Synthetic Hybrid Receptors for Safer and Programmable T Cell Therapy

Abstract Engineered T cell therapies have achieved significant clinical success in hematological malignancies but remain largely ineffective in solid tumors. Overcoming this limitation requires strategies that enhance T cell function while avoiding systemic immune toxicities and pathological T cell states. Existing approaches typically rely on constitutive gene overexpression or suppression to augment potency or remodel the tumor microenvironment, but these strategies frequently lead to dysregulated immune activation and dose-limiting toxicity. Here, we present Hybrid Receptors (Hybrid-Rs), a modular receptor platform that integrates features of chimeric antigen receptors (CARs) and SyNthetic Intramembrane Proteolysis Receptors (SNIPRs) to couple antigen-dependent T cell activation with programmable gene regulation. Hybrid-Rs enable precise, context-dependent control of T cell potency, differentiation states, and conditional expression of secreted immunotherapeutic payloads with otherwise prohibitive toxicity. Hybrid-Rs are readily humanized and compatible with precision genome editing in primary human T cells, providing a direct and practical path to clinical translation. Competing Interest Statement M.G.F., X.L., J.G., A.W., R.L, I.Z., and K.T.R. have patents for Hybrid-R receptors or variants or immunotherapeutic payloads. J.G. is an employee of Moonlight Biotherapeutics. R.L. is an employee of Dispatch Biotherapeutics. K.T.R. is a co-founder of and stockholder in Arsenal Bio, Dispatch Biotherapeutics and Moonlight Bio. M.G.F., K.T.R., and X.L. are co-inventors on a provisional patent application that incorporates discoveries described in this manuscript.