Evolutionary Regulation of Human Fas Ligand by Plasmin in Solid Cancer Immunotherapy

Research published in the journal Nature Communications by a team of scientists from the University of California Davis has revealed an unexpected discovery in the regulation of human Fas Ligand (FasL) in the context of solid cancer immunotherapy. The study found that humans are more likely to develop cancers than their closest living ancestors, the nonhuman primates, despite sharing 98% genomic similarity. Furthermore, the researchers discovered that a critical embryonic development and immune homeostasis protein called FasL contains a Pro153-Ser153 evolutionary substitution in humans, making it preferentially susceptible to cleavage by plasmin, an overly elevated protease in solid tumors.

Key Takeaways:

• The team identified a critical embryonic development and immune homeostasis protein called FasL, which contains a Pro153-Ser153 evolutionary substitution in humans, making it preferentially susceptible to cleavage by plasmin.
• Elevated plasmin levels in certain ovarian tumors interfere with the T-lymphocyte-expressed FasL death signaling, hindering the effectiveness of T-cell-based immunotherapies in solid tumors.
• Targeted inhibition or blocking plasmin accessibility to membrane FasL rescues the FasL cell-death function of activated T-lymphocytes in response to immune-checkpoint receptor targeting antibodies.
• The study suggests that elevated plasmin in metastatic tumors contributes to differential outcomes of T-cell-based immunotherapies in solid tumors.
• The research team included Jogender Tushir-Singh, Brice E. N. Wamba, Tanmoy Mondal, V. Francis Freenor, Mehr Shaheed, Oliver Pang, Sanchita Bhatnagar, Daniel Bedinger, Patrick Legembre, Laurent Devel, and Gary Scott Leiserowitz.
• The study was sponsored by the U.S. Department of Health & Human Services, the U.S. Department of Defense, and the National Cancer Institute.

Statistics:

• 98%: The genomic similarity between humans and their closest living ancestors, the nonhuman primates.
• Pro153-Ser153: The evolutionary substitution in humans that makes FasL preferentially susceptible to cleavage by plasmin.
• Solid tumors: The type of cancer where elevated plasmin levels interfere with FasL death signaling.
• Elevated plasmin: A condition present in certain ovarian tumors that hinders the effectiveness of T-cell-based immunotherapies.
• 2025: The publication year of the study in the journal Nature Communications.
• Nature Communications: The journal that published the study.

Sources:

• NewsRx. Recent Findings from University of California Davis Has Provided New Information about Solid Cancer [Evolutionary Regulation of Human Fas Ligand (Cd95l) By Plasmin In Solid Cancer Immunotherapy]. Immunotherapy Weekly. August 6, 2025; p 3328.
• Nature Communications. Evolutionary Regulation of Human Fas Ligand (Cd95l) By Plasmin In Solid Cancer Immunotherapy. 2025;16(1).
• University of California Davis. Faculty Directory: Jogender Tushir-Singh. Retrieved from ,
• U.S. Department of Health & Human Services. National Institutes of Health. Retrieved from ,