Zhang Hongyan, Huang Jingyi, Li Yujie, Jin Wanyu, Wei Jiale, Ma Ninghui, Shen Limei, Gu Mancang, Mu Chaofeng, Xu Donghang, Xiong Yang
School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China.
Academy of Chinese Medical Science, Zhejiang Chinese Medical University, Hangzhou 310053, China.
Acta Pharm Sin B. 2025 May;15(5):2687-2702. doi: 10.1016/j.apsb.2025.03.017. Epub 2025 Mar 17.
Obesity usually exacerbates the immunosuppressive tumor microenvironment (ITME), hindering CD8 T cell infiltration and function, which further represents a significant barrier to the efficacy of immunotherapy. Herein, a multifunctional liposomal system (CR-Lip) for encapsulating celastrol (CEL) was utilized to remodel obesity-related ITME and improve cancer immunotherapy, wherein Ginsenoside Rg3 (Rg3) was detected interspersed in the phospholipid bilayer and its glycosyl exposed on the surface of the liposome. CR-Lip had a relatively uniform size (116.5 nm), facilitating favorable tumor tissue accumulation through the interaction between Rg3 and glucose transporter 1 overexpressed in obese tumor cells. Upon reaching the tumor region, CR-Lip was found to induce the immunogenic cell death (ICD) of HFD tumor cells. Notably, the level of PHD3 in HFD tumor cells was effectively boosted by CR-Lip to effectively block metabolic reprogramming and increase the availability of major free fatty acids fuel sources. , experiments studies revealed that the easy-obtained nano platform stimulated enhanced the production of various cytokines in tumor tissues, DC maturation, CD8 T-cell infiltration, and synergistic anticancer therapeutic potency with aPD-1 (tumor inhibition rate = 82.1%) towards obesity-related melanoma. Consequently, this study presented an efficacious approach to tumor immunotherapy in obese mice by encompassing tumor eradication, inducing ICD, and reprogramming metabolism. Furthermore, it offered a unique insight into a valuable attempt at the immunotherapy of obesity-associated related tumors.
肥胖通常会加剧免疫抑制性肿瘤微环境（ITME），阻碍CD8 T细胞浸润和功能，这进一步成为免疫治疗疗效的重大障碍。在此，一种用于包裹雷公藤红素（CEL）的多功能脂质体系统（CR-Lip）被用于重塑与肥胖相关的ITME并改善癌症免疫治疗，其中检测到人参皂苷Rg3（Rg3）穿插在磷脂双层中，其糖基暴露在脂质体表面。CR-Lip具有相对均匀的尺寸（116.5 nm），通过Rg3与肥胖肿瘤细胞中过表达的葡萄糖转运蛋白1之间的相互作用促进肿瘤组织的良好积累。到达肿瘤区域后，发现CR-Lip可诱导高脂饮食（HFD）肿瘤细胞发生免疫原性细胞死亡（ICD）。值得注意的是，CR-Lip有效提高了HFD肿瘤细胞中PHD3的水平，以有效阻断代谢重编程并增加主要游离脂肪酸燃料来源的可用性。实验研究表明，这种易于获得的纳米平台可刺激肿瘤组织中各种细胞因子的产生、树突状细胞（DC）成熟、CD8 T细胞浸润，并与抗程序性死亡蛋白1（aPD-1）协同发挥抗癌治疗效力（肿瘤抑制率 = 82.1%），用于治疗与肥胖相关的黑色素瘤。因此，本研究提出了一种在肥胖小鼠中进行肿瘤免疫治疗的有效方法，包括根除肿瘤、诱导ICD和重编程代谢。此外，它为肥胖相关肿瘤的免疫治疗的有价值尝试提供了独特的见解。
