Low antigen sensitivity and a gradual loss of effector functions limit the clinical applicability of chimeric antigen receptor (CAR)–modified T cells and call for alternative antigen receptor designs for effective T cell–based cancer immunotherapy. Here, we applied advanced microscopy to demonstrate that TCR/CD3-based synthetic constructs (TCC) outperform second-generation CAR formats with regard to conveyed antigen sensitivities by up to a thousandfold. TCC-based antigen recognition occurred without adverse nonspecific signaling, which is typically observed in CAR–T cells, and did not depend—unlike sensitized peptide/MHC detection by conventional T cells—on CD4 or CD8 coreceptor engagement. TCC-endowed signaling properties may prove critical when targeting antigens in low abundance and aiming for a durable anticancer response.

TCR/CD3-based synthetic antigen receptors (TCC) convey superior antigen sensitivity combined with high fidelity of activation