Nanoagonist-Mediated GSDME-Dependent Pyroptosis Remodels the Inflammatory Microenvironment for Tumor Photoimmunotherapy |
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| Authors: | Lulu Zheng Yan Fan Xiang Wang Zhijin Yang Yule Zhang Tingting Liu Mengya Chen Shifei Kang Shiwei Guo Zheng Shi Yuwen Wang Kejie Zheng Shuqi Cai Bo Dai Songlin Zhuang Yuhao Li Dawei Zhang |
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| Affiliation: | 1. Engineering Research Center of Optical Instrument and System, The Ministry of Education, Shanghai Key Laboratory of Modern Optical System, Shanghai Environmental Biosafety Instruments and Equipment Engineering Technology Research Center, University of Shanghai for Science and Technology, Shanghai, 200093 China;2. Institute of Bismuth Science & School of Materials and Chemistry, University of Shanghai for Science and Technology, Shanghai, 200093 China;3. Department of Pediatric Hematology/Oncology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200092 China;4. Department of Environmental Science and Engineering, University of Shanghai for Science and Technology, Shanghai, 200092 China;5. Department of Hepatobiliary Pancreatic Surgery, Changhai Hospital, Naval Military Medical University, Shanghai, 200433 China;6. Department of Gastrointestinal Surgery, Changhai Hospital, Naval Military Medical University, Shanghai, 200433 China;7. Shanghai Institute of Intelligent Science and Technology, Tongji University, Shanghai, 200070 China |
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| Abstract: | Immunotherapy, especially immune checkpoint blockade (ICB) antibody immunotherapy, has revolutionized the treatment ways of cancers and provided remarkable clinical benefits for multiple cancers. However, the efficacy of immunotherapy in tumors with an immune-excluded or immune-suppressed phenotype is dismal due to the lack or paucity of immune infiltration in the tumor microenvironment. Herein, an emerging photoimmunotherapy based on remodeling the inflammatory microenvironment is reported, ascribed to nanoagonist-mediated gasdermin E (GSDME)-dependent pyroptosis and providing positive feedback to activate anti-PD-1 immunotherapy. An iridium-based photosensitizer (IrP) carrying methyltransferase inhibitor RG108 (R@IrP) lead to rapid cell pyroptosis via the caspase-3/GSDME pathway under the light activation. Furthermore, light-elicited pyroptosis synergized with anti-PD-1 to induce anti-tumor photoimmunotherapy. The pro-inflammatory factors released by pyroptotic cells remodel the inflammatory microenvironment and recruit immune cells to kill tumor cells, resulting in CD8+ cytotoxic T lymphocytes activation, PD-1 expression enhancement, and dendritic cell slightly maturation. Collectively, these findings present a synergistic strategy of photoimmunotherapy, that is, turning immunological cold tumors into hot tumors that can respond to anti-PD-1-based immunotherapy via precise pathway regulation. |
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| Keywords: | GSDME-dependence immune-cold tumors inflammatory microenvironment photoimmunotherapy pyroptosis |
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