Thank you. Listen to this article using the player above. ✖

New Research Reveals Mitochondrial Transfer as Key Mechanism in Cancer Immune Evasion

The immune system plays a crucial role in detecting and destroying cancer cells. Cancer immunotherapy aims to harness the body’s immune cells to recognize and eliminate these threats. However, many cancers have evolved sophisticated mechanisms to evade immune surveillance, leading to treatment resistance. Understanding these evasion strategies is vital for developing more effective therapies.

The Tumor Microenvironment and Immune Evasion

The tumor microenvironment (TME) is the complex physiological space surrounding a tumor. It includes cancer cells, immune cells, and other factors that influence tumor growth and survival. Cancer cells often reprogram the TME to their advantage, weakening tumor-infiltrating lymphocytes (TILs), the immune cells that fight against tumors. Mitochondria, often referred to as the ‘powerhouse of the cell,’ play a significant role in these processes, yet the exact mechanisms are not fully understood.

Unraveling Mitochondrial Dysfunction in Cancer

A team of researchers led by Professor Yosuke Togashi from Okayama University has identified mitochondrial transfer as a key mechanism in immune evasion. Collaborating with colleagues from Okayama University and the Chiba Cancer Center Research Institute, the team published their findings online on January 22, 2025. According to Prof. Togashi, “Our research adds a new dimension to understanding how tumors resist immune responses, potentially leading to tailored approaches in cancer treatment.”

Mitochondrial Transfer and Cancer Cells

Mitochondria contain their own DNA (mtDNA), essential for energy production and transfer. Mutations in mtDNA can drive tumor growth and metastasis. In this study, researchers found that TILs from cancer patients harbored the same mtDNA mutations as the cancer cells. Analysis revealed that these mutations were associated with abnormal mitochondrial structures and dysfunction in TILs.

Tracking Mitochondria Between Cells

Using fluorescent markers, the researchers observed mitochondrial transfer between cancer cells and T cells. Mitochondria were found to move through direct cell-to-cell connections known as tunneling nanotubes and via extracellular vesicles. Upon entering T cells, the cancer-derived mitochondria gradually replaced the original T cell mitochondria, leading to a state called ‘homoplasmy.’

Inhibiting Mitophagy and Mitochondrial Dysfunction

Healthy TILs typically remove damaged mitochondria through a process called mitophagy. However, cancer-derived mitochondria resisted this process. The study discovered that mitophagy-inhibiting factors were also transferred, preventing mitochondrial breakdown. This led to mitochondrial dysfunction in TILs, characterized by reduced cell division, altered metabolism, increased oxidative stress, and impaired immune function. Mouse models showed that these dysfunctional TILs were resistant to immune checkpoint inhibitors.

Implications for Future Cancer Treatments

Identifying mitochondrial transfer as a novel immune evasion mechanism opens new avenues for improving cancer therapy. Blocking mitochondrial transfer could enhance immunotherapy effectiveness, particularly for patients with treatment-resistant cancers. By inhibiting this process, researchers hope to reduce the burden of cancer and improve patient outcomes.

Conclusion: Overcoming Immune Evasion

Current cancer treatments are not universally effective, and new therapies are needed to overcome resistance mechanisms. Developing drugs that inhibit mitochondrial transfer between cancer cells and immune cells could enhance immunotherapies, providing personalized treatment options for patients facing resistant cancers.

Prof. Togashi concludes, “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: Ikeda H, Kawase K, Nishi T, et al. Immune evasion through mitochondrial transfer in the tumour microenvironment. Nature. 2025. doi: 10.1038/s41586-024-08439-0