Cascaded immunotherapy with implantable dual-drug depots sequentially releasing STING agonists and apoptosis inducers
Abstract Non-nucleotide stimulators of interferon gene (STING) agonists hold promise as immunotherapeutic agents for postsurgical adjuvant treatment of tumors. However, their limited effect duration hampers therapeutic effectiveness, necessitating prolonged administration of multiple doses that heig...
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Nature Portfolio
2025-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56407-7 |
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| author | Kai Li Xuan Yu Yanteng Xu Haixia Wang Zheng Liu Chong Wu Xing Luo Jiancheng Xu Youqiang Fang Enguo Ju Shixian Lv Hon Fai Chan Yeh-Hsing Lao Weiling He Yu Tao Mingqiang Li |
| author_facet | Kai Li Xuan Yu Yanteng Xu Haixia Wang Zheng Liu Chong Wu Xing Luo Jiancheng Xu Youqiang Fang Enguo Ju Shixian Lv Hon Fai Chan Yeh-Hsing Lao Weiling He Yu Tao Mingqiang Li |
| author_sort | Kai Li |
| collection | DOAJ |
| description | Abstract Non-nucleotide stimulators of interferon gene (STING) agonists hold promise as immunotherapeutic agents for postsurgical adjuvant treatment of tumors. However, their limited effect duration hampers therapeutic effectiveness, necessitating prolonged administration of multiple doses that heightens infection risk and impacts patient compliance. Here, we develop an implantable dual-drug depot in a sandwich-like configuration, with a non-nucleotide STING agonist (MSA-2) in the outer layers of 3D-printed scaffolds and an immunogenic apoptosis inducer (doxorubicin, DOX) in the inner layer of electrospun fibers. We discover that MSA-2 can elicit endoplasmic reticulum stress-mediated and general immunogenic apoptosis of cancer cells. The stimulations with tumor-associated antigens and damage-associated molecular patterns from cancer cells, along with proinflammatory factors secreted by matured dendritic cells and M1-polarized macrophages, can depolymerize intracellular microtubules guiding activated STING trafficking towards lysosomes for degradation. Collectively, the dual-drug depots can initiate a long-lasting cascaded immunotherapy and chemotherapy, suppressing postsurgical tumor recurrence and metastasis. |
| format | Article |
| id | doaj-art-c0046fb68ccd454e97da999dad85f66d |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-c0046fb68ccd454e97da999dad85f66d2025-08-20T02:12:58ZengNature PortfolioNature Communications2041-17232025-02-0116112610.1038/s41467-025-56407-7Cascaded immunotherapy with implantable dual-drug depots sequentially releasing STING agonists and apoptosis inducersKai Li0Xuan Yu1Yanteng Xu2Haixia Wang3Zheng Liu4Chong Wu5Xing Luo6Jiancheng Xu7Youqiang Fang8Enguo Ju9Shixian Lv10Hon Fai Chan11Yeh-Hsing Lao12Weiling He13Yu Tao14Mingqiang Li15Laboratory of Biomaterials and Translational Medicine, Department of Ultrasound, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen UniversityLaboratory of Biomaterials and Translational Medicine, Department of Ultrasound, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen UniversityLaboratory of Biomaterials and Translational Medicine, Department of Ultrasound, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen UniversityLaboratory of Biomaterials and Translational Medicine, Department of Ultrasound, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen UniversityLaboratory of Biomaterials and Translational Medicine, Department of Ultrasound, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen UniversityDepartment of Gastrointestinal Surgery, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen UniversityLaboratory of Biomaterials and Translational Medicine, Department of Ultrasound, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen UniversityLaboratory of Biomaterials and Translational Medicine, Department of Ultrasound, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen UniversityLaboratory of Biomaterials and Translational Medicine, Department of Ultrasound, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen UniversityLaboratory of Biomaterials and Translational Medicine, Department of Ultrasound, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen UniversitySchool of Materials Science and Engineering, Peking UniversityInstitute for Tissue Engineering and Regenerative Medicine, School of Biomedical Science, The Chinese University of Hong KongDepartment of Pharmaceutical Sciences, University at Buffalo, The State University of New YorkDepartment of Gastrointestinal Surgery, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen UniversityLaboratory of Biomaterials and Translational Medicine, Department of Ultrasound, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen UniversityLaboratory of Biomaterials and Translational Medicine, Department of Ultrasound, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen UniversityAbstract Non-nucleotide stimulators of interferon gene (STING) agonists hold promise as immunotherapeutic agents for postsurgical adjuvant treatment of tumors. However, their limited effect duration hampers therapeutic effectiveness, necessitating prolonged administration of multiple doses that heightens infection risk and impacts patient compliance. Here, we develop an implantable dual-drug depot in a sandwich-like configuration, with a non-nucleotide STING agonist (MSA-2) in the outer layers of 3D-printed scaffolds and an immunogenic apoptosis inducer (doxorubicin, DOX) in the inner layer of electrospun fibers. We discover that MSA-2 can elicit endoplasmic reticulum stress-mediated and general immunogenic apoptosis of cancer cells. The stimulations with tumor-associated antigens and damage-associated molecular patterns from cancer cells, along with proinflammatory factors secreted by matured dendritic cells and M1-polarized macrophages, can depolymerize intracellular microtubules guiding activated STING trafficking towards lysosomes for degradation. Collectively, the dual-drug depots can initiate a long-lasting cascaded immunotherapy and chemotherapy, suppressing postsurgical tumor recurrence and metastasis.https://doi.org/10.1038/s41467-025-56407-7 |
| spellingShingle | Kai Li Xuan Yu Yanteng Xu Haixia Wang Zheng Liu Chong Wu Xing Luo Jiancheng Xu Youqiang Fang Enguo Ju Shixian Lv Hon Fai Chan Yeh-Hsing Lao Weiling He Yu Tao Mingqiang Li Cascaded immunotherapy with implantable dual-drug depots sequentially releasing STING agonists and apoptosis inducers Nature Communications |
| title | Cascaded immunotherapy with implantable dual-drug depots sequentially releasing STING agonists and apoptosis inducers |
| title_full | Cascaded immunotherapy with implantable dual-drug depots sequentially releasing STING agonists and apoptosis inducers |
| title_fullStr | Cascaded immunotherapy with implantable dual-drug depots sequentially releasing STING agonists and apoptosis inducers |
| title_full_unstemmed | Cascaded immunotherapy with implantable dual-drug depots sequentially releasing STING agonists and apoptosis inducers |
| title_short | Cascaded immunotherapy with implantable dual-drug depots sequentially releasing STING agonists and apoptosis inducers |
| title_sort | cascaded immunotherapy with implantable dual drug depots sequentially releasing sting agonists and apoptosis inducers |
| url | https://doi.org/10.1038/s41467-025-56407-7 |
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