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.

线粒体基因组 (mtDNA) 编码氧化磷酸化和代谢稳态的重要机制。肿瘤 mtDNA 是癌症基因组中体细胞突变最严重的区域之一，但这些突变是否影响肿瘤生物学仍存在争议。我们将 mtDNA 编码的复合物 I 基因Mt-Nd5的截短突变设计到几种黑色素瘤小鼠模型中。这些突变促进了类似 Warburg 的代谢转变，重塑了小鼠和人类的肿瘤微环境，持续引发以常驻中性粒细胞损失为特征的抗肿瘤免疫反应。携带 mtDNA 突变的肿瘤以中性粒细胞依赖性方式对检查点封锁敏感，氧化还原失衡的诱导足以在 mtDNA 野生型肿瘤中诱导这种效应。携带 >50% mtDNA 突变异质性的患者病变表现出对检查点封锁的反应率，比 mtDNA 野生型癌症提高约 2.5 倍。这些数据表明 mtDNA 突变是癌症代谢和肿瘤生物学的功能调节因子，具有治疗开发和治疗分层的潜力。