Cancer Cells Trick the Immune System by Altering Mitochondria

The immune system plays a key role in detecting and destroying cancer cells. Cancer immunotherapy works by programming immune cells to recognize and eliminate cancer cells. However, many cancers can escape immune surveillance through various mechanisms, resulting in resistance to treatment. This highlights the need to better understand the molecular processes that enable immune evasion.

The tumor microenvironment (TME)—the space surrounding a tumor—plays a critical role in interactions between cancer and immune cells. Cancer cells can reshape the TME to their advantage, weakening tumor-infiltrating lymphocytes (TILs), the immune cells that attack tumors. Mitochondria, also known as the ‘powerhouse of the cell,’ are small organelles that produce energy for various cellular processes. They play a significant role in the metabolic reprogramming of cancer cells and TILs. However, precise mechanisms underlying mitochondrial dysfunction and its impact on the TME are poorly understood.

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.

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: 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

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