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Selective Mitochondrial Respiratory Complex I Subunit Deficiency Causes Tumor Immunogenicity

GSE263533 Mus musculus Expression profiling by high throughput sequencing 6 samples Submitted 2024/10/05 Platform GPL21103
Summary
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.
Published in
Selective deficiency of mitochondrial respiratory complex I subunits Ndufs4/6 causes tumor immunogenicity
Liang J, Vitale T, Zhang X et al. · Nature cancer 2025 · PMID 39824999 · doi:10.1038/s43018-024-00895-x
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Also filed as BioProject PRJNA1098002 and SRA study SRP500511. Searching any of these in the dataset finder brings you back here.

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