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 c...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.展开更多
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)+2 种基金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).
文摘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.
