Targeting the JAK2/STAT3 Axis and Remodeling the Tumour Microenvironment: The Dual Anti-Tumour Mechanism of Total Glucosides of Paeony in Gallbladder Cancer

BACKGROUND: Gallbladder cancer (GBC) is the most prevalent malignancy of the biliary tract, emphasizing the urgent requirement for the development of effective drugs. Here, we present our findings on total glucosides of paeony (TGP), an active compound extracted from the traditional Chinese medicine Bai Shao, as a potential candidate. PURPOSE: This study aims to evaluate the therapeutic potential of TGP in GBC and to elucidate its underlying pharmacodynamic mechanisms, with a specific focus on tumour microenvironment (TME) remodeling. STUDY DESIGN: The anti-tumour efficacy and mechanisms of TGP were comprehensively investigated using a multi-dimensional platform encompassing GBC cell lines, patient-derived xenograft (PDX) models, and patient-derived organoids. METHOD: To comprehensively assess the therapeutic potential of TGP in GBC, we established a multi-dimensional validation platform encompassing GBC cell lines, PDX models, and organoid cultures. Mechanistic investigations were conducted at multiple levels. Network pharmacology and RNA sequencing analyses identified molecular targets, while single-cell RNA sequencing (scRNA-seq) unveiled TGP's profound impact on TME remodeling. Subsequent validation studies focused on the JAK2/STAT3/IL-6 signaling axis, employing ELISA for cytokine quantification, Western blot for protein expression analysis, and immunofluorescence for spatial localization of signaling components. RESULTS: tumour-associated macrophages (TAMs) into the TME, shifting the immune contexture toward anti-tumour. CONCLUSION: By disrupting the critical crosstalk between cancer cells and TAMs, TGP effectively remodels the inflammatory immune microenvironment, highlighting its potential as a promising therapeutic agent for GBC.