# Role of autophagy in tumorigenesis and drug resistance: molecular mechanisms and therapeutic targets

## TL;DR

This review explores how autophagy can both prevent and promote cancer, depending on the context, and highlights potential therapeutic strategies targeting autophagy.

## Contribution

The paper systematically integrates molecular mechanisms of autophagy in cancer progression and drug resistance, emphasizing context-dependent roles and therapeutic implications.

## Key findings

- Autophagy suppresses early tumorigenesis by maintaining genomic stability and limiting stemness.
- In advanced tumors, autophagy supports survival and resistance to therapies under stress conditions.
- Autophagy interacts with metabolic reprogramming, immune signaling, and DNA damage responses in tumor evolution.

## Abstract

Autophagy represents a conserved lysosome-dependent catabolic mechanism that safeguards cellular energetic homeostasis and supports adaptive metabolic remodeling under diverse stress conditions. In cancer, autophagy displays a highly context-dependent “double-edged sword” behavior. During the early stages of tumorigenesis, autophagy can suppress malignant transformation by preserving genomic stability, restraining chronic inflammation, and limiting the acquisition of malignant stemness, thereby helping preserve cellular integrity in early tumorigenesis. However, as tumors progress, autophagy can be reprogrammed into an adaptive survival mechanism that supplies tumor growth, metastatic dissemination, and resistance to multiple therapeutic modalities in response to hypoxia, nutrient deprivation, and therapeutic stress. Within the framework of tumor evolution, this review systematically integrates the molecular mechanisms and regulatory networks underlying different forms of autophagy, including canonical, non-canonical, and selective forms. We explore how autophagy intersects with metabolic reprogramming, immune signaling, DNA damage responses, and regulated cell death, and discuss its involvement in tumor progression, microenvironment remodeling, metastasis, and therapy resistance, with relevance to interactions between tumor cells and the surrounding microenvironment. We also summarize recent developments in autophagy-targeted approaches, including chloroquine derivatives, emerging small-molecule inhibitors, and natural compounds, and consider the challenges that remain for clinical translation, especially those related to context-dependent effects and therapeutic application. Collectively, this review provides an updated understanding of autophagy in tumor evolution and informs future mechanistic and therapeutic investigations.