{"title":"De‐novo Design of Structure‐tunable Multivalent Chimeras for Tumor‐Targeted PD‐L1 Degradation and Potentiated Cancer Immunotherapy","authors":"Huiling Zhou, Bo Hou, Yiming Shan, Lujia Huang, Fangmin Chen, Siyuan Ren, Shunan Zhang, Jiaxing Pan, Yijing Dang, Haijun Yu, Zhiai Xu","doi":"10.1002/anie.202504233","DOIUrl":null,"url":null,"abstract":"Targeted protein degradation (TPD) technology holds significant potential for modulating protein homeostasis and treating diseases. However, current methods for degrading membrane protein 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 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 valences and spacer lengths. 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 significantly 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.","PeriodicalId":125,"journal":{"name":"Angewandte Chemie International Edition","volume":"11 1","pages":""},"PeriodicalIF":16.1000,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Angewandte Chemie International Edition","FirstCategoryId":"92","ListUrlMain":"https://doi.org/10.1002/anie.202504233","RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
引用次数: 0
Abstract
Targeted protein degradation (TPD) technology holds significant potential for modulating protein homeostasis and treating diseases. However, current methods for degrading membrane protein 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 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 valences and spacer lengths. 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 significantly 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.
期刊介绍:
Angewandte Chemie, a journal of the German Chemical Society (GDCh), maintains a leading position among scholarly journals in general chemistry with an impressive Impact Factor of 16.6 (2022 Journal Citation Reports, Clarivate, 2023). Published weekly in a reader-friendly format, it features new articles almost every day. Established in 1887, Angewandte Chemie is a prominent chemistry journal, offering a dynamic blend of Review-type articles, Highlights, Communications, and Research Articles on a weekly basis, making it unique in the field.