Light-activatable manganese carbonate nanocubes elicit robust immunotherapy by amplifying endoplasmic reticulum stress-meditated pyroptotic cell death
Abstract Although tumor immunotherapy has emerged as a promising treatment modality, it faces significant challenges stemming from the immunosuppressive characteristics of the tumor microenvironment (TME), the low immunogenicity of tumors, and the poor specificity of immunoactivation. These factors...
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BMC
2025-05-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
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| Online Access: | https://doi.org/10.1186/s13046-025-03408-5 |
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| author | Chuan Wu Mingquan Gao Weidong Xiao Xie Huang Xinrui Yang Zifei Wu Xudong Yu Banghui Mo Zaizhi Du Ziqian Shang Jing Liu Can Shi Rong Li Shenglin Luo Weidong Wang |
| author_facet | Chuan Wu Mingquan Gao Weidong Xiao Xie Huang Xinrui Yang Zifei Wu Xudong Yu Banghui Mo Zaizhi Du Ziqian Shang Jing Liu Can Shi Rong Li Shenglin Luo Weidong Wang |
| author_sort | Chuan Wu |
| collection | DOAJ |
| description | Abstract Although tumor immunotherapy has emerged as a promising treatment modality, it faces significant challenges stemming from the immunosuppressive characteristics of the tumor microenvironment (TME), the low immunogenicity of tumors, and the poor specificity of immunoactivation. These factors can hinder the efficacy of immunotherapeutic approaches and lead to immune-related adverse events. This study reports a multifunctional nanocube (Mn-ER-Cy) that integrates Mn carbonate (MnCO3) and a photosensitizer (ER-Cy) by targeting tumor-cell endoplasmic reticulum (ER). The results demonstrate that Mn-ER-Cy preferentially accumulates in tumor tissues and is retained within ER organelles, facilitating photothermal therapy (PTT) and photodynamic therapy (PDT) upon exposure to 808 nm light irradiation. Triggered by acidic TME and light irradiation, MnCO3 is rapidly degraded to Mn2+, which in turn promotes the generation of reactive oxygen species through the Mn2+-mimic Fenton reaction, enabling chemical dynamics therapy (CDT). Triple-modal synergistic therapy simultaneously happens in ER to induce excessive ER stress, which subsequently amplify highly immunogenic pyroptotic cell death through activating NLRP3 inflammasome, caspase-1, and gasdermin D (GSDMD) pathway. Meanwhile, the decomposition of MnCO3 consumes H+ and contributes to an increased intracellular pH by regulating lactic acid levels, thereby counteracting the immunosuppressive acidic TME. Furthermore, Mn-ER-Cy serves as an inherent dual-modality imaging contrast agent for near-infrared fluorescence and photoacoustic imaging, facilitating imaging-guided precision therapy. These findings underscore the potential of Mn-ER-Cy to substantially enhance the efficacy and specificity of tumor immunotherapy, portraying a bright prospect to improve the clinical outcomes of patients with cancer. |
| format | Article |
| id | doaj-art-028be14cd89040b2bdfca7c9902ebb50 |
| institution | OA Journals |
| issn | 1756-9966 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj-art-028be14cd89040b2bdfca7c9902ebb502025-08-20T01:51:36ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662025-05-0144112610.1186/s13046-025-03408-5Light-activatable manganese carbonate nanocubes elicit robust immunotherapy by amplifying endoplasmic reticulum stress-meditated pyroptotic cell deathChuan Wu0Mingquan Gao1Weidong Xiao2Xie Huang3Xinrui Yang4Zifei Wu5Xudong Yu6Banghui Mo7Zaizhi Du8Ziqian Shang9Jing Liu10Can Shi11Rong Li12Shenglin Luo13Weidong Wang14Department of Radiation Oncology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of ChinaInstitute of Combined Injury, State Key Laboratory of Trauma and Chemical Poisoning, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University (Army Medical University)Department of Pharmacy, Daping Hospital, Third Military Medical University (Army Medical University)Institute of Combined Injury, State Key Laboratory of Trauma and Chemical Poisoning, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University (Army Medical University)Institute of Combined Injury, State Key Laboratory of Trauma and Chemical Poisoning, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University (Army Medical University)Institute of Combined Injury, State Key Laboratory of Trauma and Chemical Poisoning, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University (Army Medical University)Institute of Combined Injury, State Key Laboratory of Trauma and Chemical Poisoning, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University (Army Medical University)Institute of Combined Injury, State Key Laboratory of Trauma and Chemical Poisoning, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University (Army Medical University)Institute of Combined Injury, State Key Laboratory of Trauma and Chemical Poisoning, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University (Army Medical University)Institute of Combined Injury, State Key Laboratory of Trauma and Chemical Poisoning, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University (Army Medical University)Institute of Combined Injury, State Key Laboratory of Trauma and Chemical Poisoning, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University (Army Medical University)Institute of Combined Injury, State Key Laboratory of Trauma and Chemical Poisoning, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University (Army Medical University)Institute of Combined Injury, State Key Laboratory of Trauma and Chemical Poisoning, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University (Army Medical University)Institute of Combined Injury, State Key Laboratory of Trauma and Chemical Poisoning, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University (Army Medical University)Department of Radiation Oncology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of ChinaAbstract Although tumor immunotherapy has emerged as a promising treatment modality, it faces significant challenges stemming from the immunosuppressive characteristics of the tumor microenvironment (TME), the low immunogenicity of tumors, and the poor specificity of immunoactivation. These factors can hinder the efficacy of immunotherapeutic approaches and lead to immune-related adverse events. This study reports a multifunctional nanocube (Mn-ER-Cy) that integrates Mn carbonate (MnCO3) and a photosensitizer (ER-Cy) by targeting tumor-cell endoplasmic reticulum (ER). The results demonstrate that Mn-ER-Cy preferentially accumulates in tumor tissues and is retained within ER organelles, facilitating photothermal therapy (PTT) and photodynamic therapy (PDT) upon exposure to 808 nm light irradiation. Triggered by acidic TME and light irradiation, MnCO3 is rapidly degraded to Mn2+, which in turn promotes the generation of reactive oxygen species through the Mn2+-mimic Fenton reaction, enabling chemical dynamics therapy (CDT). Triple-modal synergistic therapy simultaneously happens in ER to induce excessive ER stress, which subsequently amplify highly immunogenic pyroptotic cell death through activating NLRP3 inflammasome, caspase-1, and gasdermin D (GSDMD) pathway. Meanwhile, the decomposition of MnCO3 consumes H+ and contributes to an increased intracellular pH by regulating lactic acid levels, thereby counteracting the immunosuppressive acidic TME. Furthermore, Mn-ER-Cy serves as an inherent dual-modality imaging contrast agent for near-infrared fluorescence and photoacoustic imaging, facilitating imaging-guided precision therapy. These findings underscore the potential of Mn-ER-Cy to substantially enhance the efficacy and specificity of tumor immunotherapy, portraying a bright prospect to improve the clinical outcomes of patients with cancer.https://doi.org/10.1186/s13046-025-03408-5Heptamethine cyanine dyePhototherapyManganese carbonate nanocubesImage-guided therapyPhotoacoustic imaging |
| spellingShingle | Chuan Wu Mingquan Gao Weidong Xiao Xie Huang Xinrui Yang Zifei Wu Xudong Yu Banghui Mo Zaizhi Du Ziqian Shang Jing Liu Can Shi Rong Li Shenglin Luo Weidong Wang Light-activatable manganese carbonate nanocubes elicit robust immunotherapy by amplifying endoplasmic reticulum stress-meditated pyroptotic cell death Journal of Experimental & Clinical Cancer Research Heptamethine cyanine dye Phototherapy Manganese carbonate nanocubes Image-guided therapy Photoacoustic imaging |
| title | Light-activatable manganese carbonate nanocubes elicit robust immunotherapy by amplifying endoplasmic reticulum stress-meditated pyroptotic cell death |
| title_full | Light-activatable manganese carbonate nanocubes elicit robust immunotherapy by amplifying endoplasmic reticulum stress-meditated pyroptotic cell death |
| title_fullStr | Light-activatable manganese carbonate nanocubes elicit robust immunotherapy by amplifying endoplasmic reticulum stress-meditated pyroptotic cell death |
| title_full_unstemmed | Light-activatable manganese carbonate nanocubes elicit robust immunotherapy by amplifying endoplasmic reticulum stress-meditated pyroptotic cell death |
| title_short | Light-activatable manganese carbonate nanocubes elicit robust immunotherapy by amplifying endoplasmic reticulum stress-meditated pyroptotic cell death |
| title_sort | light activatable manganese carbonate nanocubes elicit robust immunotherapy by amplifying endoplasmic reticulum stress meditated pyroptotic cell death |
| topic | Heptamethine cyanine dye Phototherapy Manganese carbonate nanocubes Image-guided therapy Photoacoustic imaging |
| url | https://doi.org/10.1186/s13046-025-03408-5 |
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