VPS34 in Autophagy, Cancer and Cancer Therapy

Autophagy is a fundamental lysosome-dependent degradation process, which maintains cellular homeostasis in response to stress. VSP34 (Vacuolar Protein Sorting 34, PIK3C3), as the only Class III phosphatidylinositol 3-kinase, generates phosphatidylinositol 3-phosphate (PI3P) for au-to-phagosome nucleation and maturation, thereby providing a critical adaptive survival pathway for cells experiencing metabolic stress. The VPS34-autophagy axis displays a context-dependent dual roles in cancer: it can restrain early tumorigenesis; however, in established tumors it can promote survival under hypoxia, nutrient deprivation, and therapeutic pressure. Additionally, VPS34 shapes the tumor microenvironment (TME) by influencing both immune and cancer cells through modulating autophagy, cGAS-STING (cyclic GMP-AMP synthase Stimulator of Interfer-on Genes) and STAT1 pathways. VPS34 inhibition has been reported to induce interferon response that enhance CD8+ T and natural killer (NK) cell infiltration and convert cold tumor into hot, providing a rationale for combination of VPS34 inhibitors with cancer immunotherapies. In this review, we summarize the molecular functions and regulations of VPS34 in autophagy and dis-cuss recent advances linking VPS34 to tumor and cancer immunotherapy.