Another Cancer Mechanism Uncovered: Mitochondrial Transfer for Immune Evasion

• Cancer, despite being under the immune system's constant surveillance, continues to survive by developing immune evasion mechanisms (see The 14 Hallmarks of Cancer).
• One such mechanism is immune suppression through mitochondrial transfer in the tumor microenvironment.
• A notable study published on 22 January 2025 in Nature reveals that the transfer of mitochondria from cancer cells to T lymphocytes weakens the immune system's ability to fight cancer.
• This discovery could pave the way for new approaches to improve the effectiveness of immunotherapies.

Mitochondrial Transfer and Metabolic Dysfunction in TILs (Tumor-Infiltrating Lymphocytes)

Mitochondria are the cell's energy-producing organelles, responsible for ATP synthesis. They have a double membrane, contain their own DNA and regulate cellular metabolism.

Cancer cells use several mechanisms to suppress the immune system in the tumor microenvironment. One is the transfer of mitochondria to TILs. Analyses show that mitochondrial DNA (mtDNA) mutations are shared between TILs and cancer cells. These mutated mitochondria transferred to T lymphocytes cause metabolic dysfunction and loss of function in T cells.

This phenomenon leads to an imbalance in cellular energy and increased oxidative stress. T lymphocytes, already experiencing an energy shortage in the tumor environment, become further functionally suppressed. Experiments show that this mitochondrial transfer occurs through two main mechanisms: the formation of tunneling nanotubes (TNTs) and exosome-mediated mitochondrial transfer.

Weakened Immune Function

Mitochondria from tumor cells replace the native mitochondria in immune cells, causing a "homoplasmic shift." Normally, a mechanism known as mitophagy removes old or damaged mitochondria from T lymphocytes. However, mitochondria from cancer cells have become resistant to mitophagy.

A key factor behind the inhibition of mitophagy is the transfer of mitophagy-suppressing molecules such as USP30 along with mitochondria from cancer cells. These molecules increase mitochondrial dysfunction and cause T lymphocytes to lose their function. As a result, T lymphocytes either lose function or become fully senescent, making it easier for cancer to evade the immune system.

Clinical Implications and New Targets for Immunotherapy

This study shows that mitochondrial transfer may adversely affect patients' responses to immunotherapy. In samples from patients with melanoma and non-small cell lung cancer, the presence of mtDNA mutations was associated with a poor response to immunotherapy.

What Benefits Could This Discovery Offer?

1. Blocking Mitochondrial Transfer: Drugs targeting mitochondrial transfer mechanisms could help preserve the immune competence of TILs.

2. Promoting Mitophagy Activation: Treatments could be developed to suppress molecules that inhibit mitophagy, such as USP30.

3. Restoring Energy Metabolism: Nutritional supplements or drugs that increase the metabolic resilience of T lymphocytes could improve the effectiveness of immunotherapies.

Conclusion

Understanding how cancer evades the immune system is critical to developing new treatment strategies. Newly discovered mechanisms such as mitochondrial transfer offer potential targets that could make cancer immunotherapies more effective. In the future, new treatments focusing on these mechanisms may enable the immune systems of people with cancer to function more effectively.