Mahmood, Mahnoor, Liu, Eric Minwei, Shergold, Amy L et al. (21 more authors) (2024) Mitochondrial DNA mutations drive aerobic glycolysis to enhance checkpoint blockade response in melanoma. Nature cancer. ISSN 2662-1347
Abstract
The mitochondrial genome (mtDNA) encodes essential machinery for oxidative phosphorylation and metabolic homeostasis. Tumor mtDNA is among the most somatically mutated regions of the cancer genome, but whether these mutations impact tumor biology is debated. We engineered truncating mutations of the mtDNA-encoded complex I gene, Mt-Nd5, into several murine models of melanoma. These mutations promoted a Warburg-like metabolic shift that reshaped tumor microenvironments in both mice and humans, consistently eliciting an anti-tumor immune response characterized by loss of resident neutrophils. Tumors bearing mtDNA mutations were sensitized to checkpoint blockade in a neutrophil-dependent manner, with induction of redox imbalance being sufficient to induce this effect in mtDNA wild-type tumors. Patient lesions bearing >50% mtDNA mutation heteroplasmy demonstrated a response rate to checkpoint blockade that was improved by ~2.5-fold over mtDNA wild-type cancer. These data nominate mtDNA mutations as functional regulators of cancer metabolism and tumor biology, with potential for therapeutic exploitation and treatment stratification.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2024. The Author(s). |
Dates: |
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Institution: | The University of York |
Academic Units: | The University of York > Faculty of Sciences (York) > Chemistry (York) |
Funding Information: | Funder Grant number UKRI MR/T040742/1 |
Depositing User: | Pure (York) |
Date Deposited: | 04 Mar 2024 15:40 |
Last Modified: | 16 Oct 2024 19:49 |
Published Version: | https://doi.org/10.1038/s43018-023-00721-w |
Status: | Published online |
Refereed: | Yes |
Identification Number: | 10.1038/s43018-023-00721-w |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:209900 |