2. Academic Validation
  3. Immune evasion through mitochondrial transfer in the tumour microenvironment

Immune evasion through mitochondrial transfer in the tumour microenvironment

  • Nature. 2025 Feb;638(8049):225-236. doi: 10.1038/s41586-024-08439-0.
Hideki Ikeda 1 2,  Katsushige Kawase 1 3,  Tatsuya Nishi 4 5,  Tomofumi Watanabe 4 6,  Keizo Takenaga 7,  Takashi Inozume 1 8 9,  Takamasa Ishino 1 4 10,  Sho Aki 11 12,  Jason Lin 1,  Shusuke Kawashima 1 8,  Joji Nagasaki 1 4,  Youki Ueda 4,  Shinichiro Suzuki 13,  Hideki Makinoshima 14,  Makiko Itami 15,  Yuki Nakamura 1,  Yasutoshi Tatsumi 1 16,  Yusuke Suenaga 17,  Takao Morinaga 1,  Akiko Honobe-Tabuchi 9,  Takehiro Ohnuma 9 18,  Tatsuyoshi Kawamura 9,  Yoshiyasu Umeda 19,  Yasuhiro Nakamura 19,  Yukiko Kiniwa 20,  Eiki Ichihara 5,  Hidetoshi Hayashi 13,  Jun-Ichiro Ikeda 21,  Toyoyuki Hanazawa 3,  Shinichi Toyooka 22,  Hiroyuki Mano 23,  Takuji Suzuki 2 24,  Tsuyoshi Osawa 11 12 25,  Masahito Kawazu 1 23,  Yosuke Togashi 26 27 28 29
Affiliations

Affiliations

  • 1 Division of Cell Therapy, Chiba Cancer Center Research Institute, Chiba, Japan.
  • 2 Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan.
  • 3 Department of Otorhinolaryngology/Head and Neck Surgery, Chiba University Graduate School of Medicine, Chiba, Japan.
  • 4 Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
  • 5 Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama, Japan.
  • 6 Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
  • 7 Division of Innovative Cancer Therapeutics, Chiba Cancer Center Research Institute, Chiba, Japan.
  • 8 Department of Dermatology, Graduate School of Medicine, Chiba University, Chiba, Japan.
  • 9 Department of Dermatology, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan.
  • 10 Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan.
  • 11 Division of Nutriomics and Oncology, RCAST, The University of Tokyo, Tokyo, Japan.
  • 12 Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan.
  • 13 Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka, Japan.
  • 14 Tsuruoka Metabolomics Laboratory, National Cancer Center, Yamagata, Japan.
  • 15 Department of Surgical Pathology, Chiba Cancer Center, Chiba, Japan.
  • 16 Laboratory of Pediatric and Refractory Cancer, Chiba Cancer Center Research Institute, Chiba, Japan.
  • 17 Laboratory of Evolutionary Oncology, Chiba Cancer Center Research Institute, Chiba, Japan.
  • 18 Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
  • 19 Department of Skin Oncology/Dermatology, Saitama Medical University International Medical Center, Saitama, Japan.
  • 20 Department of Dermatology, Shinshu University School of Medicine, Nagano, Japan.
  • 21 Department of Diagnostic Pathology, Graduate School of Medicine, Chiba University, Chiba, Japan.
  • 22 Department of General Thoracic Surgery and Endocrinological Surgery, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
  • 23 Division of Cellular Signalling, National Cancer Center Research Institute, Tokyo, Japan.
  • 24 Synergy Institute for Futuristic Mucosal Vaccine Research and Development, Chiba University, Chiba, Japan.
  • 25 Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo, Japan.
  • 26 Division of Cell Therapy, Chiba Cancer Center Research Institute, Chiba, Japan. [email protected].
  • 27 Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan. [email protected].
  • 28 Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama, Japan. [email protected].
  • 29 Faculty of Medicine, Kindai University, Osaka, Japan. [email protected].
PMID: 39843734 DOI: 10.1038/s41586-024-08439-0
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.

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