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Cited by 330Cancer Immunotherapy and BiomarkersMitochondrial Function and PathologyAutophagy in Disease and Therapy

Immune evasion through mitochondrial transfer in the tumour microenvironment

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Ikeda, Hideki, Kawase, Katsushige, Nishi, Tatsuya, Watanabe, Tomofumi, Takenaga, Keizo, Inozume, Takashi, Ishino, Takamasa, Aki, Sho +27 more·2025·Nature
DOI 10.1038/s41586-024-08439-0PMC PMC11798832
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Abstract

Cancer cells in the tumour microenvironment use various mechanisms to evade the immune system, particularly T cell attack1. For example, metabolic reprogramming in the tumour microenvironment and mitochondrial dysfunction in tumour-infiltrating lymphocytes (TILs) impair antitumour immune responses2–4. However, detailed mechanisms of such processes remain unclear. Here we analyse clinical specimens and identify mitochondrial DNA (mtDNA) mutations in TILs that are shared with cancer cells. Moreover, mitochondria with mtDNA mutations from cancer cells are able to transfer to TILs. Typically, mitochondria in TILs readily undergo mitophagy through reactive oxygen species. However, mitochondria transferred from cancer cells do not undergo mitophagy, which we find is due to mitophagy-inhibitory molecules. These molecules attach to mitochondria and together are transferred to TILs, which results in homoplasmic replacement. T cells that acquire mtDNA mutations from cancer cells exhibit metabolic abnormalities and senescence, with defects in effector functions and memory formation. This in turn leads to impaired antitumour immunity both in vitro and in vivo. Accordingly, the presence of an mtDNA mutation in tumour tissue is a poor prognostic factor for immune checkpoint inhibitors in patients with melanoma or non-small-cell lung cancer. These findings reveal a previously unknown mechanism of cancer immune evasion through mitochondrial transfer and can contribute to the development of future cancer immunotherapies. Mitochondria with mutations in their DNA from cancer cells can be transferred to T cells in the tumour microenvironment, which leads to T cell dysfunction and impaired antitumour immunity.

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Authors
Ikeda, H., Kawase, K., Nishi, T., Watanabe, T., Takenaga, K., Inozume, T., Ishino, T., Aki, S., Lin, J., Kawashima, S., Nagasaki, J., Ueda, Y., Suzuki, S., Makinoshima, H., Itami, M., Nakamura, Y., Tatsumi, Y., Suenaga, Y., Morinaga, T., Honobe-Tabuchi, A., Ohnuma, T., Kawamura, T., Umeda, Y., Nakamura, Y., Kiniwa, Y., Ichihara, E., Hayashi, H., Ikeda, J.-I., Hanazawa, T., Toyooka, S., Mano, H., Suzuki, T., Osawa, T., Kawazu, M., & Togashi, Y.
Affiliations
  • Chiba University (JP)
  • Okayama University (JP)
  • Chiba Cancer Center Research Institute (JP)
  • The University of Tokyo (JP)
  • Kindai University Hospital (JP)
  • Chiba Cancer Center (JP)
  • Saitama International Medical Center (JP)
  • University of Yamanashi (JP)
  • Shinshu University (JP)
  • Okayama University Hospital (JP)
  • National Cancer Center Research Institute (JP)
Corresponding author
Togashi, Yosuke
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2025-01-22
Volume
638
Issue
8049
Pages
225-236
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-024-08439-0
PMC
PMC11798832
OpenAlex
W4406731670
Cited by
330
References
9
Citations by year
2026: 198 · 2025: 132
FWCI
136.66
Type
journal article
Language
en
Update notices
Open access
Licence
Locations
  • Nature (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Okayama University Scientific Achievement Repository (Okayama University) (submittedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • Institutional Repositories DataBase (IRDB) (submittedVersion)
Funders
  • Bristol-Myers Squibb
  • Eli Lilly and Company
  • Pfizer
  • AstraZeneca
  • Nvidia
  • Suzuken Memorial Foundation
  • Japan Agency for Medical Research and Development (JP 19cm0106502, CREST)
  • GlaxoSmithKline Japan
  • Kowa Company
  • Taiju Life Social Welfare Foundation
  • SGH Foundation
  • Daiichi-Sankyo
  • Inamori Foundation
  • Kato Memorial Bioscience Foundation
  • Kowa Life Science Foundation
  • Astellas Pharma
  • Astellas Foundation for Research on Metabolic Disorders
  • Kobayashi Foundation for Cancer Research
  • Princess Takamatsu Cancer Research Fund
  • Ono Pharmaceutical
  • Novartis Pharma
  • Pfizer Japan
  • Chugai Pharmaceutical
  • Eli Lilly Japan
  • Japan Society for the Promotion of Science (24K02459, 24K10137, 22KJ0489, 24K18933, 24K22071, 23K07303, 23K24337, 23K18234, 24K11153, 23KK0149, CREST, 22H04923)
  • Japan Science and Technology Agency (CREST, JPMJAX2321, JPMJFR2049)
  • Core Research for Evolutional Science and Technology
  • ACT-X
  • Fusion Oriented REsearch for disruptive Science and Technology
Topics
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
Keywords
tumor immune evasion, mitochondrial transfer, tumor microenvironment, tumor-infiltrating lymphocytes, mitochondrial DNA mutations, mitophagy, reactive oxygen species, T cell senescence, antitumor immunity, immune checkpoint inhibitors, melanoma, non-small cell lung cancer, prognostic factors
MeSH terms
Immune Checkpoint Inhibitors, Animals, Carcinoma, Non-Small-Cell Lung, DNA, Mitochondrial, Female, Humans, Lung Neoplasms, Male, Melanoma, Mitochondria, Mutation, Neoplasms, Prognosis, T-Lymphocytes, Lymphocytes, Tumor-Infiltrating, Cellular Senescence, Reactive Oxygen Species, Tumor Escape, Cell Line, Tumor, Mice, Immune Evasion, Tumor Microenvironment, Mitophagy

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