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.

肿瘤微环境（TME）通过促进癌细胞的存活和增殖，耐药性，转移和免疫抑制作用而密切影响癌症的进展。重塑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）重新极化的重要调节剂。在mTOR /代谢/免疫之间存在综合的串扰。血管生成还可以调节新陈代谢和免疫力。基于这些，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。设计了双靶点递送脂质体系统，对PD-L1纳米抗体和甘露糖配体进行了双重修饰，以共同递送mTOR抑制剂（雷帕霉素）和抗血管生成药物（regorafenib）。脂质体能够靶向过表达PD-L1和甘露糖受体的TAM和癌细胞。脂质体有效地减少了糖酵解，重新极化了TAM，抑制了血管生成，重新编程了免疫细胞，从而阻止了肿瘤的生长。