Celastrol-loaded ginsenoside Rg3 liposomes boost immunotherapy by remodeling obesity-related immunosuppressive tumor microenvironment in melanoma.
10.1016/j.apsb.2025.03.017
- Author:
Hongyan ZHANG
1
;
Jingyi HUANG
1
;
Yujie LI
1
;
Wanyu JIN
1
;
Jiale WEI
1
;
Ninghui MA
1
;
Limei SHEN
2
;
Mancang GU
1
;
Chaofeng MU
1
;
Donghang XU
3
;
Yang XIONG
1
Author Information
1. School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China.
2. Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
3. Department of Pharmacy, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310053, China.
- Publication Type:Journal Article
- Keywords:
Celastrol;
Glucose transporter 1;
Immunogenic cell death;
Immunosuppressive tumor microenvironment;
Immunotherapy;
Metabolic reprogramming;
Obesity related tumor;
Rg3-liposome
- From:
Acta Pharmaceutica Sinica B
2025;15(5):2687-2702
- CountryChina
- Language:English
-
Abstract:
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.
