The EACR’s ‘Highlights in Cancer Research’ is a regular summary of the most interesting and impactful recent papers in cancer research, curated by the Board of the European Association for Cancer Research (EACR).
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Ikeda, H. et al. Nature. 638: 225-236. (2025).
doi: 10.1038/s41586-024-08439-0.
Summary of the findings
Summary of the findingsCancer cells in the tumor microenvironment (TME) evade immune attack through various mechanisms, including metabolic reprogramming and mitochondrial dysfunction in tumor-infiltrating lymphocytes (TILs). This study reveals a novel immune evasion mechanism where cancer cells transfer mitochondria with mutated mitochondrial DNA (mtDNA) to TILs, leading to metabolic abnormalities and immune dysfunction.
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Clinical samples showed that TILs share mtDNA mutations with cancer cells, suggesting mitochondrial transfer. Using fluorescence-labeled mitochondria, we confirmed that mitochondria move from cancer cells to TILs via tunneling nanotubes (TNTs) and small extracellular vesicles (EVs). These transferred mitochondria resist mitophagy due to inhibitory molecules, resulting in homoplasmic replacement.
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TILs that acquire mutated mitochondria exhibit increased reactive oxygen species (ROS) production, impaired ATP generation, senescence, and reduced memory formation. In mouse models, tumors with an mtDNA mutation transferred mitochondria to TILs, leading to immune dysfunction and resistance to PD-1 blockade therapy. Blocking mitochondrial transfer with an EV inhibitor (GW4869) partially restored TIL function and improved PD-1 blockade efficacy. Accordingly, the presence of mtDNA mutations in tumor tissues was a poor prognostic factor for immune checkpoint inhibitors in patients with melanoma or non-small-cell lung cancer. Particularly, durable response was impaired.
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Future impact
This study highlights mitochondrial transfer (“swap”) as a critical immune evasion strategy, suggesting new therapeutic targets and biomarkers. Targeting EV-mediated mitochondrial transfer or enhancing mitophagy could restore T cell function and improve immunotherapy outcomes. The findings could lead to novel cancer treatments, particularly for patients resistant to immune checkpoint inhibitors combined with predictive biomarkers.
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