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De Novo Design of Structure-Tunable Multivalent Targeting Chimeras for Tumor-Targeted PD-L1 Degradation and Potentiated Cancer Immunotherapy

文献类型：期刊论文

作者Zhou, Huiling1,2,3; Hou, Bo1,3,4; Shan, Yiming1,3,5; Huang, Lujia1,3,5; Chen, Fangmin1,3,5; Ren, Siyuan1,3; Zhang, Shunan1,2,3; Pan, Jiaxing1,3; Dang, Yijing2; Yu, Haijun1,3,4,5
刊名ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
出版日期2025-05-05
页码17
关键词Combinatory therapy, Immune checkpoint blockade, Multivalent targeting chimeras Tumor microenvironment Tumor-specific PD-L1 degradation
DOI10.1002/anie.202504233
通讯作者Xu, Zhiai(zaxu@chem.ecnu.edu.cn)
英文摘要Targeted protein degradation (TPD) technology holds significant potential for modulating protein homeostasis and treating diseases. However, current methods for degrading membrane proteins highly depend on the lysosome-targeting ligands or membrane receptors. In this study, we present a set of multivalent targeting chimeras (multi-TACs) for tumor-specific degradation of programmed death ligand 1 (PD-L1) on the surface of the tumor cell membrane. The multi-TACs are synthesized by copolymerization of small-molecule PD-L1 inhibitor BMS-1 with acid-responsive monomers. The chemical structures of the multi-TACs are optimized by investigating the correlation between PD-L1 degradation efficacy and the key parameters, including acid-sensitive moieties, BMS-1 valency, and spacer length. Mechanistic study reveals that the multi-TACs highly efficiently degrade PD-L1 on the surface of tumor cells via the adsorption-mediated endocytosis and lysosomal degradation pathways, which differ from the reported strategies for membrane protein degradation. The outperformed multi-TAC GG56 with tumor extracellular acidity and enzyme-sensitivity dramatically reduces PD-L1 levels and suppresses tumor growth in mouse models of B16-F10 melanoma and 4T1 breast tumors. Furthermore, GG56 serves as a versatile nanoplatform for combinatory chemo-immunotherapy and radio-immunotherapy of 4T1 breast tumor by co-delivery of chemotherapeutic and radio-sensitizer, respectively.
WOS关键词IMMUNE RESISTANCE ; NANOPARTICLES
资助项目Science and Technology Commission of Shanghai Municipality ; National Natural Science Foundation of China[22474042] ; National Natural Science Foundation of China[W2412035] ; National Natural Science Foundation of China[32411530049] ; National Natural Science Foundation of China[U22A20328] ; Shanghai Oriental Talents Program[BJKL2024046] ; National Facility for Protein Science in Shanghai (NFPS), Shanghai Advanced Research Institute, CAS ; Shanghai Institute of Materia Medica, CAS ; [23490712700] ; [23ZR1475000] ; [20430711800]
WOS研究方向Chemistry
语种英语
WOS记录号WOS:001480825500001
出版者WILEY-V C H VERLAG GMBH
源URL[http://119.78.100.183/handle/2S10ELR8/317578]  
专题中国科学院上海药物研究所
通讯作者Xu, Zhiai
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Pharmaceut, Shanghai 201203, Peoples R China
2.East China Normal Univ, Sch Chem & Mol Engn, Shanghai 200241, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Chem Biol, Shanghai 201203, Peoples R China
4.Yantai Inst Mat Med, Yantai Key Lab Nanomed & Adv Preparat, Yantai 264000, Shandong, Peoples R China
5.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
推荐引用方式
GB/T 7714		 Zhou, Huiling,Hou, Bo,Shan, Yiming,et al. De Novo Design of Structure-Tunable Multivalent Targeting Chimeras for Tumor-Targeted PD-L1 Degradation and Potentiated Cancer Immunotherapy[J]. ANGEWANDTE CHEMIE-INTERNATIONAL EDITION,2025:17.
APA Zhou, Huiling.,Hou, Bo.,Shan, Yiming.,Huang, Lujia.,Chen, Fangmin.,...&Xu, Zhiai.(2025).De Novo Design of Structure-Tunable Multivalent Targeting Chimeras for Tumor-Targeted PD-L1 Degradation and Potentiated Cancer Immunotherapy.ANGEWANDTE CHEMIE-INTERNATIONAL EDITION,17.
MLA Zhou, Huiling,et al."De Novo Design of Structure-Tunable Multivalent Targeting Chimeras for Tumor-Targeted PD-L1 Degradation and Potentiated Cancer Immunotherapy".ANGEWANDTE CHEMIE-INTERNATIONAL EDITION (2025):17.

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来源：上海药物研究所

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