Conditionally Activatable Pyroptosis‐Inducing Agents for Cancer Therapy

Abstract

Pyroptosis is a recently defined form of immunogenic cell death that shows great promise in cancer immunotherapy. However, almost all small‐molecule pyroptosis‐inducing agents (PyAs) reported to date indiscriminately induce pyroptosis in multiple cell types, leading to off‐target pyroptotic death of normal and immune cells. One promising approach to addressing this biosafety issue is the design of conditionally activatable PyAs that specifically respond to disease biomarkers. Herein, a general solution for facilely tailoring and synthesizing activatable PyAs based on a newly developed class of photoactive PyAs, termed PyPSs, is reported. The unique structurally encoded properties of PyPSs, including endo reticulum targeting, hypoxia tolerance, and sensing properties, excitingly meet a demanding set of performance requirements for constructing conditionally activatable PyAs for cancer immunotherapy. Based on PyPS‐1 scaffold, hypoxia‐activatable PyPS‐NF as a proof‐of‐concept example is prepared, demonstrating specific hypoxia‐activated pyroptotic cell death and favorable immunotherapeutic efficacy of solid tumors. Herein, a general design strategy for tailoring activatable PyAs to precisely control GSDME‐mediated cell pyroptosis is established, with great potential to advance cancer immunotherapy.