Background: Autophagy is a fundamental cellular recycling mechanism with complex and often opposing roles in cancer, functioning as both a tumor suppressor and a pro-survival mechanism in established tumors. This duality has attracted considerable attention, particularly regarding the therapeutic modulation of autophagy to overcome chemoresistance, a major challenge in cancer treatment. However, the function of autophagy is highly context-dependent and varies with tumor stage, cellular subpopulations, and the tumor microenvironment (TME).

Discussion: This perspective examines the multifaceted role of autophagy in cancer, its therapeutic modulation to enhance chemosensitivity, the molecular pathways that regulate autophagy, and the current status of clinical trials with autophagy-targeting agents. We critically discuss the limitations of first-generation autophagy inhibitors, including hydroxychloroquine (HCQ) and chloroquine (CQ). Although these agents show chemosensitizing effects in some preclinical studies and have been evaluated clinically, they lack specificity and may cause off-target toxicities. Particular emphasis is placed on the emerging understanding of selective autophagy pathways, such as mitophagy and ER-phagy, and their context-dependent impact on therapeutic outcomes. We further highlight that successful autophagy-targeted therapy requires a nuanced, precision-based approach that accounts for tumor heterogeneity and microenvironmental influences and integrates advanced drug delivery strategies, including nanomedicine, to achieve spatiotemporal control of autophagy.

Conclusion: Targeting autophagy represents a promising yet highly complex strategy for overcoming chemoresistance and requires a transition from global autophagy modulation to selective, context-specific interventions. Future research should focus on developing highly selective autophagy modulators, identifying robust predictive biomarkers, and integrating precision nanomedicine approaches to safely manage autophagy's dual roles and optimize therapeutic outcomes across diverse tumor contexts.