Mayo Clinic Finds Immune 'Off Switch' Cancer Uses

Cancer cells have been hiding in plain sight by flipping an "off switch" that prevents the immune system from attacking them, and Mayo Clinic researchers just figured out how.

The team identified a protein called TRAILshort that cancer cells use to shut down T cells, the immune system's primary cancer-fighting soldiers. When researchers blocked this protein in preclinical studies, the immune system sprang back to life and started attacking cancer cells again.

Dr. Andrew Badley, an infectious diseases specialist at Mayo Clinic, first discovered TRAILshort while studying HIV 15 years ago. What surprises him most is where else the protein shows up.

"TRAILshort appears in cancer, HIV, COVID-19, tuberculosis, lupus and Crohn's disease—almost every condition where the immune system is failing or misfiring," Dr. Badley explains. "That tells us we may have identified a fundamental switch in human immunity, not just a curiosity in one disease."

The research team found elevated TRAILshort levels in melanoma, lung, breast, pancreatic, and ovarian cancers, plus Hodgkin lymphoma. They discovered the protein activates SHP-1, which acts like a molecular brake that stops T cells before they can destroy diseased cells.

This discovery could make existing cancer treatments work better. The researchers found that TRAILshort significantly reduced the effectiveness of CAR-T cell therapy, one of the most advanced immunotherapies available today. When they blocked the protein, the therapy worked again.

Dr. Saad Kenderian, an oncologist at Mayo Clinic Comprehensive Cancer Center, sees immediate applications. "Discovering the role of TRAILshort and how it inhibits CAR-T cells opens the door for a new therapeutic strategy to improve their activity," he says.

The Ripple Effect

The implications reach far beyond cancer treatment. Because TRAILshort appears in so many different conditions, targeting it could help millions of people facing various diseases.

For cancer and chronic infections where there's too much TRAILshort, doctors could use antibodies to remove it and strengthen immune responses. For autoimmune diseases like lupus and Crohn's where there's not enough, they could deliver more to calm harmful immune activity.

This approach could revolutionize how doctors treat immune-related conditions without broadly suppressing the entire immune system. Instead of using a sledgehammer, they'd have a precision tool.

The research is part of Mayo Clinic's Precure Research initiative, which focuses on detecting and addressing disease-related changes before symptoms appear or conditions become harder to treat. By identifying the exact molecular mechanism behind T-cell failure, scientists now have a clear target and road map for developing new therapies.

More studies are needed to confirm these approaches work safely in patients, but the discovery gives researchers their first actionable way to regulate this fundamental immune switch.