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: (i) cell surface antigen targeting
(ii) small-molecule regulation
and (iii) 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.