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bioRxiv · 10.64898/2026.01.31.693596

MtDNA heteroplasmy controls tumor immune reprogramming through mitochondrial translation

Liu, N.·Chai, G.·Lv, Q.·Deng, X.·Chen, J.·Zhang, Q.·Zhang, L.·Liu, X.·Tang, R.·Xu, Z.·Cai, S.·Jiang, M.
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Abstract

Mitochondrial DNA (mtDNA) mutations are among the most frequent genetic alterations in human cancers, yet their molecular mechanisms in shaping tumor progression and metastasis under physiological conditions remain poorly understood. Here, we show that mtDNA heteroplasmy acts as a tumor cell-intrinsic rheostat that orchestrates fate decisions between progression and suppression. Moderate heteroplasmy induces a ribosomal storm of mitochondrial translation and ribosome biogenesis, driven by leucyl-tRNA synthetase 2 (LARS2). This response enhances metabolic fitness and licenses the secretion of S100A8/A9, enabling tumor cells to actively remodel the immune microenvironment through recruitment of myeloid-derived suppressor cells and exclusion of CD8 T cells, thereby promoting immune evasion and metastatic progression. In contrast, high heteroplasmy impairs tumorigenesis due to oxidative phosphorylation collapse. Disruption of LARS2, mitochondrial translation, or S100A9 signalling abrogates tumor progression. Our findings establish mtDNA heteroplasmy as a key regulator of cancer evolution, linking mitochondrial genetic variation to immune modulation, and reveal the LARS2-mitochondrial translation-S100A8/A9 axis as a therapeutically targetable programme within the pro-tumorigenic window of mtDNA heteroplasmy.

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Liu, N., Chai, G., Lv, Q., Deng, X., Chen, J., Zhang, Q., Zhang, L., Liu, X., Tang, R., Xu, Z., Cai, S., Jiang, M.. 2026-02-03. MtDNA heteroplasmy controls tumor immune reprogramming through mitochondrial translation. https://doi.org/10.64898/2026.01.31.693596

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