Selective Mitochondrial Respiratory Complex I Subunit Deficiency Causes Tumor Immunogenicity

Abstract

Targeting of specific metabolic pathways in tumor cells has the potential to sensitize them to immune-mediated attack. Here we provide evidence for a specific means of mitochondrial respiratory Complex I (CI) inhibition that improves tumor immunogenicity and sensitivity to immune checkpoint blockade (ICB). Targeted genetic deletion of the CI subunitsNdufs4andNdufs6, but not other subunits, induces an immune-dependent tumor growth attenuation in mouse melanoma models. We show that deletion ofNdufs4induces expression of the transcription factorNlrc5and genes in the MHC class I antigen presentation and processing pathway. This induction of MHC-related genes is driven by an accumulation of pyruvate dehydrogenase-dependent mitochondrial acetyl-CoA downstream of CI subunit deletion. This work provides a novel functional modality by which selective CI inhibition restricts tumor growth, suggesting that specific targeting ofNdufs4, or related CI subunits, increases T-cell mediated immunity and sensitivity to ICB.