Targeting autophagy in dysfunctional tumor vasculature

Tumor vasculature drives cancer progression and therapeutic resistance, with autophagy serving as a critical regulator of endothelial cell function. This review synthesizes current knowledge of autophagy in tumor vasculature, examining molecular mechanisms, cellular interactions, and therapeutic applications. Tumor endothelial cell autophagy is controlled through mTOR/AMPK signaling, VEGF-mediated pathways, and stress responses. Stromal components, particularly pericytes and proteoglycans, modulate these processes via direct interactions and paracrine signaling, while the interplay between vascular autophagy and immune responses shapes tumor microenvironment dynamics. Therapeutic strategies combining autophagy inhibitors with anti-angiogenic agents, immune checkpoint inhibitors, or chemotherapy demonstrate enhanced preclinical efficacy. However, clinical translation faces challenges including non-specific inhibition and context-dependent effects. Successful therapeutic development requires tumor endothelial cell (TEC)-specific modulators, robust biomarkers for patient stratification, and optimized dosing strategies. Understanding vascular autophagy's dual roles-promoting both tumor survival and vulnerability-provides essential insights for developing effective cancer treatments.