Metabolic modulation via mTOR pathway and anti-angiogenesis remodels tumor microenvironment using PD-L1-targeting codelivery
Metabolic modulation via mTOR pathway and anti-angiogenesis remodels tumor microenvironment using PD-L1-targeting codelivery
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通过 mTOR 通路的代谢调节和抗血管生成利用 PD-L1 靶向共传递重塑肿瘤微环境
DOI：
10.1016/j.biomaterials.2020.120187
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发表时间：
2020-10-01
期刊：
影响因子：
14
通讯作者：
Huang, Yongzhuo
中科院分区：
文献类型：
--
作者：
Chen, Binfan;Gao, Ang;Huang, Yongzhuo
肿瘤微环境（TME）通过促进肿瘤细胞的存活和增殖、耐药性、转移以及免疫抑制等，与肿瘤的进展密切相关。重建TME是一种有前途的抗癌治疗策略。mTOR信号传导是细胞代谢和肿瘤相关巨噬细胞（TAM）复极化的重要调节剂。mTOR/代谢/免疫之间存在综合串扰。血管生成还可以调节代谢和免疫。在此基础上，通过靶向mTOR和血管生成来重塑肿瘤免疫微环境（TIME），从而开发了一种潜在的治疗途径。设计了具有PD-L1纳米抗体和甘露糖配体的双重修饰的双靶向递送脂质体系统，用于共递送mTOR抑制剂（雷帕霉素）和抗血管生成药物（瑞戈非尼）。脂质体能够靶向TAM和过表达PD-L1和甘露糖受体的癌细胞。脂质体有效地减少糖酵解，重新极化TAM，抑制血管生成，重新编程免疫细胞，并因此阻止肿瘤生长。
Tumor microenvironment (TME) closely affects cancer progression by promoting cancer cell survival and proliferation, drug resistance, metastasis, and immunosuppression as well. Remodeling TME is a promising therapeutic strategy for anticancer. mTOR signaling is an essential regulator for cellular metabolism and tumor-associated macrophages (TAMs) repolarization. There is an integrated crosstalk among mTOR/metabolism/ immunity. Angiogenesis can also regulate metabolism and immunity. Based on these, a potential therapeutic avenue was developed by targeting mTOR and angiogenesis to remodel tumor immune microenvironment (TIME). A dual-targeting delivery liposomal system was designed with dual-modification of PD-L1 nanobody and mannose ligands for co-delivering an mTOR inhibitor (rapamycin) and an anti-angiogenic drug (regorafenib). The liposomes were able to target both TAMs and cancer cells that overexpressed PD-L1 and mannose receptors. The liposomes efficiently reduced glycolysis, repolarized TAMs, inhibited angiogenesis, reprogrammed immune cells, and consequently arrested tumor growth.