Immune evasion through mitochondrial transfer in the tumour microenvironment

Hideki Ikeda, Katsushige Kawase, Tatsuya Nishi, Tomofumi Watanabe, Keizo Takenaga, Takashi Inozume, Takamasa Ishino, Sho Aki, Jason Lin, Shusuke Kawashima, Joji Nagasaki, Youki Ueda, Shinichiro Suzuki, Hideki Makinoshima, Makiko Itami, Yuki Nakamura, Yasutoshi Tatsumi, Yusuke Suenaga, Takao Morinaga, Akiko Honobe-Tabuchi, Takehiro Ohnuma, Tatsuyoshi Kawamura, Yoshiyasu Umeda, Yasuhiro Nakamura, Yukiko Kiniwa, Eiki Ichihara, Hidetoshi Hayashi, Jun-ichiro Ikeda, Toyoyuki Hanazawa, Shinichi Toyooka, Hiroyuki Mano, Takuji Suzuki, Tsuyoshi Osawa, Masahito Kawazu and Yosuke Togashi ()
Additional contact information
Hideki Ikeda: Chiba Cancer Center Research Institute
Katsushige Kawase: Chiba Cancer Center Research Institute
Tatsuya Nishi: Okayama University
Tomofumi Watanabe: Okayama University
Keizo Takenaga: Chiba Cancer Center Research Institute
Takashi Inozume: Chiba Cancer Center Research Institute
Takamasa Ishino: Chiba Cancer Center Research Institute
Sho Aki: The University of Tokyo
Jason Lin: Chiba Cancer Center Research Institute
Shusuke Kawashima: Chiba Cancer Center Research Institute
Joji Nagasaki: Chiba Cancer Center Research Institute
Youki Ueda: Okayama University
Shinichiro Suzuki: Kindai University Faculty of Medicine
Hideki Makinoshima: National Cancer Center
Makiko Itami: Chiba Cancer Center
Yuki Nakamura: Chiba Cancer Center Research Institute
Yasutoshi Tatsumi: Chiba Cancer Center Research Institute
Yusuke Suenaga: Chiba Cancer Center Research Institute
Takao Morinaga: Chiba Cancer Center Research Institute
Akiko Honobe-Tabuchi: University of Yamanashi
Takehiro Ohnuma: University of Yamanashi
Tatsuyoshi Kawamura: University of Yamanashi
Yoshiyasu Umeda: Saitama Medical University International Medical Center
Yasuhiro Nakamura: Saitama Medical University International Medical Center
Yukiko Kiniwa: Shinshu University School of Medicine
Eiki Ichihara: Okayama University Hospital
Hidetoshi Hayashi: Kindai University Faculty of Medicine
Jun-ichiro Ikeda: Chiba University
Toyoyuki Hanazawa: Chiba University Graduate School of Medicine
Shinichi Toyooka: Okayama University
Hiroyuki Mano: National Cancer Center Research Institute
Takuji Suzuki: Chiba University
Tsuyoshi Osawa: The University of Tokyo
Masahito Kawazu: Chiba Cancer Center Research Institute
Yosuke Togashi: Chiba Cancer Center Research Institute

Nature, 2025, vol. 638, issue 8049, 225-236

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41586-024-08439-0

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