Multifunctional nanoagent for enhanced cancer radioimmunotherapy via pyroptosis and cGAS-STING activation
Abstract 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) a...
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BMC
2025-07-01
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| Series: | Journal of Nanobiotechnology |
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| Online Access: | https://doi.org/10.1186/s12951-025-03608-3 |
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| author | Ziting Xu Yang Gao Li Zhang Yingshan Gao Yushu Liao Yu Liang Zhen Yuan Yingjia Li Bingxia Zhao Ge Wen |
| author_facet | Ziting Xu Yang Gao Li Zhang Yingshan Gao Yushu Liao Yu Liang Zhen Yuan Yingjia Li Bingxia Zhao Ge Wen |
| author_sort | Ziting Xu |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-028ae9e5bd424af8b50cf68bec09c1ad |
| institution | DOAJ |
| issn | 1477-3155 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Nanobiotechnology |
| spelling | doaj-art-028ae9e5bd424af8b50cf68bec09c1ad2025-08-20T03:05:59ZengBMCJournal of Nanobiotechnology1477-31552025-07-0123111610.1186/s12951-025-03608-3Multifunctional nanoagent for enhanced cancer radioimmunotherapy via pyroptosis and cGAS-STING activationZiting Xu0Yang Gao1Li Zhang2Yingshan Gao3Yushu Liao4Yu Liang5Zhen Yuan6Yingjia Li7Bingxia Zhao8Ge Wen9Department of Medical Imaging, Department of Ultrasound, Nanfang Hospital, Southern Medical UniversityDepartment of Medical Imaging, Department of Ultrasound, Nanfang Hospital, Southern Medical UniversityDepartment of Medical Imaging, Department of Ultrasound, Nanfang Hospital, Southern Medical UniversityDepartment of Medical Imaging, Department of Ultrasound, Nanfang Hospital, Southern Medical UniversityCancer Research Institute, School of Basic Medical Sciences, Southern Medical UniversityDepartment of Medical Imaging, Department of Ultrasound, Nanfang Hospital, Southern Medical UniversityFaculty of Health Sciences, University of MacauDepartment of Medical Imaging, Department of Ultrasound, Nanfang Hospital, Southern Medical UniversityCancer Research Institute, School of Basic Medical Sciences, Southern Medical UniversityDepartment of Medical Imaging, Department of Ultrasound, Nanfang Hospital, Southern Medical UniversityAbstract 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.https://doi.org/10.1186/s12951-025-03608-3RadiosensitizationPyroptosiscGAS-STING pathwayCa overloadRadioimmunotherapy |
| spellingShingle | Ziting Xu Yang Gao Li Zhang Yingshan Gao Yushu Liao Yu Liang Zhen Yuan Yingjia Li Bingxia Zhao Ge Wen Multifunctional nanoagent for enhanced cancer radioimmunotherapy via pyroptosis and cGAS-STING activation Journal of Nanobiotechnology Radiosensitization Pyroptosis cGAS-STING pathway Ca overload Radioimmunotherapy |
| title | Multifunctional nanoagent for enhanced cancer radioimmunotherapy via pyroptosis and cGAS-STING activation |
| title_full | Multifunctional nanoagent for enhanced cancer radioimmunotherapy via pyroptosis and cGAS-STING activation |
| title_fullStr | Multifunctional nanoagent for enhanced cancer radioimmunotherapy via pyroptosis and cGAS-STING activation |
| title_full_unstemmed | Multifunctional nanoagent for enhanced cancer radioimmunotherapy via pyroptosis and cGAS-STING activation |
| title_short | Multifunctional nanoagent for enhanced cancer radioimmunotherapy via pyroptosis and cGAS-STING activation |
| title_sort | multifunctional nanoagent for enhanced cancer radioimmunotherapy via pyroptosis and cgas sting activation |
| topic | Radiosensitization Pyroptosis cGAS-STING pathway Ca overload Radioimmunotherapy |
| url | https://doi.org/10.1186/s12951-025-03608-3 |
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