A kinetic gatekeeper: TCR ‐ pMHC dissociation dynamics determine T cell activation efficacy

Abstract T‐cell receptor (TCR) engineering is central to modern immunotherapy, but predicting T‐cell functional potency remains challenging, as conventional binding affinity often poorly correlates with cellular responses. Here, we demonstrate that the kinetic properties of the TCR–pMHC dissociation—profiled via steered molecular dynamics (SMD)—serve as a robust predictor of T‐cell activation. While affinity‐based prediction falls short, peak rupture force and total unbinding work resolve iso‐affinity TCRs and correctly rank ligands across the functional spectrum, from antagonist to super‐agonist. Notably, we uncover a stage‐specific signaling signature: a near‐perfect linear correlation between these mechanical metrics and intermediate signaling, which transitions to a strong exponential correlation with final cellular potency (EC 50 ). This linear‐to‐exponential shift suggests that a high‐fidelity mechanical signal at the membrane is amplified by downstream enzymatic cascades. Our physics‐based framework advances the understanding of immunoreceptor mechanobiology and provides a predictive tool for designing next‐generation T‐cell therapies.