A covalent peptide-based lysosome-targeting protein degradation platform for cancer immunotherapy
Abstract The lysosome-targeting chimera (LYTAC) strategy provided a very powerful tool for the degradation of membrane proteins. However, the synthesis of LYTACs, antibody-small molecule conjugates, is challenging. The ability of antibody-based LYTACs to penetrate solid tumor is limited as well, esp...
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Nature Portfolio
2025-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56648-6 |
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| author | Youmei Xiao Zhuoying He Wanqiong Li Danhong Chen Xiaoshuang Niu Xin Yang Wenxuan Zeng Mengfan Wang Yuzhen Qian Ye Su Feiyu Luo Guanyu Chen Juan Liu Xinghua Sui Xiuman Zhou Yanfeng Gao |
| author_facet | Youmei Xiao Zhuoying He Wanqiong Li Danhong Chen Xiaoshuang Niu Xin Yang Wenxuan Zeng Mengfan Wang Yuzhen Qian Ye Su Feiyu Luo Guanyu Chen Juan Liu Xinghua Sui Xiuman Zhou Yanfeng Gao |
| author_sort | Youmei Xiao |
| collection | DOAJ |
| description | Abstract The lysosome-targeting chimera (LYTAC) strategy provided a very powerful tool for the degradation of membrane proteins. However, the synthesis of LYTACs, antibody-small molecule conjugates, is challenging. The ability of antibody-based LYTACs to penetrate solid tumor is limited as well, especially to cross the blood-brain barrier (BBB). Here, we propose a covalent chimeric peptide-based targeted degradation platform (Pep-TACs) by introducing a long flexible aryl sulfonyl fluoride group, which allows proximity-enabled cross-linking upon binding with the protein of interest. The Pep-TACs platform facilitates the degradation of target proteins through the mechanism of recycling transferrin receptor (TFRC)-mediated lysosomal targeted endocytosis. Biological experiments demonstrate that covalent Pep-TACs can significantly degrade the expression of PD-L1 on tumor cells, dendritic cells and macrophages, especially under acidic conditions, and markedly enhance the function of T cells and tumor phagocytosis by macrophages. Furthermore, both in anti-PD-1-responsive and -resistant tumor models, the Pep-TACs exert significant anti-tumor immune response. It is noteworthy that Pep-TACs can cross the BBB and prolong the survival of mice with in situ brain tumor. As a proof-of-concept, this study introduces a modular TFRC-based covalent peptide degradation platform for the degradation of membrane protein, and especially for the immunotherapy of brain tumors. |
| format | Article |
| id | doaj-art-2d8efaf86f23473f8f91653016caf904 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-2d8efaf86f23473f8f91653016caf9042025-02-09T12:45:07ZengNature PortfolioNature Communications2041-17232025-02-0116111610.1038/s41467-025-56648-6A covalent peptide-based lysosome-targeting protein degradation platform for cancer immunotherapyYoumei Xiao0Zhuoying He1Wanqiong Li2Danhong Chen3Xiaoshuang Niu4Xin Yang5Wenxuan Zeng6Mengfan Wang7Yuzhen Qian8Ye Su9Feiyu Luo10Guanyu Chen11Juan Liu12Xinghua Sui13Xiuman Zhou14Yanfeng Gao15School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen UniversitySchool of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen UniversityThe Seventh Affiliated Hospital, Sun Yat-sen UniversitySchool of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen UniversitySchool of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen UniversitySchool of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen UniversitySchool of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen UniversitySchool of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen UniversitySchool of Life Sciences, Zhengzhou UniversitySchool of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen UniversitySchool of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen UniversitySchool of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen UniversitySchool of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen UniversitySchool of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen UniversitySchool of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen UniversitySchool of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen UniversityAbstract The lysosome-targeting chimera (LYTAC) strategy provided a very powerful tool for the degradation of membrane proteins. However, the synthesis of LYTACs, antibody-small molecule conjugates, is challenging. The ability of antibody-based LYTACs to penetrate solid tumor is limited as well, especially to cross the blood-brain barrier (BBB). Here, we propose a covalent chimeric peptide-based targeted degradation platform (Pep-TACs) by introducing a long flexible aryl sulfonyl fluoride group, which allows proximity-enabled cross-linking upon binding with the protein of interest. The Pep-TACs platform facilitates the degradation of target proteins through the mechanism of recycling transferrin receptor (TFRC)-mediated lysosomal targeted endocytosis. Biological experiments demonstrate that covalent Pep-TACs can significantly degrade the expression of PD-L1 on tumor cells, dendritic cells and macrophages, especially under acidic conditions, and markedly enhance the function of T cells and tumor phagocytosis by macrophages. Furthermore, both in anti-PD-1-responsive and -resistant tumor models, the Pep-TACs exert significant anti-tumor immune response. It is noteworthy that Pep-TACs can cross the BBB and prolong the survival of mice with in situ brain tumor. As a proof-of-concept, this study introduces a modular TFRC-based covalent peptide degradation platform for the degradation of membrane protein, and especially for the immunotherapy of brain tumors.https://doi.org/10.1038/s41467-025-56648-6 |
| spellingShingle | Youmei Xiao Zhuoying He Wanqiong Li Danhong Chen Xiaoshuang Niu Xin Yang Wenxuan Zeng Mengfan Wang Yuzhen Qian Ye Su Feiyu Luo Guanyu Chen Juan Liu Xinghua Sui Xiuman Zhou Yanfeng Gao A covalent peptide-based lysosome-targeting protein degradation platform for cancer immunotherapy Nature Communications |
| title | A covalent peptide-based lysosome-targeting protein degradation platform for cancer immunotherapy |
| title_full | A covalent peptide-based lysosome-targeting protein degradation platform for cancer immunotherapy |
| title_fullStr | A covalent peptide-based lysosome-targeting protein degradation platform for cancer immunotherapy |
| title_full_unstemmed | A covalent peptide-based lysosome-targeting protein degradation platform for cancer immunotherapy |
| title_short | A covalent peptide-based lysosome-targeting protein degradation platform for cancer immunotherapy |
| title_sort | covalent peptide based lysosome targeting protein degradation platform for cancer immunotherapy |
| url | https://doi.org/10.1038/s41467-025-56648-6 |
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