Abstract
Autophagy is a highly conserved cellular degradation process essential for maintaining cellular homeostasis, yet its role in cancer is fundamentally context dependent. Increasing evidence indicates that autophagy suppresses tumor initiation by preserving genomic and metabolic integrity, while paradoxically supporting tumor progression, therapy resistance, and immune evasion at advanced stages. This functional duality presents a major challenge for therapeutic targeting and largely reflects the spatiotemporal heterogeneity of autophagy regulation across tumor stages, cancer cell subpopulations, and the tumor microenvironment (TME). In this review, we argue that autophagy-related proteins should be conceptualized as context-dependent therapeutic nodes rather than universally actionable targets. We systematically examine key autophagy regulators, including Beclin-1, p62/SQSTM1, mTOR, and p53, and analyze how their functions are shaped by tumor stage, genetic background, and microenvironmental cues such as hypoxia, immune pressure, and stromal interactions. We further highlight the pivotal role of the TME in determining autophagy dependency and therapeutic vulnerability, providing mechanistic insight into why autophagy modulation without microenvironmental consideration often yields inconsistent outcomes. From a precision medicine perspective, we discuss how nanotechnology-based delivery systems enable spatially and temporally controlled modulation of autophagy, thereby addressing intratumoral heterogeneity and reducing systemic toxicity. By integrating molecular profiling, TME characteristics, and nanomedicine-enabled targeting strategies, this review outlines a rational framework for exploiting autophagy in cancer therapy. Together, these insights provide a foundation for the development of context-aware, autophagy-targeted interventions and advance the pursuit of more effective and personalized cancer treatments.