BACKGROUND: Triple-negative breast cancer (TNBC), characterized by high heterogeneity and invasiveness. 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 anti-programmed death-ligand 1 antibody (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. Celastrol exhibits broad-spectrum and potent anti-tumor activity, efficiently inducing ICD without increasing PD-L1 levels in tumor cells. PURPOSE: This study aims to elucidate the tumor-targeting effects of celastrol-loaded liposomes and its synergistic efficacy and mechanism of action in combination with aPD-L1 against TNBC. METHODS: The Rg3 liposomes loaded with celastrol (Cel-Rg3-Lp) were prepared using the thin-film hydration method. BALB/c mice were utilized to establish an in situ breast cancer model. Mice were intravenously injected with Cel-Rg3-Lp at a dosage of celastrol 1 mg/kg once every two days for a total of 7 injections. Flow cytometry, western blot, and immunofluorescence techniques were employed to investigate the synergistic effects and mechanisms of Cel-Rg3-Lp combined with aPD-L1 in the treatment of TNBC. RESULTS: The findings of this study demonstrate that after 7 administrations of Cel-Rg3-Lp (1 mg/kg celastrol, intravenously), significant anti-tumor effects are observed, including the recruitment of CD8 CONCLUSION: This study successfully constructed a multifunctional liposome and proposed a mechanism for inducing ICD through the GRP78-endoplasmic reticulum stress pathway. The liposome downregulates GRP78, triggering endoplasmic reticulum stress in tumor cells, inducing ICD, activating DCs, and enhancing antigen presentation to T cells. This improves the tumor immune microenvironment and provides a theoretical foundation for combining Cel-Rg3-Lp with aPD-L1 in the treatment of TNBC. This mechanism opens unique prospects for using celastrol in TNBC therapy and enhancing the effectiveness of immunotherapy.