Current Research Status of ATP6V Gene Family in Human Cancers

Vacuolar H⁺-ATPase (V-ATPase), encoded by the ATP6V gene family, is an evolutionarily conserved, a multisubunit proton pump that plays a fundamental role in maintaining intracellular pH homeostasis, ion balance, and lysosomal function. Increasing evidence indicates that dysregulation of V-ATPase expression and activity is closely associated with tumorigenesis and cancer progression. V-ATPase mediates ATP-dependent proton transport across membranes, thereby acidifying various intracellular compartments such as lysosomes, endosomes, the Golgi apparatus, and secretory vesicles, which is essential for protein degradation, trafficking, and autophagy. Beyond its canonical roles, V-ATPase has been shown to participate in multiple oncogenic signaling pathways, including mTORC1 and Wnt/β-catenin, thereby modulating cellular metabolism, proliferation, and survival. Notably, overexpression of V-ATPase in cancer cells contributes to the acidification of the extracellular microenvironment, facilitating invasion, metastasis, and resistance to therapy. This review summarizes current advances in the understanding of ATP6V family genes and V-ATPase function in cancer biology, highlighting their potential as diagnostic biomarkers and therapeutic targets.