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

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 (EC₅₀). 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.