This disclosure describes a method for de novo bottom-up assembly and rational design of allosteric biosensors with programmable input-output behaviors that respond to soluble factors selectively enriched in tumors and trigger co-stimulation and cytokine signals. The disclosed method of effective mechanical coupling and biosensor signaling potency correlates with anti-tumor function. This disclosure provides synthetic biosensors with custom-built sensing and responses for basic and translational cell engineering applications.