Branched glycopolymer prodrug-derived nanoassembly combined with a STING agonist activates an immuno-supportive status to boost anti-PD-L1 antibody therapy  

作　　者：Zhilin Li Qianfeng Zhang Zhiqian Li Long Ren Dayi Pan Qiyong Gong Zhongwei Gu Hao Cai Kui Luo 

机构地区：[1]Department of Radiology,Huaxi MR Research Center(HMRRC),Clinical Research Center for Breast,Department of Breast Surgery,Department of Thoracic Surgery and Institute of Thoracic Oncology,Frontiers Science Center for Disease-Related Molecular Network,State Key Laboratory of Biotherapy,West China Hospital Sichuan University,Chengdu 610041,China [2]Functional and Molecular Imaging Key Laboratory of Sichuan Province,and Research Unit of Psychoradiology,Chinese Academy of Medical Sciences,Chengdu 610041,China [3]Department of Radiology,West China Xiamen Hospital of Sichuan University,Xiamen 361021,China [4]Key Laboratory of Medicinal Chemistry for Natural Resource,Ministry of Education,Yunnan Key Laboratory of Research and Development for Natural Products,School of Pharmacy,Yunnan University,Kunming 650500,China

出　　处：《Acta Pharmaceutica Sinica B》2024年第5期2194-2209,共16页药学学报（英文版）

基　　金：This work was supported by National Natural Science Foundation of China(32271445,52073193,and 82202322);National Science and Technology Major Project of China(2023YFB3810004);1·3·5 Project for Disciplines of Excellence,West China Hospital,Sichuan University(ZYJC21013,China);the Sichuan Science and Technology Program(2023NSFSC1592,China),the China Postdoctoral Science Foundation(2021M692255,China);the Post-Doctor Research Project,West China Hospital,Sichuan University(2020HXBH094,China).

摘　　要：Despite the great potential of anti-PD-L1 antibodies for immunotherapy,their low response rate due to an immunosuppressive tumor microenvironment has hampered their application.To address this issue,we constructed a cell membrane-coated nanosystem(mB4S)to reverse an immunosuppressive microenvironment to an immuno-supportive one for strengthening the anti-tumor effect.In this system,Epirubicin(EPI)as an immunogenic cell death(ICD)inducer was coupled to a branched glycopolymer via hydrazone bonds and diABZI as a stimulator of interferon genes(STING)agonist was encapsulated into mB4S.After internalization of mB4S,EPI was acidic-responsively released to induce ICD,which was characterized by an increased level of calreticulin(CRT)exposure and enhanced ATP secretion.Meanwhile,diABZI effectively activated the STING pathway.Treatment with mB4S in combination with an anti-PD-L1 antibody elicited potent immune responses by increasing the ratio of matured dendritic cells(DCs)and CD8+T cells,promoting cytokines secretion,up-regulating M1-like tumor-associated macrophages(TAMs)and down-regulating immunosuppressive myeloid-derived suppressor cells(MDSCs).Therefore,this nanosystem for co-delivery of an ICD inducer and a STING agonist achieved promotion of DCs maturation and CD8+T cells infiltration,creating an immuno-supportive microenvironment,thus potentiating the therapy effect of the anti-PD-L1 antibody in both 4T1 breast and CT26 colon tumor mice.

关 键 词：GLYCOPOLYMER Polymer prodrug Immunogenic cell death Nanoassembly EPIRUBICIN STING pathway Immuno-supportive microenvironment Immunotherapy 

分 类 号：R943[医药卫生—药剂学]