A Human Mutation That Undermines Cancer Immunotherapy
Humans experience higher rates of cancer than our closest primate relatives, despite sharing more than 98% our genome. A recent study published in Nature Communications identifies a previously unrecognised factor that may help explain this discrepancy.
Past comparative studies have shown high conservation of cancer-related genes between humans and chimpanzees. However, key functional differences have been identified in major tumour suppressors such as TP53, BRCA1, and BRCA21,2.
Now, Wamba et al. (2025)3 describe how a single amino acid difference in the human Fas ligand (FasL) protein renders it uniquely vulnerable to cleavage by plasmin, a protease often elevated in solid tumors. This vulnerability compromises a key immune elimination pathway and may limit the efficacy of T cell-based immunotherapies in certain cancers.
The findings connect a subtle evolutionary change to a measurable loss of immune function in modern tumors; a difference that could affect both natural T cell responses and adoptive cell therapies such as CAR T, since both rely in part on FasL-mediated cytotoxicity.
FasL is one of several mechanisms central to immune surveillance. Displayed on the surface of activated T cells and some CAR T cells, it triggers apoptosis in diseased or malignant cells through engagement with Fas receptors. It also plays a role in immune regulation, helping to control T cell expansion and prevent lymphoproliferative disorders.
In humans, this system is compromised by a subtle but consequential mutation. At position 153, the human FasL protein contains a serine, whereas other primates retain a proline. This single substitution exposes the protein to cleavage by plasmin. Once cleaved, FasL can no longer initiate cell death, resulting in impaired T cell-mediated apoptosis.
This susceptibility is most pronounced in solid tumors, where high plasmin activity is already known to support invasion and metastasis. The same enzymatic activity now appears to disarm incoming immune cells, weakening their cytotoxic effect.
To test how this affects immune function, the researchers examined CAR T cells engineered to express human FasL. In co-culture experiments, the presence of plasmin reduced CAR T cells’ ability to eliminate tumor cells that lacked a target antigen. Replacing human FasL with the chimpanzee version, or using antibodies to block plasmin access, restored this function.
These results suggest that the serine substitution creates a cleavage-sensitive form of FasL that limits T cell activity in certain tumor environments. Importantly, the defect is reversible, either by modifying FasL itself or by protecting it from degradation.
FasL cleavage may help explain why solid tumors often respond less effectively to immunotherapy than blood cancers. While factors such as poor T cell infiltration and antigen loss are well recognised, this study adds a biochemical barrier not typically assessed.
In tumors with high plasmin activity, FasL is cleaved at the cell surface before it can engage Fas receptors. This prevents apoptotic signalling, even when T cells are present, active, and accurately targeted. Therapies that rely on FasL function may underperform, not because of immune exhaustion or antigen escape, but because of protease-driven interference with cytotoxic signalling.
Recognising this could support new approaches to patient stratification. Measuring plasmin activity or assessing FasL integrity may help identify tumors that would benefit from protective strategies to preserve FasL activity during treatment.
The authors tested two strategies to prevent FasL degradation. One involved antibodies, such as Nok2h and 9F5, that bind to FasL and shield it from plasmin. The other used chemical inhibition, applying plasmin-blocking agents like aprotinin. Both approaches successfully preserved FasL-mediated apoptosis in cell cultures and animal models.
In patient-derived ovarian cancer cells with high plasmin activity, human FasL was ineffective. However, these cells remained responsive to chimpanzee FasL or human FasL protected by an antibody. Similar results were seen in CAR T models, where the same antibodies restored the ability to remove antigen-negative tumor cells, confirming the role of FasL in managing tumor heterogeneity.
These findings suggest that FasL stability could serve as a biomarker for selecting patients or treatment planning. In tumours with high plasmin activity, combining immunotherapy with FasL-protective strategies may improve therapeutic response.
The degradation of FasL by tumour-derived plasmin is not caused by treatment. In many tumors, this process may already be underway before therapy begins. Therefore, it is a background process that interferes with immune function. This raises several questions. Should FasL stability be evaluated before starting T cell-based therapy? Could patients be screened for elevated plasmin activity using existing diagnostic tools? Might future generations of CAR T therapies include FasL variants engineered to resist cleavage?
These possibilities deserve close attention. Identifying patients whose tumors degrade FasL early could help tailor immunotherapy strategies and improve responses.
Not all evolutionary changes are beneficial. The P153S substitution in FasL appears to have no known adaptive advantage, yet it undermines an important immune function in humans. This single amino acid change makes FasL vulnerable to cleavage, weakening T cell responses in tumor environments and potentially contributing to increased cancer risk relative to other primates. It is a reminder that evolution acts on genes, not individuals. Changes that are neutral or mildly deleterious can persist if they do not affect reproductive success, only to surface later as clinical vulnerabilities.
The evolutionary forces that drove this substitution remain unclear. It may have persisted due to genetic drift, lack of selective pressure, or unknown pleiotropic effects. This is not a failure of drug design, but a structural limitation shaped by our evolutionary history. Still, it can be addressed: FasL stability could be assessed before treatment; plasmin levels could help identify patients who may benefit from adjunctive strategies; and future therapies could include FasL variants that resist cleavage.
These findings are compelling, but they are not yet definitive. Larger clinical studies are needed to determine how often FasL cleavage occurs across tumor types and whether it consistently diminishes immunotherapy responses. Broader in vivo testing and patient cohort analysis will be important steps for translating this mechanism into clinical practice.
As immunotherapy advances, the focus can not stay solely on antigens and T cell activation. The structural resilience of immune proteins and how tumors interfere with them may also determine treatment success. In the case of FasL, one evolutionary compromise has clinical consequences. Recognising that may influence how we design and deliver cancer therapies.