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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 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE263533 | GEO | 2024/10/05

REPOSITORIES: GEO

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