Cancer Research · us
How Do Tumors Cause CAR-T Cells to Lose Momentum? TRAILshort Reveals a Blockable Immune-Braking Pathway
Using cellular and humanized mouse models, a Mayo Clinic team traced the mechanism by which TRAILshort suppresses T-cell signaling through DR5 and SHP-1. Although a neutralizing antibody offers a new avenue for enhancing CAR-T therapy, human efficacy and safety still remain to be validated.
Even when CAR-T cells can recognize cancer cells, they may not be able to sustain an attack. A Mayo Clinic research team reported that a protein called TRAILshort may act as an “immune brake” around tumors, weakening activation signals from within T cells. Blocking it may restore immune activity and enable CAR-T cells to regain better tumor control.
TRAILshort is a splice variant of tumor necrosis factor-related apoptosis-inducing ligand, or TRAIL. It lacks the key structure required to form a normal trimer. It was already known to interfere with cell death induced by full-length TRAIL and can be present on cell surfaces or in extracellular vesicles, allowing nearby cells to also acquire resistance to apoptosis. This study further showed that its effects are not limited to cancer cells but also directly suppress T-cell function.
Using phosphoproteomic analysis and mechanistic experiments to trace the signaling pathway, the team found that after TRAILshort binds to death receptor DR5, it recruits and activates the phosphatase SHP-1. SHP-1 then removes phosphate groups from ZAP-70, disrupting the interaction between ZAP-70 and CD3ζ and preventing the T-cell receptor from properly transmitting antigen-recognition signals. This consequently reduces T-cell activation, proliferation, and cytokine production.
When the researchers inhibited SHP-1 genetically or pharmacologically, the functional defects caused by TRAILshort were reversed. Strategies targeting TRAILshort itself also restored the immune response. In humanized mouse models, TRAILshort promoted the persistence of transformed cells and L428 Hodgkin lymphoma cells and weakened the antitumor effects of CD19 CAR-T cells, supporting the possibility that this pathway may be one cause of cell therapy failure.
The finding also suggests two potential applications. One is to combine a TRAILshort-neutralizing antibody with immunotherapies such as CAR-T to relieve suppressive signals during treatment. The other is to develop TRAILshort levels as a biomarker for identifying patients who may be more likely to respond poorly to cell therapy. The Mayo Foundation has a U.S. patent application still under review covering humanized TRAILshort antibodies and proposing their use in combination with CD8 T cells, natural killer cells, CAR-T, and oncolytic virus therapies. However, the various hematologic and solid tumor indications listed in the patent represent areas of development and cannot be regarded as evidence of clinical efficacy.
The current evidence comes mainly from cell experiments, proteomic data, and humanized mice. It has not yet been demonstrated that administering TRAILshort antibodies to patients with cancer can improve CAR-T response rates or prolong survival. Research is still needed to determine which tumors truly depend on this pathway, what testing thresholds can be used to select patients, and whether long-term relief of TRAILshort-mediated immune regulation may increase the risk of inflammation or autoimmunity. When the related proteomic data were added to a public database in May 2026, the linked formal paper was still marked as pending publication, and the full study design and peer-review details also await further confirmation.