Alpha‐Emitter Radium‐223 Induces STING‐Dependent Pyroptosis to Trigger Robust Antitumor Immunity

Abstract Radium‐223 ( 223 Ra) is the first‐in‐class alpha‐emitter to mediate tumor eradication, which is commonly thought to kill tumor cells by directly cleaving double‐strand DNA. However, the immunogenic characteristics and cell death modalities triggered by 223 Ra remain unclear. Here, it is reported that the 223 Ra irradiation induces the pro‐inflammatory damage‐associated molecular patterns including calreticulin, HMGB1, and HSP70, hallmarks of tumor immunogenicity. Moreover, therapeutic 223 Ra retards tumor progression by triggering pyroptosis, an immunogenic cell death. Mechanically, 223 Ra‐induced DNA damage leads to the activation of stimulator of interferon genes (STING)‐mediated DNA sensing pathway, which is critical for NLRP3 inflammasome‐dependent pyroptosis and subsequent DCs maturation as well as T cell activation. These findings establish an essential role of STING in mediating alpha‐emitter 223 Ra‐induced antitumor immunity, which provides the basis for the development of novel cancer therapeutic strategies and combinatory therapy.