Immune evasion through mitochondrial transfer in the tumour microenvironment

Cancer cells in the tumour microenvironment use various mechanisms to evade the immune system, particularly T cell attack<sup>1</sup>. For example, metabolic reprogramming in the tumour microenvironment and mitochondrial dysfunction in tumour-infiltrating lymphocytes (TILs) impair antitumour immune responses<sup>2-4</sup>. 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.

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Publication Details

Journal
Nature
Published
2025-01-22
DOI
https://doi.org/10.1038/s41586-024-08439-0
Citations
195
Primary Topic
Immune cells in cancer
Type
article
Field-Weighted Citation Impact
155.51

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article

Immune evasion through mitochondrial transfer in the tumour microenvironment

Hideki Ikeda, Takamasa Ishino, Yoshiyasu Umeda, Jason Lin et al.
195 citations
Nature
Immune cells in cancer
155.51
article

Immune evasion through mitochondrial transfer in the tumour microenvironment

Hideki Ikeda, Takamasa Ishino, Yoshiyasu Umeda, Jason Lin, Yukiko Kiniwa, Toyoyuki Hanazawa, Tsuyoshi Osawa, Katsushige Kawase, Shinichi Toyooka, Yusuke Suenaga, Takao Morinaga, Masahito Kawazu, Yosuke Togashi, Hidetoshi Hayashi, Takashi Inozume, Youki Ueda, Takehiro Ohnuma, Yasuhiro Nakamura, Keizo Takenaga, Tatsuyoshi Kawamura, Eiki Ichihara, Tomofumi Watanabe, Shinichiro Suzuki, Sho Aki, Shusuke Kawashima, Yasutoshi Tatsumi, Hideki Makinoshima, Joji Nagasaki, Akiko Honobe‐Tabuchi, Hiroyuki Mano, Makiko Itami, Yuki Nakamura, Takuji Suzuki, Tatsuya Nishi, Jun‐ichiro Ikeda
article en
195 citations

Abstract

Cancer cells in the tumour microenvironment use various mechanisms to evade the immune system, particularly T cell attack<sup>1</sup>. For example, metabolic reprogramming in the tumour microenvironment and mitochondrial dysfunction in tumour-infiltrating lymphocytes (TILs) impair antitumour immune responses<sup>2-4</sup>. 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.

NatureVol. 638(8049)
Shinshu University (JP), Chiba University (JP), Okayama University (JP), National Cancer Centre Japan (JP), Okayama University Hospital (JP), Chiba Cancer Center (JP), National Institute of Technology, Tsuruoka College (JP), University of Yamanashi (JP), The University of Tokyo (JP), Saitama Medical University (JP), Kindai University (JP), Kumamoto University (JP)
Bristol-Myers Squibb, Eli Lilly and Company, Pfizer, AstraZeneca, Nvidia, Suzuken Memorial Foundation, Japan Agency for Medical Research and Development, 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, Japan Science and Technology Agency, Core Research for Evolutional Science and Technology, ACT-X
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