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. In vivo, 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.

中文翻译：

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载有 Celastrol 的人参皂苷 Rg3 脂质体通过重塑黑色素瘤中肥胖相关的免疫抑制肿瘤微环境来促进免疫治疗


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，这进一步构成了免疫治疗疗效的重大障碍。在此，利用一种用于包埋 celastrol （CEL） 的多功能脂质体系统 （CR-Lip） 重塑与肥胖相关的 ITME 并改进癌症免疫治疗，其中检测到人参皂苷 Rg3 （Rg3） 散布在磷脂双层中，其糖基暴露在脂质体表面。CR-Lip 具有相对均匀的大小 （116.5 nm），通过肥胖肿瘤细胞中过表达的 Rg3 和葡萄糖转运蛋白 1 之间的相互作用促进有利的肿瘤组织积累。到达肿瘤区域后，发现 CR-Lip 诱导 HFD 肿瘤细胞的免疫原性细胞死亡 （ICD）。值得注意的是，CR-Lip 有效提高了 HFD 肿瘤细胞中 PHD3 的水平，有效阻断了代谢重编程并增加了主要游离脂肪酸燃料来源的可用性。在 体内，实验研究表明，易于获得的纳米平台刺激增强了肿瘤组织中各种细胞因子的产生、DC 成熟、CD8+ T 细胞浸润以及与 aPD-1 的协同抗癌治疗效力（肿瘤抑制率 = 82.1%）对肥胖相关黑色素瘤。因此，本研究通过包括肿瘤根除、诱导 ICD 和重编程代谢，提出了一种有效的肥胖小鼠肿瘤免疫治疗方法。此外，它为肥胖相关肿瘤免疫治疗的宝贵尝试提供了独特的见解。