Summary

Cancer cells avoid being killed by using immune evasion, allowing tumor cells to grow unchecked in cancer patients

Immune evasion is a strategy used by tumor cells to avoid detection and elimination by the immune system, and is a predominant characteristic of most cancers. For example, in non-small cell lung cancer, ovarian cancer, and colorectal cancer more than 80% of tumors exhibited multiple immune-escape factors (1).

A subset of immune cells (T-cells) in the tumor microenvironment are normally active in killing and suppressing tumor growth. Ikeda et al.’ in a 2025 article published in the journal Nature demonstrates a novel mechanism of immune evasion in the tumor microenvironment (2). Cancer cell mitochondria with inhibitory DNA mutations are transferred to T cells resulting in suppression of their function.

Immune evasion and cancer

Tumors employ multiple mechanisms to suppress the immune system and evade destruction. These mechanisms involve various cell types and molecular factors within the tumor microenvironment.

Molecular Mechanisms include

  • Expression of non-classical MHC class I molecules that suppress immune response
  • Production of immunosuppressive factors
  • Expression of inhibitory ligands for receptors on T cells
  • Metabolic reprogramming

Understanding these complex mechanisms of immune suppression is crucial for developing effective immunotherapies and overcoming resistance to current treatments.

What is mitochondrial transfer?

Mitochondria are essential organelles and the main energy source for cellular processes. They have bacteria-like appearance and contain their own genetic material (DNA).

Mitochondrial transfer is a process where mitochondria are moved from one cell to another. The mechanisms of mitochondrial transfer between cells are well known. The key mechanisms include:

  1. Tunneling Nanotubes: These are thin, tube-like structures that connect cells and allow for the transfer of cellular components, including mitochondria.
  2. Cell-to-Cell Fusion: This involves the merging of two cells, resulting in the exchange of cellular components.
  3. Extracellular Vesicle Transfer: Extracellular vesicles released by cells, can carry mitochondria and transfer them to recipient cells.
  4. Gap Junction Channels: These are specialized channels that allow for direct communication between adjacent cells.

Consequences of mitochondrial transfer from cancer cells to immune cells

Research by Ikeda et al. discover a previously unknown immune-evasion mechanism of cancer cells that uses mitochondrial transfer.

Major findings

  1. Transfer of mutated mitochondrial DNA from cancer cells causes mitochondrial dysfunction in T cells.
  2. T-cells that acquire mutated mitochondrial DNA from cancer cells exhibit multiple abnormalities that inhibit their function.
  3. Mutated mitochondria DNA transferred from cancer cells to tumor infiltrating lymphocytes can reduce antitumor immunity, through T cell dysfunction in vivo.
  4. Initially, scientists analyzed tumor cells from cancer patients and found DNA changes (mutations) in cancer cells mitochondria match those found in immune cells (T cells).
  5. Mutated mitochondria in cancer cells have impaired function.
  6. Mitochondria from cancer cells are able to transfer to T cells found in tumors (tumor-infiltrating T-cells.
  7. Tumor-infiltrating T cells acquire mitochondrial DNA mutations from cancer cells through the formation of tunneling nanotubes, and extracellular vesicles.
  8. Clinical data from melanoma and non-small-cell lung cancer samples showed that the presence of mitochondrial DNA mutations is a poor prognostic factor for immuno- therapies but not for chemotherapies alone.

 
These findings demonstrate tumor cells can shut down attacking immune cells by filling them with mutant mitochondria, resulting in immune evasion in cancer patients. A major question is will these findings contribute to the development of future cancer immunotherapies

Looking ahead. Is it worth considering blocking mitochondrial transfer as a therapeutic approach for treating cancer?

Surprisingly, the answer is yes. There are drugs that inhibit mitochondrial transfer by blocking tunneling nanotubes. Some key examples include F-actin depolymerizing compounds such as Cytochalasin D and Latrunculin-B that completely block tunneling nanotube formation (3). Although the idea has yet to be tested, inhibiting transfer of mutant mitochondria from cancer cells to T-cells has the potential to help prevent immune evasion.

References

  1. Waldman, A.D., Fritz, J.M. & Lenardo, M.J. A guide to cancer immunotherapy: from T cell basic science to clinical practice. Nat Rev Immunol 20, 651–668 (2020).

  2. Ikeda, H., Kawase, K., Nishi, T. et al. Immune evasion through mitochondrial transfer in the tumour microenvironment. Nature 638, 225–236 (2025). https://doi.org/10.1038/s41586-024-08439-0

  3. Dilsizoglu Senol, A., Pepe, A., Grudina, C. et al. Effect of tolytoxin on tunneling nanotube formation and function. Sci Rep 9, 5741 (2019). https://doi.org/10.1038/s41598-019-42161-6

Disclaimer: This information is intended solely for research purposes and does not serve as medical advice.

 

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