Proteasomal and lysosomal degradation for specific and durable suppression of immunotherapeutic targets

作     者：Yungang Wang Shouyan Deng Jie Xu Yungang Wang;Shouyan Deng;Jie Xu

作者机构：Institutes of Biomedical SciencesZhongshan-Xuhui Hospitaland Shanghai Key Laboratory of Medical EpigeneticsFudan UniversityShanghai 200433China Department of Laboratory MedicineThe First People's Hospital of Yancheng CityYancheng 224006China Renji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai 200127China 

出 版 物：《Cancer Biology & Medicine》 (癌症生物学与医学（英文版）)

年 卷 期：2020年第17卷第3期

页      面：583-598页

核心收录：

学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

基　　金：This work was supported by the National Natural Science Foundation of China(Grant Nos.81874050,81572326,81322036,81421001,and 81902906) National Key R&D Program of China(Grant No.2016YFC0906002) Startup Research Funding from Fudan University(Grant No.2019XJ) Jiangsu Province's Medical Scientific Research Project(Grant No.H2019102) 

主　　题：Cancer immunotherapy membrane protein PROTAC targeted degradation 

摘      要：Cancer immunotherapy harness the body s immune system to eliminate cancer,by using a broad panel of soluble and membrane proteins as therapeutic *** signaling mediated by ligand-receptor interaction may be blocked by monoclonal antibodies,but because of repopulation of the membranevia intracellular organelles,targets must be eliminated in whole *** protein degradation,as exemplified in proteolysis targeting chimera(PROTAC)studies,is a promising strategy for selective inhibition of target *** recently reported use of lysosomal targeting molecules to eliminate immune checkpoint proteins has paved the way for targeted degradation of membrane proteins as crucial anti-cancer *** studies on these molecules modes of action,target-bindingwarheads,lysosomal sorting signals,and linker design should facilitate their rational *** and derivatives may improve their cell-penetrating ability and thein vivo stability of these *** studies suggest the promise of alternative strategies for cancer immunotherapy,with the aim of achieving more potent and durable suppression of tumor ***,the successes and limitations of antibody inhibitorsin cancer immunotherapy,as well as research progress on PROTAC-and lysosomal-dependent degradation of target proteins,are reviewed.