Multifunctional nanoagent for enhanced cancer radioimmunotherapy via pyroptosis and cGAS-STING activation

作者：Ziting Xu, Yang Gao, Li Zhang, Yingshan Gao, Yushu Liao, Yu Liang, Zhen Yuan, Yingjia Li, Bingxia Zhao, Ge Wen · 发表于：Journal of Nanobiotechnology · 年份：2025 · DOI：10.1186/s12951-025-03608-3 · 被引用次数：17 · 研究领域：Inflammasome and immune disorders、interferon and immune responses、Ferroptosis and cancer prognosis

The immunosuppressive tumor microenvironment (ITME) and inherent radioresistance of tumor cells limit the effectiveness of radioimmunotherapy and exacerbate immune evasion. To address these challenges, PEGylated Azacitidine-loaded and Mn 2+ -doped calcium carbonate nanoparticles (A@MCP NPs) are synthesized as multifunctional nanoagent to enhance radioimmunotherapy outcomes. Upon acidic TME, the release of Ca 2+ and Mn 2+ from A@MCP NPs co-triggers intracellular reactive oxygen species (ROS) generation via Ca 2+ overload and Fenton-like reactions, inducing cytochrome C release and caspase-3 activation. Concurrently, released Azacitidine inhibits DNA methylation, upregulating GSDME expression in irradiated tumor cells, which synergistically amplifies caspase-3/GSDME-induced pyroptosis. The resulting pyroptotic cell damage, coupled with radiotherapy (RT)-induced DNA, activates Mn 2+ -sensitized cGAS-STING pathways, amplifying immune responses. Collectively, A@MCP, as a nano radiosensitizer, together with RT, co-activates pyroptosis and cGAS-STING to further amplify anti-tumor immune response, overcome ITME-mediated resistance and offer significant potential for improved cancer radioimmunotherapy.