Scientists uncover how cancer cells hijack T-cells, making it harder for the body to fight back

Researchers have discovered a surprising way cancer evades the immune system. It essentially hacks the immune cells, transferring its own faulty mitochondrial DNA (mtDNA) into the T-cells meant to attack it.

This sneaky move weakens the immune cells, making them less effective at stopping the tumor. The findings could help explain why some cancer treatments, like immunotherapy, are effective for some patients but not others.

In the study, "Immune evasion through mitochondrial transfer in the tumour microenvironment," published in Nature, the multi-group collaboration looked at how cancer cells interact with tumor-infiltrating lymphocytes, a type of T-cell that typically fights tumors. The research is also featured in a News and Views piece.

Clinical specimens from melanoma and non-small-cell lung cancer patients were analyzed for mtDNA mutations. Mitochondrial transfer was studied using mitochondrial-specific fluorescent reporters and multiple in vitro and in vivo models. Tumor-infiltrating lymphocyte functions, metabolic profiles, and responses to immune checkpoint inhibitors were evaluated.

Melanoma and lung sample analysis showed that mitochondria, the energy-making engines of cells, could jump from cancer cells into T-cells. These transferred mitochondria carried functional errors in their DNA that interfered with the T-cells' energy production and function processes.

Mitochondria are essential for powering cells, including T-cells, which depend heavily on energy production to fight cancer. But when cancer cells pass on their defective mitochondria, they lose their ability to function properly, throttling the energy of the T-cells and causing them to become exhausted.

Transfer was observed in two main ways: tunneling nanotubes and extracellular vesicles. The nanotubes extend out and tunnel into the T-cell, creating tiny passages between cells that deliver mitochondria directly. Extracellular vesicles form as bubbles released by the cancer cells, encapsulating mtDNA and other molecules.

Once inside the T-cells, the damaged mitochondria replace the healthy ones through a mechanism that would normally operate in reverse, where healthy mitochondria would migrate to replace damaged ones. The study found that cancer cells protect their transferred mitochondria by attaching molecules that prevent the T-cells from breaking them down.

Immune checkpoint inhibitors have revolutionized cancer treatment. But not everyone responds well to these drugs. This study found that patients whose tumors had more mitochondrial mutations were less likely to benefit from checkpoint inhibitors, likely because the mitochondrial hack already compromised their T-cells.

Researchers blocked extracellular vesicle release from cancer cells using a compound called GW4869, which inhibits the production of small extracellular vesicle-like exosomes. Applying this inhibitor in their models showed a significant reduction in mitochondrial transfer from cancer cells to T-cells. This intervention helped prevent the T-cells from taking up damaged mitochondria, reducing their dysfunction.

As a result, T-cells showed improved energy production, reduced markers of exhaustion, and a better ability to perform their immune functions. The blocking strategy restored the effectiveness of immune checkpoint inhibitors, particularly in tumors with high levels of mitochondrial transfer. These findings suggest that targeting extracellular vesicles could be a promising strategy to counteract cancer's immune-evasion tactic.
Typically, science works in small, iterative steps toward discovery, with each new element of knowledge putting a piece of the larger puzzle into place. This discovery helps explain why some treatments are ineffective and discovers the mechanism behind their ineffectiveness. Remarkably, it also found a potential solution, representing a significant leap for future research to build from.

Hideki Ikeda et al, Immune evasion through mitochondrial transfer in the tumour microenvironment, Nature (2025). DOI: 10.1038/s41586-024-08439-0

Jonathan R. Brestoff, Mitochondrial swap from cancer to immune cells thwarts anti-tumour defences, Nature (2025). DOI: 10.1038/d41586-025-00077-4