<p>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 Mn²⁺-doped calcium carbonate nanoparticles (A@MCP NPs) are synthesized as multifunctional nanoagent to enhance radioimmunotherapy outcomes. Upon acidic TME, the release of Ca²⁺ and Mn²⁺ from A@MCP NPs co-triggers intracellular reactive oxygen species (ROS) generation via Ca²⁺ 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 Mn²⁺-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.</p>