Daurisoline Modulates the TBK1-Dependent Type I Interferon Pathway to Boost Anti-tumor Immunity via Targeting of LRP1
A promising therapeutic approach in oncology involves immune checkpoint blockade (ICB), which stimulates anti-tumor immune responses. Nevertheless, the effectiveness of this treatment in clinical settings remains limited, underscoring the need for complementary strategies. Recent studies highlight t...
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| Language: | English |
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American Association for the Advancement of Science (AAAS)
2025-01-01
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| Series: | Research |
| Online Access: | https://spj.science.org/doi/10.34133/research.0764 |
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| author | Borui Tang Yuting Wang Liping Li Cuicui Sun Jingwen Dong Ruoqi Li Jianfeng Wang Yu Long Mingxiao Yin Fei Xie Dian Xiao Xinbo Zhou Na Zhang Xiuli Zhao Yanchun Feng Hongbin Deng |
| author_facet | Borui Tang Yuting Wang Liping Li Cuicui Sun Jingwen Dong Ruoqi Li Jianfeng Wang Yu Long Mingxiao Yin Fei Xie Dian Xiao Xinbo Zhou Na Zhang Xiuli Zhao Yanchun Feng Hongbin Deng |
| author_sort | Borui Tang |
| collection | DOAJ |
| description | A promising therapeutic approach in oncology involves immune checkpoint blockade (ICB), which stimulates anti-tumor immune responses. Nevertheless, the effectiveness of this treatment in clinical settings remains limited, underscoring the need for complementary strategies. Recent studies highlight the potential of type I interferon (IFN-I) inducers to reprogram the tumor microenvironment and enhance ICB outcomes. Herein, through high-content screening of a natural compound library, we identified daurisoline (DS), a bioactive alkaloid extracted from the Chinese herbal medicine Rhizoma Menispermi, as a potent inducer of IFN-I signaling. Our findings indicated that DS up-regulates interferon responses and pro-inflammatory cytokine expression in a TANK-binding kinase 1 (TBK1)-dependent manner. In vivo, DS exhibited marked tumor growth inhibition by activating dendritic cells, macrophages, and CD8+ T cells, thereby enhancing anti-tumor immunity. Utilizing the LiP-SMap approach, we identified low-density lipoprotein receptor-related protein 1 (LRP1) as the direct target of DS. Mechanistically, the binding of DS to LRP1 substantially disrupted lysosomal function, which subsequently triggered 5′-azacytidine-induced protein 2-mediated TBK1 activation and IFN-I production. Furthermore, DS demonstrated synergistic effects with anti-programmed death 1 therapy and a stimulator of interferon genes agonist by remodeling the immunosuppressive microenvironment. Collectively, our findings establish LRP1 as a novel therapeutic target for cancer immunotherapy and highlight DS-driven immune reprogramming as a translatable strategy to potentiate ICB efficacy. |
| format | Article |
| id | doaj-art-cd407e7a221344a58f00aad8243c0f92 |
| institution | DOAJ |
| issn | 2639-5274 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | American Association for the Advancement of Science (AAAS) |
| record_format | Article |
| series | Research |
| spelling | doaj-art-cd407e7a221344a58f00aad8243c0f922025-08-20T02:43:15ZengAmerican Association for the Advancement of Science (AAAS)Research2639-52742025-01-01810.34133/research.0764Daurisoline Modulates the TBK1-Dependent Type I Interferon Pathway to Boost Anti-tumor Immunity via Targeting of LRP1Borui Tang0Yuting Wang1Liping Li2Cuicui Sun3Jingwen Dong4Ruoqi Li5Jianfeng Wang6Yu Long7Mingxiao Yin8Fei Xie9Dian Xiao10Xinbo Zhou11Na Zhang12Xiuli Zhao13Yanchun Feng14Hongbin Deng15School of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, China.Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.Department of Pharmacy, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, China.National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.School of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, China.National Institutes for Food and Drug Control, Beijing 102629, China.Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.A promising therapeutic approach in oncology involves immune checkpoint blockade (ICB), which stimulates anti-tumor immune responses. Nevertheless, the effectiveness of this treatment in clinical settings remains limited, underscoring the need for complementary strategies. Recent studies highlight the potential of type I interferon (IFN-I) inducers to reprogram the tumor microenvironment and enhance ICB outcomes. Herein, through high-content screening of a natural compound library, we identified daurisoline (DS), a bioactive alkaloid extracted from the Chinese herbal medicine Rhizoma Menispermi, as a potent inducer of IFN-I signaling. Our findings indicated that DS up-regulates interferon responses and pro-inflammatory cytokine expression in a TANK-binding kinase 1 (TBK1)-dependent manner. In vivo, DS exhibited marked tumor growth inhibition by activating dendritic cells, macrophages, and CD8+ T cells, thereby enhancing anti-tumor immunity. Utilizing the LiP-SMap approach, we identified low-density lipoprotein receptor-related protein 1 (LRP1) as the direct target of DS. Mechanistically, the binding of DS to LRP1 substantially disrupted lysosomal function, which subsequently triggered 5′-azacytidine-induced protein 2-mediated TBK1 activation and IFN-I production. Furthermore, DS demonstrated synergistic effects with anti-programmed death 1 therapy and a stimulator of interferon genes agonist by remodeling the immunosuppressive microenvironment. Collectively, our findings establish LRP1 as a novel therapeutic target for cancer immunotherapy and highlight DS-driven immune reprogramming as a translatable strategy to potentiate ICB efficacy.https://spj.science.org/doi/10.34133/research.0764 |
| spellingShingle | Borui Tang Yuting Wang Liping Li Cuicui Sun Jingwen Dong Ruoqi Li Jianfeng Wang Yu Long Mingxiao Yin Fei Xie Dian Xiao Xinbo Zhou Na Zhang Xiuli Zhao Yanchun Feng Hongbin Deng Daurisoline Modulates the TBK1-Dependent Type I Interferon Pathway to Boost Anti-tumor Immunity via Targeting of LRP1 Research |
| title | Daurisoline Modulates the TBK1-Dependent Type I Interferon Pathway to Boost Anti-tumor Immunity via Targeting of LRP1 |
| title_full | Daurisoline Modulates the TBK1-Dependent Type I Interferon Pathway to Boost Anti-tumor Immunity via Targeting of LRP1 |
| title_fullStr | Daurisoline Modulates the TBK1-Dependent Type I Interferon Pathway to Boost Anti-tumor Immunity via Targeting of LRP1 |
| title_full_unstemmed | Daurisoline Modulates the TBK1-Dependent Type I Interferon Pathway to Boost Anti-tumor Immunity via Targeting of LRP1 |
| title_short | Daurisoline Modulates the TBK1-Dependent Type I Interferon Pathway to Boost Anti-tumor Immunity via Targeting of LRP1 |
| title_sort | daurisoline modulates the tbk1 dependent type i interferon pathway to boost anti tumor immunity via targeting of lrp1 |
| url | https://spj.science.org/doi/10.34133/research.0764 |
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