A Cyclometalated Gold(III) Complex Targets Mitochondrial VDAC1 to Drive Immunometabolic Reprogramming in Cancer

Chemotherapeutic agents can modulate inflammatory and immune pathways in cancer, yet the molecular mechanisms linking small-molecule target engagement to immune remodeling remain poorly defined. Here, we identify the mitochondrial voltage-dependent anion channel 1 (VDAC1) as a direct target of a cyclometalated gold(III) bisphosphine complex (AuPhos), establishing a mechanistic connection between VDAC1 engagement and immunometabolic reprogramming in tumor cells. Using complementary chemical proteomics, cellular thermal shift assays, intact mass spectrometry, and top-down proteomics, we demonstrate that AuPhos covalently engages and stabilizes VDAC1 at cysteine 232. In cancer cells, VDAC1 targeting by AuPhos disrupts mitochondrial metabolic homeostasis, including selective downregulation of respiratory electron transport chain transcripts, and induces intrinsic inflammatory signaling characterized by cytokine and chemokine expression (IL-6, IL-18, IL-8, IL-1β, and CXCL10). Notably, pro-inflammatory transcriptional responses are selectively induced in cancer cells, while mitochondrial metabolic responses occur in both cell-type-dependent directions. Beyond tumor cell–intrinsic effects, AuPhos enhances peripheral blood mononuclear cell (PBMC) activation and augments immune cell-mediated killing of cancer cells. Together, these findings identify VDAC1 as a previously unrecognized target of gold(III) complexes and establish AuPhos as a chemical probe and prototype for redox-active, metal-based agents capable of coupling mitochondrial targeting to immunometabolic remodeling in cancer with implications for several pathologies.