How Cancer Outsmarts Your Immune System: The Role of Mitochondrial Hijacking

Imagine your immune system trying to fight off cancer. Normally, your T cells are like soldiers, ready to attack and destroy cancer cells. But cancer cells have sneaky ways to avoid being attacked. They change the environment around them and disrupt the mitochondria—the energy factories—in your immune cells, particularly in tumor-infiltrating lymphocytes (TILs). This makes it harder for your immune system to do its job.

Now picture this: the cancer cells’ mitochondria, which may carry harmful mutations in their DNA, can actually transfer to your T cells. Typically, your T cells can get rid of damaged mitochondria through a process called mitophagy, triggered by harmful byproducts called reactive oxygen species. But cancer mitochondria come equipped with special molecules that prevent this cleanup process. These molecules stick to the cancer mitochondria and hitch a ride into your T cells, replacing your healthy mitochondria.

When your T cells take on these faulty mitochondria, they start to malfunction. They lose energy, stop working properly, and can no longer "remember" how to fight the cancer effectively. This weakens your immune system’s ability to attack the tumor. If your tumor has these mitochondrial DNA mutations, treatments like immune checkpoint inhibitors might not work as well, especially if you have melanoma or non-small-cell lung cancer.

This discovery shows you how cancer can trick your immune system in ways scientists didn’t fully understand before. Knowing this could lead to new, better treatments that help your immune system fight back.

In the study linked below, researchers looked at tissue samples from patients and found that the mitochondria in TILs sometimes carry the same DNA mutations as the cancer cells. The researchers also found that if a patient’s tumor has these mitochondrial DNA mutations, treatments like immune checkpoint inhibitors may not work as well, especially for melanoma or non-small-cell lung cancer.

These findings uncover a new way that cancer tricks the immune system and could help scientists develop better cancer treatments in the future.

From text: Fig. 5: mtDNA-mutated mitochondrial transfer reduces antitumour immunity in vivo.

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