Cancer cells have a favorite trick for escaping the immune system: flipping a molecular 'off switch' that silences the very cells sent to kill them. Mayo Clinic researchers have now identified how that switch works — and how to flip it back.
In a study published in the Journal of Clinical Investigation, the team revealed a previously unknown role for a protein called TRAILshort. Cancer cells use it as an immune 'off switch': TRAILshort prevents T cells — the immune system's primary cancer fighters — from recognizing and destroying cancer and virus-infected cells. It does so by activating SHP-1, a protein that acts as a molecular brake, shutting T cells down before they can attack. '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,' said lead author Shahrzad Jalali, a research scientist at Mayo Clinic.
Mayo researchers first discovered TRAILshort while studying HIV nearly 15 years ago; in 2020 they found cancer cells also produce it, but the mechanism remained unknown. The new work found elevated TRAILshort in melanoma, lung, breast, pancreatic and ovarian cancers and Hodgkin lymphoma — as well as in infectious diseases such as COVID-19, tuberculosis and hepatitis C.
The therapeutic implications are direct. In preclinical models, TRAILshort significantly reduced the ability of CAR-T cell therapy — one of the most advanced forms of cancer immunotherapy — to control tumors. Blocking the protein restored T-cell activity and improved the immune response, suggesting that antibody-based therapies against TRAILshort could boost CAR-T and other immunotherapies. The protein could also serve as a biomarker for tumors likely to respond to treatment.
The discovery may reach far beyond cancer. '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,' said senior author Dr. Andrew Badley. 'That tells us we may have identified a fundamental switch in human immunity.' In autoimmune disease, where there is too little TRAILshort, delivering more of it could one day selectively calm harmful immune activity without broadly suppressing the immune system.
