VDAC2 is a voltage-dependent anion channel localized to the mitochondrial outer membrane that functions as a critical metabolic and immune checkpoint. Beyond its classical ion transport role, VDAC2 catalyzes phospholipid scrambling across the outer mitochondrial membrane 1. VDAC2 regulates mitochondrial permeability and function through multiple mechanisms: it forms oligomeric pores mediating mitochondrial DNA release 2, participates in mitochondria-ER contact sites controlling calcium and ROS homeostasis 3, and facilitates mitophagy by recruiting PRKN to damaged mitochondria 4. Post-translational modifications of VDAC2, including lysine malonylation, alter channel structure and promote ferroptotic pathways 5. In cancer, VDAC2 emerges as a dual-action immunotherapeutic target: its loss unleashes BAK-dependent mitochondrial damage and cGAS-STING activation, sensitizing tumors to CD8+ T cell-mediated immunity 1. Conversely, VDAC2 degradation by ubiquitination protects melanoma cells from ferroptosis 6 and suppresses radiation-induced antitumor immunity in nasopharyngeal carcinoma 2. VDAC2 also integrates with the mitochondrial protein import machinery at TOM complexes, facilitating PINK1 stabilization in Parkinson's disease pathogenesis 7.