Autophagy in cancer - functional plasticity, therapeutic paradox, and the road to precision modulation: a...

Autophagy is an evolutionarily conserved lysosomal degradation pathway. In cancer, its role is paradoxical: it functions as a tumor-suppressive gatekeeper during initiation in part by preserving genomic stability, but it is frequently co-opted by established tumors to maintain metabolic fitness and therapeutic resistance. Early clinical efforts using broad, non-selective lysosomal inhibition (e.g., chloroquine) produced mixed outcomes and toxicities, prompting a paradigm shift toward modular, context-specific modulation.This review synthesizes the dynamic spatiotemporal evolution of autophagy in tumorigenesis, and characterizes it as an adaptable evolutionary trajectory governed by stress, tumor genotype, and microenvironmental context. We outline four conceptual pillars: genotype-defined modular networks, dynamic spatiotemporal adaptation, autophagy as an immunometabolic rheostat, and rational therapeutic modulation. Importantly, autophagy exerts cell-type-specific effects-promoting immune evasion in tumor cells while remaining indispensable for lymphocyte fitness. To address this paradox, we evaluate the transition from empirical global blockade to precision-guided intervention, including pathway-selective modulators, exploitation of selective vulnerabilities, and advanced targeted degradation technologies. Autophagy in cancer is a highly dynamic, context-dependent variable. Therapeutic control requires movement beyond universal flux inhibition toward pathway-specific, biomarker-guided interventions that match a tumor's distinct autophagic dependencies. Integration of dynamic monitoring with precise delivery systems may allow active modulation of the tumor microenvironment, transforming autophagy from a tumor resilience mechanism into an exploitable therapeutic vulnerability.