Conditionally Activatable Pyroptosis-Inducing Agents for Cancer Therapy

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.