Computational design of synthetic receptors with programmable signalling activity for enhanced cancer T cell therapy.

The tumour microenvironment (TME) plays a key role in tumour progression, and soluble and cellular TME components can limit CAR-T cell function and persistence. Targeting soluble TME factors to enhance anti-tumour responses of engineered T cells through chimeric receptors is not broadly explored owing to the unpredictable signalling characteristics of synthetic protein receptors. Here we develop a computational protein design platform for the de novo bottom-up assembly of allosteric receptors with programmable input-output behaviours that respond to soluble TME factors with co-stimulation and cytokine signals in T cells, called TME-sensing switch receptor for enhanced response to tumours (T-SenSER). We develop two sets of T-SenSERs targeting vascular endothelial growth factor (VEGF) or colony-stimulating factor 1 (CSF1) that are both selectively enriched in a variety of tumours. Combination of CAR and T-SenSER in human T cells enhances anti-tumour responses in models of lung cancer and multiple myeloma, in a VEGF- or CSF1-dependent manner. Our study sets the stage for the accelerated development of synthetic biosensors with custom-built sensing and responses for basic and translational cell engineering applications.