biostudies-literatureUnknown33(4)Leleux JChimeric antigen receptor (CAR) T cells are effective cancer therapies, particularly in indications with high, stable, and tumor-specific antigen expression. Other settings may require improved targeting sensitivity, controllable targeting selectivity, and/or additional potency enhancements to achieve robust efficacy. Here, we describe a novel receptor architecture called RESET (rapamycin-enabled, switchable endogenous T cell receptor) that combines (1) cell surface antigen targeting, (2) small-molecule regulation, and (3) the signaling proficiency and inherent sensitivity of native T cell receptors. RESET-T cells outperformed both constitutive and drug-regulated CAR-T cells and show hallmarks of TCR activation that suggest improved fidelity to native T cell responses. Pharmacological control then increases safety through toggling T cell activation between active and resting states and may mitigate T cell exhaustion caused by continuous antigen exposure. This convergence of drug-regulated targeting and natural immune receptor signal transduction may better replicate the kinetics and physiology of a classical T cell response and potentiate more successful and safer immunotherapies.Molecular therapy : the journal of the American Society of Gene Therapy1608-1620https://www.ebi.ac.uk/biostudies/studies/S-EPMC11997482biostudies-literatureRESET: A TCR-coupled antigen receptor with superior targeting sensitivity and reversible drug-regulated anti-tumor activity.PMC11997482Jarjour JGregory PDSonzogni OJin NWalker RLRosenberg JGarrison SMVenkitaraman ALeleux JfalseRESET: A TCR-coupled antigen receptor with superior targeting sensitivity and reversible drug-regulated anti-tumor activity.Chimeric antigen receptor (CAR) T cells are effective cancer therapies, particularly in indications with high, stable, and tumor-specific antigen expression. Other settings may require improved targeting sensitivity, controllable targeting selectivity, and/or additional potency enhancements to achieve robust efficacy. Here, we describe a novel receptor architecture called RESET (rapamycin-enabled, switchable endogenous T cell receptor) that combines (1) cell surface antigen targeting, (2) small-molecule regulation, and (3) the signaling proficiency and inherent sensitivity of native T cell receptors. RESET-T cells outperformed both constitutive and drug-regulated CAR-T cells and show hallmarks of TCR activation that suggest improved fidelity to native T cell responses. Pharmacological control then increases safety through toggling T cell activation between active and resting states and may mitigate T cell exhaustion caused by continuous antigen exposure. This convergence of drug-regulated targeting and natural immune receptor signal transduction may better replicate the kinetics and physiology of a classical T cell response and potentiate more successful and safer immunotherapies.2025-01-01T00:00:00Z2025 Apr2026-06-02T20:14:18.76Z2026-04-20T03:10:11.394ZS-EPMC119974823998019410.1016/j.ymthe.2025.02.026