The Journal of pharmacy and pharmacology · 2026
Atorvastatin potentiates the efficacy of gemcitabine in diabetic pancreatic cancer via remodeling the tumor immune microenvironment and attenuating vascular endothelial.
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Li Lu, He Yong, Tian Peikai, Chen Jinxin, Gong Xun, Li Xiaowu
Аннотация
OBJECTIVES: This study aimed to explore the potential of atorvastatin as an adjuvant on endothelial inflammation, vascular function, and the tumor microenvironment in diabetic pancreatic cancer.
METHODS: Utilizing a diabetic model of pancreatic cancer, we performed integrated analyses including single-cell RNA sequencing (scRNA-seq), receptor-ligand interaction profiling between endothelial and immune cells, proteomic profiling, and interrogation of the TIMER 2.0 database. Key findings were validated via immunohistochemistry (IHC).
KEY FINDINGS: An atorvastatin (Lipitor, Lip) dose of 0.05 g/kg was identified as optimal for vascular repair in diabetic mice. In diabetic pancreatic cancer models, combination therapy with this dose of atorvastatin and gemcitabine (Gem-Lip) significantly reduced tumor-induced endothelial cells (TECs) and exhausted CD8+ T cells compared with gemcitabine monotherapy. scRNA-seq further revealed an immune-remodeled microenvironment in the Gem-Lip group, characterized by enhanced T-cell cytolytic activity and an increase in CD4+ subsets such as HelperT_Ecm1. Receptor-ligand analysis indicated strengthened interactions between CD8Teff_Fcer1g/CD8Teff_Nusap1 immune subtypes and other cells. Proteomics validated the upregulation of proteins involved in positive immune regulation. Consistently, TIMER database analysis and IHC indicate increased infiltration of CD4+ and CD8+ T cells in tumors from the combination treatment group.
CONCLUSIONS: These findings support the potential of atorvastatin plays a crucial role in suppressing vascular endothelial inflammation and reprogramming immune cell infiltration, thereby potentiating the efficacy of gemcitabine in diabetic pancreatic cancer.
METHODS: Utilizing a diabetic model of pancreatic cancer, we performed integrated analyses including single-cell RNA sequencing (scRNA-seq), receptor-ligand interaction profiling between endothelial and immune cells, proteomic profiling, and interrogation of the TIMER 2.0 database. Key findings were validated via immunohistochemistry (IHC).
KEY FINDINGS: An atorvastatin (Lipitor, Lip) dose of 0.05 g/kg was identified as optimal for vascular repair in diabetic mice. In diabetic pancreatic cancer models, combination therapy with this dose of atorvastatin and gemcitabine (Gem-Lip) significantly reduced tumor-induced endothelial cells (TECs) and exhausted CD8+ T cells compared with gemcitabine monotherapy. scRNA-seq further revealed an immune-remodeled microenvironment in the Gem-Lip group, characterized by enhanced T-cell cytolytic activity and an increase in CD4+ subsets such as HelperT_Ecm1. Receptor-ligand analysis indicated strengthened interactions between CD8Teff_Fcer1g/CD8Teff_Nusap1 immune subtypes and other cells. Proteomics validated the upregulation of proteins involved in positive immune regulation. Consistently, TIMER database analysis and IHC indicate increased infiltration of CD4+ and CD8+ T cells in tumors from the combination treatment group.
CONCLUSIONS: These findings support the potential of atorvastatin plays a crucial role in suppressing vascular endothelial inflammation and reprogramming immune cell infiltration, thereby potentiating the efficacy of gemcitabine in diabetic pancreatic cancer.