In a groundbreaking discovery that may revolutionize the future of cancer immunotherapy, researchers at the UC Davis Comprehensive Cancer Center have identified a subtle yet crucial evolutionary shift in human immune systems that underlies their relative inefficiency in combating solid tumors. Published recently in Nature Communications, the study illuminates how a minute genetic variation in the immune protein Fas Ligand (FasL) fundamentally alters its function, providing tumors with an unexpected mechanism to evade immune attack. This revelation not only sheds light on a longstanding medical mystery but also paves the way for novel strategies to enhance the effectiveness of immunotherapies in some of the most challenging cancers.
Fas Ligand (FasL), a protein expressed on the surface of activated immune cells, is a critical mediator of apoptosis, or programmed cell death. This process, indispensable for immune cells, allows them to identify and induce death in cells that are damaged or malignant. Among these immune warriors are CAR-T cells, a form of adoptive cell therapy engineered from the patient’s own immune system, which utilize FasL to trigger apoptosis in cancer cells. Yet, despite remarkable success against hematologic malignancies, CAR-T cell therapies have struggled to replicate such efficacy in solid tumors. The mystery behind this discrepancy now finds a compelling explanation rooted in evolutionary biology.
The team at UC Davis discovered that a single amino acid substitution in the human FasL protein — where serine replaces proline at position 153 — renders FasL highly susceptible to cleavage by plasmin. Plasmin is a proteolytic enzyme abundantly present within the microenvironments of aggressive solid tumors, including triple-negative breast cancer, colon cancer, and ovarian cancer. Through enzymatic cleavage, plasmin effectively disables FasL, neutralizing a key mechanism by which immune cells eliminate cancer cells. This evolutionary mutation appears unique to humans, as FasL in non-human primates such as chimpanzees retains proline at this position, making them less vulnerable to plasmin’s disruptive effects.
From an evolutionary perspective, this mutation in FasL might have been a trade-off that facilitated the development of larger, more complex human brains by modulating immune pathways, particularly pathways involved in cell death. However, in the context of oncology, this beneficial mutation for brain development becomes detrimental. By weakening FasL’s integrity, tumors exploit this vulnerability to disarm one of the immune system’s vital weapons, thus promoting immune evasion and enabling tumor progression and metastasis.
The study’s experimental investigations demonstrated that human immune cells, despite being activated and primed to attack cancer cells, often find their FasL function compromised within plasmin-rich tumor microenvironments. This discovery elegantly explains the limited success of immunotherapies like CAR-T and T-cell-based therapies in solid tumors, which are frequently characterized by an elevated presence of plasmin. In contrast, blood cancers, typically devoid of such high plasmin levels, are more susceptible to FasL-mediated immune eradication, accounting for the pronounced effectiveness of these therapies in hematologic malignancies.
Perhaps the most promising aspect of the UC Davis research lies in its therapeutic implications. By introducing plasmin inhibitors or developing antibodies engineered to shield FasL from plasmin-mediated cleavage, it is now conceivable to protect and restore FasL’s apoptotic function within the hostile solid tumor microenvironment. Such interventions could dramatically enhance the cytotoxic capabilities of immune cells, thereby potentiating immunotherapy responses in cancers that have previously been refractory to treatment.
Importantly, the research underscores a nuanced evolutionary dimension to cancer immunology, suggesting that intricate genetic variations shaped by millions of years of human development bear profound consequences for disease vulnerabilities. The authors emphasize the remarkable difference in cancer incidence and immune system efficacy between humans and their closest evolutionary relatives, primates, and invite deeper comparative study that may unlock further therapeutic avenues.
This breakthrough also challenges the oncology field to reconsider how immune escape mechanisms are understood and addressed. Rather than focusing solely on tumor cell mutations or immune checkpoint pathways, attention must now turn toward these evolutionary genetic alterations within key immune proteins and their interactions with the tumor milieu. Integrating such insights into the design of next-generation immunotherapies could bring personalized and more effective cancer treatments closer to reality.
As the researchers pursue further preclinical and clinical validation of their findings, the overall aim remains clear: to overcome the immunosuppressive tactics of plasmin-positive solid tumors by fortifying the immune system’s molecular arsenal. Should plasmin inhibition or FasL protection prove successful in human trials, it may usher in an unprecedented era of immunotherapy—one that can unlock durable and powerful anti-cancer responses in diverse solid tumors.
The implications of this discovery extend beyond oncology into the broader realm of immunobiology and evolutionary medicine. It highlights how evolutionary gains, such as those enabling cerebral complexity, can inadvertently introduce vulnerabilities in immune defense. Understanding these evolutionary trade-offs not only expands scientific knowledge but also guides the rational development of innovative therapies that reconcile our biological heritage with contemporary medical needs.
In conclusion, the identification of plasmin-mediated FasL inactivation as a unique human evolutionary vulnerability opens an exciting frontier in cancer research. It champions a paradigm wherein evolutionary biology informs precision medicine and offers hope for patients grappling with hard-to-treat solid tumors. As the research community embraces this knowledge, the prospect of more potent, personalized immunotherapies grows ever brighter, signaling a promising shift in the war against cancer.
Subject of Research: People
Article Title: Evolutionary regulation of human Fas ligand (CD95L) by plasmin in solid cancer immunotherapy
News Publication Date: 1-Jul-2025
Web References:
References:
- Tushir-Singh, J. et al. Evolutionary regulation of human Fas ligand (CD95L) by plasmin in solid cancer immunotherapy. Nature Communications (2025). https://doi.org/10.1038/s41467-025-60990-0
Keywords:
Cancer research, Cancer, Cancer cells, Cancer immunotherapy, Primates, Nonhuman primates
