Rewiring the Mitochondrial Electron Transport Chain Enhances Tumor Immunogenicity

Although tumor growth requires the mitochondrial electron transport chain (ETC), the relative contribution of Complex I (CI) and II (CII), the gatekeepers for initiating electron flow, remains unclear. Here, we report that loss of CII, but not CI, reduces melanoma tumor growth by increasing antigen presentation and T cell-mediated killing. This is driven by succinate-mediated transcriptional and epigenetic activation of major histocompatibility complex I-antigen processing and presentation (MHC-APP) genes that is independent of interferon signaling. Furthermore, knock-out of MCJ, to promote electron entry preferentially via CI, provides proof-of-concept of ETC rewiring to achieve anti-tumor responses without side effects associated with an overall reduction in mitochondrial respiration in non-cancer cells. Our results hold therapeutic potential for tumors that have reduced MHC-APP expression, a common mechanism of cancer immunoevasion. Overall design: Chromatin immunoprecipitation DNA-sequencing (ChIP-seq) for the histone modifications H3K4me3 and H3K36me3 in YUMM1.7 cells treated with DMSO, 3-NPA, or 3-NPA + aKG, as well as inputs.