Fig. 1: Concept and design of de novo assembled biosensors (T-SenSERs).
a, Schematic representation of T cells expressing CAR and T-SenSERs responding to VEGFA or CSF1 in the TME. TAM, tumour-associated macrophage; VMR, VEGFR2-MPL receptor; CMR, CSF1R-MPL receptor. b, A basic biosensor composed of the sensor and responder elements behaves differently depending on the fulfilled criteria for biosensor activity. c, Overview of the computational platform for the design of de novo assembled T-SenSERs. The desired behaviour regimes (constitutive or inducible or low constitutive-inducible) can be met by two scoring metrics, communication and dimerization propensity. d, Concept of inducible VMR T-SenSER activated by VEGFA (left) and low constitutive-inducible CMR T-SenSER responsive to CSF1 (right). VEGFR2-MPL receptor (VMR): presence of VEGFA induces c-MPL signalling in VMR+ T cells, which enhances tumour killing and T cell proliferative capacity. CSF1R-MPL receptor (CMR): low constitutive c-MPL signalling in CMR+ T cells improves T cell proliferative capacity, homeostatic expansion and tumour killing. CMR activity is further enhanced with CSF1. e, Schematics and structural models of three different selected T-SenSERs. For VMR, VMRSHORT, VMRINT and VMRFL. For CMR, CMRSHORT, CMRINT and CMRFL. Variants were classified by active state dimerization propensity and EC–IC communication. Parts of these figure panels were generated with bioRender (b,c,e).