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On-demand integrated nano-engager converting cold tumors to hot via increased DNA damage and dual immune checkpoint inhibition

查看全文 作　　者：Xiaoqing [1]Liu;Shuang [1]Liang;Xiao [1]Sang;Lili [1]Chang;Shunli [1]Fu;Han [1]Yang;Huizhen [1]Yang;Yongjun [1]Liu;Na [1]Zhang 高影响力作者 机构地区：[1]Department of Pharmaceutics,Key Laboratory of Chemical Biology(Ministry of Education),NMPA Key Laboratory for Technology Research and Evaluation of Drug Products,School of Pharmaceutical Sciences,Cheeloo College of Medicine,Shandong University,Jinan 250012,China高影响力机构 出　　处：《Acta Pharmaceutica Sinica B》索引2023年第13卷第4期,共15页高影响力期刊 基　　金：supported by National Natural Science Foundation of China(81974498 and 82173757);Translational Medicine Core Facility of Shandong University;Pharmaceutical biology sharing platform of Shandong University for supporting the work。 摘　　要：Cancer immunotherapy has become a promising strategy.However,the effectiveness of immunotherapy is restricted in'cold tumors'characterized with insufficient T cells intratumoral infiltration and failed T cells priming.Herein,an on-demand integrated nano-engager(JOT-Lip)was developed to convert cold tumors to hot via'increased DNA damage and dual immune checkpoint inhibition'strategy.JOT-Lip was engineered by co-loading oxaliplatin(Oxa)and JQ1 into liposomes with T-cell immunoglobulin mucin-3 antibodies(Tim-3 mAb)coupled on the liposomal surface by metalloproteinase-2(MMP-2)-sensitive linker.JQ1 inhibited DNA repair to increase DNA damage and immunogenic cell death(ICD)of Oxa,thus promoting T cells intratumoral infiltration.In addition,JQ1 inhibited PD-1/PD-L1 pathway,achieving dual immune checkpoint inhibition combining with Tim-3 mAb,thus effectively promoting T cells priming.It is demonstrated that JOT-Lip not only increased DNA damage and promoted the release of damage-associated molecular patterns(DAMPs),but also enhanced T cells intratumoral infiltration and promoted T cell priming,which successfully converted cold tumors to hot and showed significant anti-tumor and anti-metastasis effects.Collectively,our study provides a rational design of an effective combination regimen and an ideal co-delivery system to convert cold tumors to hot,which holds great potential in clinical cancer chemoimmunotherapy. 关 键 词：Nano-engager Cold tumors Increased DNA damage Augmented immunogenic cell death Dual immune checkpoint inhibition BRD4 inhibition Differ-targeting delivery MMP-2 sensitive
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