Alpha-emitter radium-223 mediates STING-dependent pyroptosis to trigger robust tumor immunogenicity

Abstract Purpose Radium-223 (223Ra) is the first-in-class alpha-emitter to mediate tumor eradication, which radiation emitted from alpha-emitter are routinely regarded can reduce tumor burden by directly cleaving double-strand DNA and killing tumor cells. However, the immunogenic characteristics and various cell death modalities triggered by alpha-emitter are remain unclear.MethodsWe evaluated biological effects of 223Ra in cancer cell lines and mice models by biological endpoints. Concurrently, we explored immunogenicity and cell death modalities triggered by 223Ra and excavated its mechanisms of pyroptosis induction. Besides, synergistic effect with checkpoint blockade was also assessed.Results223Ra has efficient therapeutic antitumor effects, which examined by cell viability study, foci analysis for DNA damage, and tumor regression. We further demonstrated that irradiated cells released pro-inflammatory damage-associated molecular patterns (DAMPs), including surface-exposed calreticulin (CALR), released high mobility group protein B1 (HMGB1), and secreted heat shock protein 70 (HSP70), which actively shape tumor immunogenicity. Pyroptosis, an immunogenic cell death (ICD) accompanied by activation of inflammasome, was also found to play significant roles in the modulation of cancer progression under the therapeutic 223Ra. Mechanically, this effect relies on 223Ra-induced DNA damage, which activates the STING-mediated DNA sensing pathway, leading to NLRP3 inflammasome-dependent pyroptosis. When combined with anti-CD47 therapy, 223Ra can trigger robust antitumor effect. ConclusionThese findings highlight the tumor eradication effect of 223Ra, which exhibit both direct antitumor effects and indirect immune-stimulating capabilities. Importantly, STING/NLRP3 axis has a crucial role in pyroptosis under the therapeutic 223Ra, which may shed light on promising targets for therapeutic interventions.