The L.G. laboratory is/has been supported (as a PI unless otherwise indicated) by one NIH R01 grant (no. CA271915), by two Breakthrough Level 2 grants from the US DoD BCRP (nos BC180476P1 and BC210945), by a grant from the STARR Cancer Consortium (no. I16-0064), by a Transformative Breast Cancer Consortium Grant from the US DoD BCRP (no. W81XWH2120034, PI: Formenti), by a U54 grant from NIH/NCI (no. CA274291, PI: Deasy, Formenti, Weichselbaum), by the 2019 Laura Ziskin Prize in Translational Research (no. ZP-6177, PI: Formenti) from the Stand Up to Cancer (SU2C), by a Mantle Cell Lymphoma Research Initiative (MCL-RI, PI: Chen-Kiang) grant from the Leukaemia and Lymphoma Society (LLS), by a Rapid Response Grant from the Functional Genomics Initiative (New York, USA), by a pre-SPORE grant (PI: Demaria, Formenti), a Collaborative Research Initiative Grant and a Clinical Trials Innovation Grant from the Sandra and Edward Meyer Cancer Center (New York, USA), by startup funds from the Department of Radiation Oncology at Weill Cornell Medicine (New York, USA), by startup funds from Fox Chase Cancer Center (Philadelphia, USA), by industrial collaborations with Lytix Biopharma (Oslo, Norway), Promontory (New York, USA) and Onxeo (Paris, France), as well as by donations from Promontory (New York, USA), the Luke Heller TECPR2 Foundation (Boston, USA), Sotio a.s. (Prague, Czech Republic), Lytix Biopharma (Oslo, Norway), Onxeo (Paris, France), Ricerchiamo (Brescia, Italy), Noxopharm (Chatswood, Australia) and Ms Pat Pasquarello (Philadelphia). The AB laboratory is/has been supported (as a PI unless otherwise indicated) by a Collaborative Research Initiative Grant from the Sandra and Edward Meyer Cancer Center (New York, USA), by startup funds from Fox Chase Cancer Center (Philadelphia, USA) as well as by donations from The Eileen Stein Jacoby Fund (Philadelphia, USA), and Ms Pat Pasquarello (Philadelphia, USA).
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E.G. and L.G. conceived the article. E.G. and L.G. wrote the first version of the manuscript with critical input from K.M.R. and D.R.G. E.G. prepared display items under supervision from L.G. All authors approve the submitted version of the article.
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D.R.G. is/has been holding research contracts with Amgen and has consulted for Sonata Pharmaceuticals, Ventus Pharmaceuticals and ASHA Therapeutics. L.G. is/has been holding research contracts with Lytix Biopharma, Promontory and Onxeo, has received consulting/advisory honoraria from Boehringer Ingelheim, AstraZeneca, OmniSEQ, Onxeo, The Longevity Labs, Inzen, Imvax, Sotio, Promontory, Noxopharm, EduCom and the Luke Heller TECPR2 Foundation and holds Promontory stock options. E.G. and K.M.R. have no conflicts of interest to disclose.
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Glossary
- Abscopal effect
-
Control of non-irradiated (out-of-field) neoplastic lesions by focal radiation therapy delivered to a distant (target) tumour, most often manifest in the context of systemic (but ineffective) immunotherapy.
- Autophagic flux
-
A measure of the amount of cytoplasmic material that is effectively degraded by lysosomes upon uptake and delivery by the autophagic machinery.
- Caloric cycling
-
Experimental dietary regimen involving alternating periods of unrestricted access to food and periods of caloric restriction.
- Caloric restriction mimetics
-
Pharmacological agents that mimic the biological effects of caloric restriction, notably autophagy activation, in the absence of a sizeable effect on body weight (for example, α-ketoglutarate, hydroxycitrate and spermidine).
- Canonical inflammasome
-
Supramolecular cytoplasmic platform that promotes the activation of CASP1 and the consequent release of mature IL1B and IL18 coupled with lytic cell death.
- CD8+ cytotoxic T lymphocytes
-
Lymphoid cells that mediate robust cytotoxic effects upon recognition of target cells exposing antigenic peptides in complex with autologous MHC class I molecules.
- Dendritic cells
-
Myeloid cells that have a fundamental role in the initiation of CD8+ CTL-dependent immune responses against malignant cells.
- Epithelial-to-mesenchymal transition
-
Phenotypic shift of epithelial cancer cells towards a mesenchymal state that is associated with increased motility and capacity for local and distant dissemination.
- Ferroptosis
-
Regulated form of necrosis that is precipitated by catastrophic lipid peroxidation at cellular membranes.
- Healthspan
-
Period of life not affected by debilitating chronic disorders normally associated with ageing, including cardiovascular conditions, cancer and neurodegeneration.
- Immune checkpoint inhibitors
-
Immunotherapeutic agent targeting co-inhibitory T cell receptors (for example, PD-1, CTLA4) or the co-inhibitory ligands thereof (for example, PD-L1), thus unleashing anticancer immune responses.
- Immunogenic cell death
-
Type of cell death that — in immunocompetent syngeneic hosts and in the context of a permissive microenvironment — is sufficient to elicit antigen-specific immune responses associated with an effector and memory phase.
- Immunosurveillance
-
Process through which the immune system controls developing tumours, either by eradicating newly formed malignant cells or by preventing the growth and dissemination of microscopic neoplasms.
- LC3-associated phagocytosis
-
Phagocytic mechanism involving single-membraned LC3-decorated vesicles that shares multiple, but not all, regulators with autophagy.
- Micronuclei
-
Small portions of the nucleus that generally originate from defective mitosis and are poorly delimited by nuclear envelope components.
- Mitophagy
-
Specialized form of autophagy that ensures the lysosomal degradation of permeabilized or otherwise dysfunctional mitochondria.
- Myeloid-derived suppressor cells
-
Immature myeloid cells with monocytic or granulocytic features that often expand in the circulation of patients with cancer and mediate immunosuppressive effects.
- Natural killer (NK) cells
-
Innate lymphoid cells that respond to infected or malignant cells by recognizing general signals of distress (rather than specific antigens as CTLs).
- Necroptotic cell death
-
Regulated variant of necrosis executed by the RIPK3-driven formation of MLKL pores into the plasma membrane.
- Oncocytomas
-
Benign tumours mostly composed of oncocytes, which are cells with an abnormally overdeveloped mitochondrial network.
- Oncogene-driven senescence
-
A permanent proliferative arrest coupled with considerable secretory alterations that (at least in some cells) operate as an endogenous oncosuppressor in response to potentially oncogenic alterations.
- Pattern recognition receptors
-
(PRRs). Evolutionary conserved family of receptors that respond to microbial components as well as endogenous molecules with inflammatory functions.
- Regulatory T (Treg) cells
-
Lymphoid cells that respond to the recognition of specific antigens in complex with autologous MHC class I molecules by orchestrating immunosuppressive responses.
- Xenophagy
-
A specialized variant of autophagy that selectively degrades microbial pathogens that access the cytoplasm, including viruses and selected bacterial strains.
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Guilbaud, E., Ryan, K.M., Green, D.R. et al. Autophagy modulation in cancer. Nat Rev Drug Discov (2026). https://doi.org/10.1038/s41573-026-01449-9
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DOI: https://doi.org/10.1038/s41573-026-01449-9
