Selective Mitochondrial Respiratory Complex I Subunit Deficiency Causes Tumor Immunogenicity

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 subunits Ndufs4 and Ndufs6 , but not other subunits, induces an immune-dependent tumor growth attenuation in mouse melanoma models. We show that deletion of Ndufs4 induces expression of the transcription factor Nlrc5 and 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 of Ndufs4 , or related CI subunits, increases T-cell mediated immunity and sensitivity to ICB. ### Competing Interest Statement K.W.W. serves on the scientific advisory boards of TScan Therapeutics, Bisou Bioscience Company, DEM BioPharma, Solu Therapeutics and Nextechinvest, and he receives sponsored research funding from Novartis. K.W.W. is a co-founder, stockholder and advisory board member of Immunitas Therapeutics, a biotech company.