Why Humans Are More Susceptible to Cancer

Despite sharing over 98% of our genome with non-human primates, humans are far more prone to developing cancers.

Researchers at the University of California Davis Comprehensive Cancer Center have uncovered an evolutionary change that may explain why human immune cells are less effective at combating solid tumors compared to our closest living ancestors.

The study, recently published in Nature Communications, explains this discovery and its implications for cancer treatment.

Immunotherapy’s struggles with solid tumors

Immunotherapies have revolutionized cancer treatment, especially in hematological cancers, where they effectively activate the immune system to target tumor cells. However, they face significant challenges in treating solid tumors. Factors such as T-cell activation issues and the tumor microenvironment inhibit immune cell infiltration, allowing tumors to evade detection.

One strategy to overcome these challenges involves targeting death receptors, including Fas (CD95), which is essential for apoptosis (cell death). Fas signaling, particularly through Fas ligand (FasL) on chimeric antigen receptor (CAR) T cells, has shown promise for triggering the death of tumor cells, even in cases where tumors evade antigen detection. However, its efficacy in solid tumors remains uncertain, and understanding how FasL is regulated could unlock better T-cell therapies.

FasL is a membrane protein on immune cells that plays a role in apoptosis, enabling immune cells, including CAR T cells, to kill cancer cells.

The UC Davis research team has identified a small genetic mutation in FasL that may explain why humans struggle to target solid tumors effectively. This mutation makes FasL more susceptible to deactivation by plasmin, a tumor-associated enzyme. This vulnerability is exclusive to humans and is absent in non-human primates, like chimpanzees.

"The evolutionary mutation in FasL may have contributed to the larger brain size in humans,” said Dr. Jogender Tushir-Singh,  senior author for the study and an associate professor in the Department of Medical Microbiology and Immunology. “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.”

Tumor environment neutralizes FasL protein

The researchers pinpointed a critical amino acid change in FasL – serine replacing proline at position 153 – which makes the protein more vulnerable to cleavage by plasmin in humans.

Plasmin, a protease enzyme, is often elevated in aggressive solid tumors, such as triple-negative breast cancer, colon cancer and ovarian cancer.

This increased plasmin activity can neutralize FasL, even when immune cells are activated and primed to attack tumors. As a result, FasL's ability to trigger tumor cell death is compromised, reducing the effectiveness of immunotherapies.

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This discovery helps explain why T-cell therapies are successful in blood cancers but less effective in solid tumors, which rely heavily on plasmin for metastasis.

Plasmin inhibitors may enhance immunotherapy

The team’s results point towards the potential for inhibiting plasmin or shielding FasL from cleavage to restore its cancer-killing abilities. This strategy could enhance immunotherapy, particularly in patients with plasmin-positive solid tumors.

By combining current immunotherapies with plasmin inhibitors or antibodies designed to protect FasL, researchers may improve immune responses and overcome one of the major barriers in treating solid cancers. This approach could lead to more effective tumor targeting, improving therapeutic outcomes and paving the way for more durable, targeted cancer treatments.

“Humans have a significantly higher rate of cancer than chimpanzees and other primates. 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.”

Reference: Wamba BEN, Mondal T, Freenor V F, et al. Evolutionary regulation of human Fas ligand (CD95L) by plasmin in solid cancer immunotherapy. Nat Commun. 2025;16(1):5748. doi: 10.1038/s41467-025-60990-0

This article is a rework of a press release issued by the University of California - Davis Health. Material has been edited for length and content.