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Synthetic receptors enable bioengineers to build cell-based therapies that perform therapeutic functions in a targeted or conditional fashion to enhance specificity and efficacy. Although many synthetic receptors exist, it remains challenging to generate new receptors that sense soluble cues and relay that detection through orthogonal mechanisms independent of native pathways. Towards this goal, we investigated co-opting natural cytokine receptor ectodomains into Modular Extracellular Sensor Architecture receptors (yielding natural ectodomain, NatE MESA receptors). We generated multiple high-performing, orthogonal synthetic cytokine receptors, identified design principles and constraints, and propose guidance for extending this approach to other natural receptors. We demonstrate utility of NatE MESA by engineering T cells to sense an immunosuppressive cue and respond with customized transcriptional output to support CAR T-cell activity. Finally, we multiplex NatE MESA to logically evaluate multiple cues associated with the tumor microenvironment. These technologies and learnings will enable engineering cellular functions for new applications.