Researchers identify mitochondrial transfer between cancer and immune cells as a crucial mechanism for immune evasion.
The immune system is essential for identifying and eliminating cancer cells. Cancer immunotherapy enhances this process by training immune cells to recognize and attack tumors. However, many cancers develop mechanisms to evade immune detection, leading to resistance to treatment. Understanding the molecular basis of this immune evasion is crucial for improving therapeutic strategies.
The tumor microenvironment (TME)—the area surrounding a tumor—plays a pivotal role in interactions between cancer and immune cells. Cancer cells can manipulate the TME to suppress tumor-infiltrating lymphocytes (TILs), the immune cells responsible for attacking tumors. Mitochondria, often called the “powerhouse of the cell,” generate energy for various cellular functions and play a key role in the metabolic reprogramming of both cancer cells and TILs. However, the exact mechanisms of mitochondrial dysfunction and its impact on the TME remain poorly understood.
New Research on Mitochondrial Dysfunction in Cancer
To address this knowledge gap, a team of researchers led by Professor Yosuke Togashi from Okayama University, Japan, has uncovered novel insights into mitochondrial dysfunction in cancer immune evasion. Working alongside Tatsuya Nishi and Tomofumi Watanabe from Okayama University, as well as Hideki Ikeda, Katsushige Kawase, and Masahito Kawazu from the Chiba Cancer Center Research Institute, the team identified mitochondrial transfer as a key mechanism of immune evasion. This study was published online in Nature on January 22, 2025.
Prof. Togashi explains, “We have discovered mitochondrial transfer as one of the key mechanisms of immune evasion. Our research adds a new dimension to the understanding of how tumors resist immune responses, potentially leading to the development of more comprehensive and tailored approaches in treating different cancers.”
Mitochondria carry their own DNA (mtDNA), which encodes proteins crucial for energy production and transfer. However, mtDNA is prone to damage, and mutations in mtDNA can promote tumor growth and metastasis. In this study, the researchers examined TILs from patients with cancer and found that they contained the same mtDNA mutations as the cancer cells. Further analysis revealed that these mutations were linked to abnormal mitochondrial structures and dysfunction in TILs.
Using a fluorescent marker, the researchers tracked mitochondrial movement between cancer cells and T cells. They found that mitochondria were transferred via direct cell-to-cell connections called tunneling nanotubes, as well as through extracellular vesicles. Once inside T cells, the cancer-derived mitochondria gradually replaced the original T cell mitochondria, leading to a state called ‘homoplasmy,’ where all mtDNA copies in the cell are identical.
How Cancer Cells Protect Transferred Mitochondria
Normally, damaged mitochondria in TILs are removed through a process called mitophagy. However, mitochondria transferred from cancer cells appeared to resist this degradation. The researchers discovered that mitophagy-inhibiting factors were co-transferred with the mitochondria, preventing their breakdown. As a result, TILs experienced mitochondrial dysfunction, leading to reduced cell division, metabolic changes, increased oxidative stress, and impaired immune response. In mouse models, these dysfunctional TILs also showed resistance to immune checkpoint inhibitors, a type of immunotherapy.
By identifying mitochondrial transfer as a novel immune evasion mechanism, this study opens new possibilities for improving cancer treatment. Blocking mitochondrial transfer could enhance immunotherapy response, particularly in patients with treatment-resistant cancers.
Cancer therapies often involve high costs and significant side effects, particularly when they are ineffective. Enhancing the success of immunotherapy by inhibiting mitochondrial transfer could reduce the burden of cancer and improve patient outcomes.
Prof. Togashi concludes by saying, “Existing cancer treatments are not universally effective, and there is a pressing need for new therapies that can overcome resistance mechanisms. Developing drugs that inhibit mitochondrial transfer between cancer cells and immune cells may enhance the efficacy of immunotherapies, thereby providing personalized treatment options for patients with cancers that are resistant to current therapies.”
This discovery offers exciting new insights into cancer biology and could pave the way for more effective therapies in the future.
Reference: “Immune evasion through mitochondrial transfer in the tumour microenvironment” by 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, 22 January 2025, Nature.
DOI: 10.1038/s41586-024-08439-0
Funding: Grants-in-Aid for Scientific Research, Challenging Exploratory Research, Grant-in-Aid for Research Fellow from the Japan Society for the Promotion of Science, Project for Cancer Research and Therapeutic Evolution, Practical Research for Innovative Cancer Control, Core Research for Evolutional Science and Technology, Practical Research Project for Rare/Intractable Diseases, Research Program for Hepatitis from the Japan Agency for Medical Research and Development, Fusion Oriented Research for disruptive Science and Technology, ACT-X from the Japan Science and Technology Agency, National Cancer Center Research and Development Fund, Chiba Prefecture Research Grant, Takeda Science Foundation, Naito Foundation, Mochida Memorial Foundation, MSD Life Science Foundation, GSK Japan foundation, Research Grant of the Princess Takamatsu Cancer Research Fund, Kowa Life Science Foundation, Kato Memorial Bioscience Foundation, Inamori Foundation, Astellas Foundation for Research on Metabolic Disorders, Suzuken Memorial Foundation, SGH Foundation, Sumitomo Foundation Grant for Basic Science Research Projects, Terumo Life Science Foundation, Chugai Foundation for Innovative Drug Discovery Science, The Ono Pharmaceutical Foundation for Oncology, Immunology, and Neurology, Kobayashi Foundation for Cancer Research, Taiju Life Social Welfare Foundation, 2023 Healthcare Innovation Research Grant established with donations from T. Togawa, Sequencing and bioinformatics analyses were performed on institutional computing resources that included hardware provided by NVIDIA
Never miss a breakthrough: Join the SciTechDaily newsletter.
Follow us on Google and Google News.