CAR priming lowers TCR activation threshold to enhance recognition of low affinity tumor antigens

Chimeric antigen receptor (CAR)-T cell therapy has shown remarkable efficacy in hematologic malignancies but has achieved limited success in solid tumors due to barriers such as immunosuppressive tumor microenvironments and poor antigen presentation1. Primary brain tumors, across pediatric and adult settings, represent a particularly difficult target: they display profound intratumoral heterogeneity, frequently downregulate MHC class I2, and often present low-avidity or subclonally expressed antigens that are poorly recognized by conventional T cell receptors (TCRs). Prior studies have reported crosstalk between CAR and TCR signaling, suggesting that TCR expression is important for optimal CAR function3, and others indicate that CAR function may be suppressed when encountering low-avidity TCR antigens4. Our preliminary data show that CAR priming enhances TCR responses against weak antigens and promotes a more memory-like, less effector-like phenotype, a state linked to improved persistence and durable tumor control. Together, these findings highlight a key gap: how CAR signaling influences TCR function in the setting of weak antigens. Addressing this question is particularly critical in brain tumors, where recognition of low-avidity and poorly presented antigens limits the efficacy of current CAR T-cell therapies.