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Business Standard
08-07-2025
- Health
- Business Standard
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 New Delhi 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.
Newsweek
07-07-2025
- Health
- Newsweek
Evolution: Single Mutation May Explain Humans' Higher Cancer Risk
Based on facts, either observed and verified firsthand by the reporter, or reported and verified from knowledgeable sources. Newsweek AI is in beta. Translations may contain inaccuracies—please refer to the original content. A newly discovered genetic mutation unique to humans may help explain why we are significantly more vulnerable to cancer than our closest evolutionary relatives. Researchers at the University of California, Davis, identified a single amino acid change in a key immune system protein—dubbed "Fas Ligand" (FasL)—that appears to give solid tumors in humans a biological loophole, allowing them to evade immune attack. The same vulnerability is not present in chimpanzees or other non-human primates, the team report. "The evolutionary mutation in FasL may have contributed to the larger brain size in humans," said lead author Jogender Tushir-Singh, an associate professor of medical microbiology and immunology at UC Davis. "But in the context of cancer, it was an unfavorable tradeoff because the mutation gives certain tumors a way to disarm parts of our immune system." 3d rendering DNA and flying molecule cells on microscope background, Depth Of Field. 3d rendering DNA and flying molecule cells on microscope background, Depth Of Field. mustafaU Fas Ligand plays a critical role in the immune system's ability to kill cancer cells. Found on the surface of immune cells—including the CAR-T cells used in cutting-edge cancer therapies—FasL triggers a process known as apoptosis, or programmed cell death, in target cells. The team's investigation reveals that in humans, a single amino acid substitution—from proline to serine at position 153—renders FasL vulnerable to plasmin, an enzyme frequently elevated in aggressive solid tumors like ovarian, colon and triple-negative breast cancers. When plasmin cleaves FasL, it effectively disarms one of the immune system's key cancer-fighting tools, allowing tumors to grow and spread despite an active immune response. This mechanism may help explain why immunotherapies like CAR-T cells, which have revolutionized treatment for blood cancers, often struggle to achieve similar success with solid tumors. Solid tumors create a hostile microenvironment that actively neutralizes FasL using plasmin, the researchers explained. In blood cancers, where plasmin isn't a major factor, immune cells retain more of their killing power. The team also found that blocking plasmin or modifying FasL to resist cleavage can restore its tumor-killing ability, potentially improving the effectiveness of immunotherapy for solid tumors. These findings open up new possibilities for enhancing immune-based treatments using plasmin inhibitors or engineered antibodies that shield FasL from degradation. This could help us overcome one of the key reasons why immune therapies work well in leukemia or lymphoma but have limited success in solid tumors. While the mutation in FasL may have weakened immune defenses against cancer, the researchers speculate that it may also have been tied to benefits during human evolution—possibly linked to the development of a larger brain. Such evolutionary tradeoffs, the study suggests, might help explain why cancer rates are significantly higher in humans compared to chimpanzees, despite our shared genetic ancestry. "There is a lot that we do not know and can still learn from primates and apply to improve human cancer immunotherapies," said Tushir-Singh. "Regardless, this is a major step toward personalizing and enhancing immunotherapy for the plasmin-positive cancers that have been difficult to treat." Researchers are now exploring clinical strategies to apply these findings. Trials investigating the use of plasmin inhibitors in combination with CAR-T or T-cell therapies for solid tumors may be on the horizon. Do you have a tip on a science story that Newsweek should be covering? Do you have a question about science? Let us know via health@ Reference Chen, G., Tat, T., Zhou, Y., Duan, Z., Zhang, J., Scott, K., Zhao, X., Liu, Z., Wang, W., Li, S., Cross, K. A., & Chen, J. (2025). Neural network-assisted personalized handwriting analysis for Parkinson's disease diagnostics. Nature Chemical Engineering, 2(6), 358–368.
