Researchers Discover Immune 'Off Switch' Used by Cancer Cells

Mayo Clinic researchers have identified a protein that cancer cells use to shut down the body's immune response, a discovery that could help scientists develop new treatments that make cancer immunotherapies more effective.

Published in the Journal of Clinical Investigation, the study identifies a previously unknown role for a protein called TRAILshort, which acts like an immune "off switch." The researchers found that TRAILshort prevents T cells — the immune system's primary cancer-fighting cells — from recognizing and destroying cancer and virus-infected cells. In preclinical models, blocking the protein restored T-cell activity and improved immune response. 

The researchers also found that TRAILshort reduces the effectiveness of chimeric antigen receptor-T cell therapy (CAR-T cell therapy), one of the most advanced forms of cancer immunotherapy. Their findings suggest that therapies designed to block TRAILshort could improve CAR-T treatment and potentially benefit other immune-based cancer therapies.

"What strikes me most is that TRAILshort appears in cancer, HIV, COVID-19, tuberculosis, lupus and Crohn's disease — almost every condition where the immune system is failing or misfiring. That tells us we may have identified a fundamental switch in human immunity, not just a curiosity in one disease," says Andrew Badley, M.D., senior author of the study. Dr. Badley is the HH Sheikh Khalifa Bin Zayed Al Nahyan Professor of Infectious Diseases and an immunologist at Mayo Clinic.

How Cancer Disrupts the Immune Response

Mayo Clinic researchers first discovered TRAILshort while studying HIV nearly 15 years ago. In 2020, they found that cancer cells also produce the protein, but how it suppressed T-cell activity remained unknown. This new study reveals the mechanism for the first time.

Researchers found elevated levels of TRAILshort in melanoma, lung, breast, pancreatic and ovarian cancers, as well as Hodgkin lymphoma. Elevated levels also were found in infectious diseases, including COVID-19, tuberculosis and hepatitis C.

Using highly specific antibodies and engineered preclinical models, the team found that TRAILshort activates SHP-1, a protein that acts as a molecular brake, shutting down T cells before they can attack diseased cells.

"This is the first study to show that TRAILshort doesn't just block cell death — it also acts as a signaling molecule that directly suppresses T-cell activity," says Shahrzad Jalali, Ph.D., a research scientist at Mayo Clinic and lead author of the study. "That reveals an entirely new role for the protein in regulating the immune response."

Why TRAILshort Is a Potential Target for New Therapies

The findings suggest several potential therapeutic applications.

Researchers found that TRAILshort significantly reduced CAR-T therapy's ability to control tumors in preclinical models. Blocking the protein restored immune activity, suggesting that targeting it could be a new strategy to improve CAR-T therapy and other immunotherapies. The researchers also believe that TRAILshort could serve as a biomarker to help identify tumors more likely to respond to targeted therapies.

"Discovering the role of TRAILshort and how it inhibits CAR-T cells opens the door for a new therapeutic strategy to improve their activity," says Saad Kenderian, M.B. Ch.B., an oncologist at Mayo Clinic Comprehensive Cancer Center and study co-author. "This is an important step as we work to make CAR-T therapy more effective for patients with cancer."

Beyond cancer, researchers say TRAILshort may eventually provide a way to selectively reduce harmful immune activity in autoimmune diseases or transplantation without broadly suppressing the immune system.

"In cancer, there's too much TRAILshort, so our goal is to get rid of it with antibodies that remove it. In autoimmune disease, there's not enough TRAILshort, so our goal is to deliver more," Dr. Badley says.

Additional studies are needed to determine whether these approaches are safe and effective in patients.

"What excites us most is that this discovery gives us a new, actionable way to regulate the immune system," Dr. Badley says. "By targeting TRAILshort, we may be able to strengthen immune responses against cancer and chronic infections or, in other diseases, reduce harmful immune activity."

This research is part of a broader effort at Mayo Clinic known as the Precure Research initiative. It focuses on developing tools to help clinicians detect and address disease-related changes earlier, before symptoms appear or conditions become harder to treat. This discovery identifies the molecular mechanism behind T-cell failure across cancer and chronic infection, giving researchers a defined target and a road map for therapeutic development.

For a complete list of authors, disclosures and funding, review the study.