On-demand integrated nano-engager converting cold tumors to hot via increased DNA damage and dual immune checkpoint inhibition.
On-demand integrated nano-engager converting cold tumors to hot via increased DNA damage and dual immune checkpoint inhibition.
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按需集成的纳米粒子通过增加DNA损伤和双重免疫检查点抑制将冷肿瘤转化为热肿瘤。
DOI：
10.1016/j.apsb.2022.09.004
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发表时间：
2023-04
影响因子：
14.5
通讯作者：
Zhang, Na
中科院分区：
文献类型：
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作者：
Liu, Xiaoqing;Liang, Shuang;Sang, Xiao;Chang, Lili;Fu, Shunli;Yang, Han;Yang, Huizhen;Liu, Yongjun;Zhang, Na
关键词：
癌症免疫治疗已成为一种很有前途的策略。然而，免疫治疗的效果仅限于“冷肿瘤”，其特点是T细胞在肿瘤内的浸润不足和T细胞启动失败。在这里，我们开发了一种按需集成纳米接合器(jot-Lip)，通过“增加DNA损伤和双重免疫检查点抑制”策略将冷肿瘤转化为热肿瘤。将奥沙利铂(oxaliplatin，OxA)和JQ1与T细胞免疫球蛋白粘蛋白-3抗体(TIM-3mAb)通过金属蛋白酶-2(MMP2)敏感连接物偶联到脂质体表面，构建了JOT-Lip。JQ1抑制DNA修复，增加OXA的DNA损伤和免疫原性细胞死亡(ICD)，从而促进T细胞在肿瘤内的浸润。此外，JQ1还可抑制PD-1/PD-L1通路，与TIM-3单抗结合实现双重免疫关卡抑制，从而有效促进T细胞的启动。研究表明，该制剂不仅增加了DNA损伤，促进了损伤相关分子模式(DAMP)的释放，而且增强了T细胞在肿瘤内的侵袭，促进了T细胞的启动，成功地将冷肿瘤转化为热肿瘤，显示出显著的抗肿瘤和抗转移作用。总之，我们的研究提供了一种合理的设计有效的联合方案和理想的共给药系统来将冷肿瘤转化为热肿瘤，这在临床肿瘤的化学免疫治疗中具有巨大的潜力。通过增加DNA损伤和双重免疫检查点抑制策略，开发了一种按需集成纳米接合器(jot-Lip)，以将冷肿瘤转化为热肿瘤。
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. 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.
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影响因子：
37.3
作者：
Donati B;Lorenzini E;Ciarrocchi A
通讯作者：
Ciarrocchi A
影响因子：
16.6
作者：
Koyama S;Akbay EA;Li YY;Herter-Sprie GS;Buczkowski KA;Richards WG;Gandhi L;Redig AJ;Rodig SJ;Asahina H;Jones RE;Kulkarni MM;Kuraguchi M;Palakurthi S;Fecci PE;Johnson BE;Janne PA;Engelman JA;Gangadharan SP;Costa DB;Freeman GJ;Bueno R;Hodi FS;Dranoff G;Wong KK;Hammerman PS
通讯作者：
Hammerman PS
DOI：
10.1038/nrc3239
发表时间：
2012-03-22
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
Pardoll DM
通讯作者：
Pardoll DM
影响因子：
16.6
作者：
Lam FC;Morton SW;Wyckoff J;Vu Han TL;Hwang MK;Maffa A;Balkanska-Sinclair E;Yaffe MB;Floyd SR;Hammond PT
通讯作者：
Hammond PT
DOI：
10.1038/nrc3258
发表时间：
2012-03-22
期刊：
Nature reviews. Cancer
影响因子：
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作者：
通讯作者：
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