Autophagy Modulation in Cancer: Therapeutic Promise and Complexity : Nat Rev Drug Discov | May 2026

Introduction

Autophagy is a highly conserved cellular homeostatic mechanism that enables recycling of intracellular components, removal of damaged organelles and adaptation to metabolic stress. In cancer biology, autophagy has emerged as a paradoxical process with context-dependent tumor-suppressive and tumor-promoting roles. Increasingly, modulation of autophagy is being explored as a therapeutic strategy across multiple stages of oncogenesis and anticancer treatment.

Problem Statement

Despite intense therapeutic interest, targeting autophagy in cancer remains highly challenging because autophagy exerts divergent effects depending on tumor type, disease stage, immune context and treatment setting. Furthermore, currently available pharmacologic autophagy inhibitors lack specificity and may adversely affect normal tissues and antitumor immune responses.

Summary

This comprehensive review outlines the multifaceted role of autophagy across cancer initiation, progression, immune regulation and therapeutic resistance. In early carcinogenesis, defective autophagy promotes genomic instability, oxidative stress, chronic inflammation and accumulation of damaged cellular components, thereby facilitating malignant transformation. These observations support the tumor-suppressive role of basal autophagy during early oncogenesis.

Conversely, once tumors are established, proficient autophagic activity often becomes advantageous for malignant cells. Tumor cells exploit autophagy to survive hypoxia, nutrient deprivation, oxidative stress and therapeutic pressure within hostile tumor microenvironments. Autophagy additionally supports mitochondrial fitness, metabolic plasticity and adaptation to cytotoxic therapies, thereby contributing to tumor persistence and treatment resistance.

The review highlights growing evidence that autophagy strongly influences anticancer immunity. Depending on context, autophagy may either enhance or impair immune-mediated tumor elimination. In some settings, autophagy facilitates antigen presentation, immunogenic cell death and T-cell activation, thereby supporting immunosurveillance. Conversely, autophagic pathways may also protect tumor cells from immune-mediated cytotoxicity and contribute to resistance against immune checkpoint blockade.

Importantly, the authors emphasize that healthy immune cells themselves depend heavily on autophagy for maturation, survival and effector function. Cytotoxic T lymphocytes, dendritic cells and other immune effectors require intact autophagic machinery to sustain antitumor responses. This creates major therapeutic complexity because indiscriminate systemic autophagy inhibition could simultaneously impair both tumor survival and immune-mediated tumor control.

The review further discusses current pharmacologic strategies targeting autophagy, including lysosomal inhibitors such as hydroxychloroquine, upstream kinase modulators and novel selective autophagy-targeting agents. However, most clinically available inhibitors remain relatively nonspecific and incompletely suppress autophagic flux. Variable pharmacodynamic activity, compensatory resistance pathways and systemic toxicity have limited clinical success thus far.

A major conceptual advance emphasized throughout the review is that autophagy should no longer be viewed as a binary therapeutic target. Instead, future approaches will likely require precision modulation tailored to tumor genotype, metabolic state, immune microenvironment and treatment timing. Context-specific strategies integrating autophagy modulation with chemotherapy, radiotherapy, targeted therapy or immunotherapy may ultimately prove most effective.

Overall, this state-of-the-art review positions autophagy as one of the most biologically complex therapeutic vulnerabilities in oncology. The authors underscore that successful clinical translation will require highly selective, context-aware approaches capable of exploiting tumor-specific autophagic dependencies while preserving protective homeostatic and immune functions in normal tissues.