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

Radium-223 (223Ra) 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 223Ra remain unclear. Here, it is reported that the 223Ra irradiation induces the pro-inflammatory damage-associated molecular patterns including calreticulin, HMGB1, and HSP70, hallmarks of tumor immunogenicity. Moreover, therapeutic 223Ra retards tumor progression by triggering pyroptosis, an immunogenic cell death. Mechanically, 223Ra-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 223Ra-induced antitumor immunity, which provides the basis for the development of novel cancer therapeutic strategies and combinatory therapy. Alpha-emitter 223Ra can activate the stimulator of interferon genes (STING) signaling pathway by inducing DNA damage. Subsequently, the STING activates the NLRP3-dependent pyroptosis, a typical form of immunogenic cell death, to enhance antitumor immune response. this study highlights the pivotal role of the STING pathway in the effects of alpha-emitter 223Ra-induced pyroptosis, which leads even more opportunities for broadening the therapeutic window of alpha-emitter.image