Demethylzeylasteral induces PD-L1 ubiquitin-proteasome degradation and promotes antitumor immunity via targeting USP22

作     者：Yanyan Zhang Yun Huang Dianping Yu Mengting Xu Hongmei Hu Qing Zhang Minchen Cai Xiangxin Geng Hongwei Zhang Jianhua Xia Mengmeng Guo Dong Lu Hanchi Xu Linyang Li Xing Zhang Qun Wang Sanhong Liu Weidong Zhang 

作者机构：Shanghai Frontiers Science Center of TCM Chemical BiologyInstitute of Interdisciplinary Integrative Medicine ResearchShanghai University of Traditional Chinese MedicineShanghai 201203China Department of PhytochemistrySchool of PharmacySecond Military Medical UniversityShanghai 200433China Institute of Medicinal Plant DevelopmentChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100193China The Research Center for Traditional Chinese MedicineShanghai Institute of Infectious Diseases and BiosafetyInstitute of Interdisciplinary Integrative Medicine ResearchShanghai University of Traditional Chinese MedicineShanghai 201203China 

出 版 物：《Acta Pharmaceutica Sinica B》 (药学学报（英文版）)

年 卷 期：2024年第14卷第10期

页      面：4312-4328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：funded by the National Key Research and Development Program of China(2022YFC3502000) National Natural Science Foundation of China(Nos.82141203,82374086,and 82104459) Shanghai Municipal Science and Technology Major Project(ZD2021CY001,China) Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine(ZYYCXTDD-202004,China) Science and Technology Commission of Shanghai Municipality(20YF1458700,China) Organizational Key Research and Development Program of Shanghai University of Traditional Chinese Medicine(2023YZZ02,China) 

主　　题：Demethylzeylasteral PD-L1 USP22 Deubiquitination Tumor-infiltrating lymphocytes Colorectal cancer Immune checkpoint blockade Antitumor immunity 

摘      要：Programmed cell death ligand-1(PD-L1)is a T cell inhibitory immune checkpoint molecule that interacts with programmed cell death-1(PD-1)to promote immune escape of tumor *** with antibody therapies,small molecule drugs show better prospects due to their advantages such as higher bioavailability,better tissue penetration,and reduced risk of ***,we found that the small molecule demethylzeylasteral(Dem)can significantly downregulate the expression of PD-L1 in colorectal cancer cells and enhance the killing effect of T cells on tumor ***,Dem binds to the deubiquitinating enzyme USP22 and promotes its degradation,resulting in increased ubiquitination and degradation of PD-L1 through the proteasome *** addition,Dem increased the activity of cytotoxic T cells and reduced the number of myeloid-derived suppressor cells(MDSCs)and regulatory T cells(Tregs)in tumor-infiltrating lymphocytes(TILs),thereby activating the tumor immune microenvironment and inhibiting the growth of subcutaneous MC38 tumors in C57BL/6 ***,we also found that the combination of Dem and CTLA4 antibodies can further improve the efficacy of antitumor *** study reveals the mechanism by which Dem promotes PD-L1 degradation and suggests that the combination of Dem and CTLA4 antibodies may improve the efficacy of immunotherapy.