Manipulating mitochondrial electron flow enhances tumor immunogenicity

Science. 2023 Sep 22;381(6664):1316-1323. doi: 10.1126/science.abq1053. Epub 2023 Sep 21.

Abstract

Although tumor growth requires the mitochondrial electron transport chain (ETC), the relative contribution of complex I (CI) and complex II (CII), the gatekeepers for initiating electron flow, remains unclear. In this work, we report that the loss of CII, but not that of 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-antigen processing and presentation (MHC-APP) genes independent of interferon signaling. Furthermore, knockout of methylation-controlled J protein (MCJ), to promote electron entry preferentially through CI, provides proof of concept of ETC rewiring to achieve antitumor responses without side effects associated with an overall reduction in mitochondrial respiration in noncancer cells. Our results may hold therapeutic potential for tumors that have reduced MHC-APP expression, a common mechanism of cancer immunoevasion.

MeSH terms

  • Antigen Presentation
  • Antigens, Neoplasm* / immunology
  • Cell Line, Tumor
  • Electron Transport Complex I* / genetics
  • Electron Transport Complex I* / metabolism
  • Electron Transport Complex II* / genetics
  • Electron Transport Complex II* / metabolism
  • Electrons
  • Gene Knockout Techniques
  • HSP40 Heat-Shock Proteins / genetics
  • Histones / metabolism
  • Humans
  • Melanoma / immunology
  • Melanoma / pathology
  • Methylation
  • Mitochondria* / enzymology
  • Neoplasms* / immunology
  • Neoplasms* / pathology

Substances

  • Antigens, Neoplasm
  • DNAJC15 protein, human
  • Electron Transport Complex I
  • Electron Transport Complex II
  • Histones
  • HSP40 Heat-Shock Proteins