Celastrol-loaded ginsenoside Rg3 liposomes enhance anti-PD-L1 immunotherapy by inducing immunogenic cell death in triple-negative breast cancer
Triple-negative breast cancer (TNBC), characterized by high heterogeneity and invasiveness. The efficacy of immune checkpoint inhibitors (ICIs), particularly anti-PD1/PD-L1 antibodies (aPD-1/PD-L1), is relatively limited when treating TNBC with monotherapy. Currently, inducing immunogenic cell death (ICD) of tumor cells through approaches such as radiotherapy and chemotherapy is an effective strategy to enhance the response to aPD-L1 therapy in TNBC. However, radiotherapy and chemotherapy treatments often upregulate PD-L1 expression in tumor cells, thereby weakening the tumor cells' response to aPD-L1. Considering that TNBC cells already exhibit high baseline levels of PD-L1, additional upregulation of PD-L1 induced by external factors may deplete some aPD-L1 and potentially impair its efficacy. Therefore, there is an urgent need to identify more effective agents that can induce ICD in TNBC cells without increasing PD-L1 expression in tumor cells. Nowadays, extensive research has demonstrated that celastrol (Cel) effectively induces ICD and reduces PD-L1 expression on the tumor cell membrane, thereby enhancing the efficacy of immunotherapy. Herein, a multifunctional liposomal system which encapsulated Cel using ginsenoside Rg3 (Rg3) as the lipid membrane (Cel-Rg3-Lp) was developed. Cel-Rg3-Lp enhances the solubility and decrease the toxicity of Cel. Additionally, substituting ginsenoside Rg3 (Rg3) for cholesterol (Cho) not only mitigates the potential issue of Cho which would elevate PD-L1 levels, and also promote the accumulation of the drug in tumor tissue through the interaction between Rg3 and glucose transporter 1 (Glut1), which is overexpressed on TNBC tumor cells. Overall, although there are reports that Cel exerts anti-cancer effects by inducing ICD, its mechanism through reducing glucose regulatory protein 78 (GRP78) -mediated ER stress has not been explored. This mechanism may open unique prospects for the use of Cel in treating TNBC and enhancing the efficacy of immunotherapy.