The Farnesoid X receptor-bile acid axis contributes to immune evasion in gastric cancer and its inhibition enhances efficacy of anti-PD-L1 therapy

Gastric cancer ranks among the most prevalent malignancies globally and remains a major contributor to cancer-related mortality. Its progression is profoundly shaped by the tumor microenvironment (TME), a dynamic milieu comprising extracellular matrix components, soluble mediators, and diverse non-malignant immune populations that collectively influence tumor initiation and evolution. Although immunotherapeutic strategies have recently attracted increasing attention in the management of solid tumors, including gastric carcinoma, the determinants of immune evasion in this context are still not fully delineated. The Farnesoid X receptor (FXR), a key nuclear receptor for bile acids, has recently been implicated in regulating TME composition and immune cell recruitment within gastric tumors. Yet, how bile acid signaling contributes to the bidirectional interactions between malignant and immune cells remains largely undefined. This study aimed to investigate the role of FXR in modulating immune-regulatory networks associated with PD-L1/PD-1 in gastric cancer. RNA-seq analysis of paired gastric mucosa from 39 gastric cancer patients revealed significant molecular differences between intestinal and diffuse tumors. FXR was overexpressed in the intestinal subtype and correlated with poor prognosis. MS/MS analysis demonstrated enrichment of tumor tissues by cholic acid and chenodeoxycholic acid compared to non-neoplastic pairs, supporting the hypothesis of dysregulated bile acid metabolism. In vitro, exposure of gastric cancer cell lines and patient-derived organoids to FXR ligands increased PD-L1 expression through direct binding of FXR-responsive elements in the PD-L1 promoter. Targeting FXR may offer a therapeutic approach to improve the effectiveness of immunotherapies in intestinal gastric cancer.