Could this tiny genetic mutation be making humans more prone to cancer?

A mutation in the immune protein FasL may make humans more vulnerable to solid tumours, but scientists say it could be fixed through combination immunotherapy

A genetic mutation in humans may be making our immune system less effective at fighting solid tumours, according to a new study.

 

The study, titled Evolutionary regulation of human Fas ligand (CD95L) by plasmin in solid cancer immunotherapy, published in Nature Communications by scientists at the University of California, Davis, has identified a small but significant change in the immune protein Fas Ligand (FasL) that does not exist in non-human primates.

 

This mutation makes FasL vulnerable to being disabled by plasmin, an enzyme commonly found in aggressive cancers like ovarian, colon, and breast tumours. The study may help explain why immunotherapy works better for blood cancers and opens the door for new, more effective treatments for solid tumours.

What did the study find about humans and cancer risk?

The study revealed that humans have a specific genetic mutation in a protein called Fas Ligand (FasL), which plays a key role in how immune cells kill cancer cells. Unlike non-human primates, humans have a serine amino acid at position 153 in FasL, instead of the DNA-encoded amino acid proline.

 

This tiny difference makes the human version of FasL vulnerable to attack by plasmin, an enzyme commonly found in aggressive solid tumours. Once plasmin cuts FasL, it loses its cancer-killing ability. This vulnerability does not exist in our primate cousins, who seem to have natural protection.

 

FasL helps immune cells, especially CAR-T cells and T-cells, kill cancer cells by triggering a self-destruct process called apoptosis. But when FasL is cut by plasmin, its power is neutralised, and the immune attack weakens.

 

Solid tumours like ovarian, breast, and colon cancers often produce high levels of plasmin, which allows them to disarm FasL and escape immune destruction. This might explain why T-cell therapies work well in blood cancers but fail to perform against solid tumours.

 

According to the researchers, this evolutionary change may have helped humans develop larger brains, but it came with an unintended cost: a higher risk of developing cancer.

Can this genetic weakness be overcome?

The researchers said in the study that they found blocking plasmin or protecting FasL from plasmin’s attack can restore its cancer-killing power. They successfully used plasmin inhibitors and specially designed antibodies to prevent FasL from being cut.

 

According to the study, this opens the door to new combination therapies where existing immunotherapies could be paired with plasmin blockers to improve outcomes in patients with solid tumours. The findings suggest that personalised immunotherapy could be developed for solid tumours by adding a new layer of protection for FasL. By targeting the plasmin–FasL interaction, doctors might make CAR-T and T-cell therapies more effective against stubborn cancers that have so far resisted these treatments.

 

The study highlighted that humans have a higher cancer rate not just due to lifestyle factors but also because of evolutionary differences in our immune system. Learning from how primates naturally resist some cancers could help scientists design smarter, more durable cancer treatments for humans. 

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