Bile acids activate cancer-associated fibroblasts and induce an immunosuppressive microenvironment in cholangiocarcinoma.

Cholangiocarcinoma (CCA) is a highly lethal malignancy originating from the biliary tract and characterized with exposure to high levels of bile acids (BAs). Immunotherapies have demonstrated limited efficacy in CCA, but the underlying mechanism remains elusive. In this study, we reveal that the excessive BAs specifically activate GPBAR1 on cancer-associated fibroblasts (CAFs) to express high levels of CXCL10, enhancing epithelial-mesenchymal transition (EMT) and metastasis of CCA cells and creating an immunosuppressive tumor microenvironment (TME) by recruiting neutrophils in CCA. Interestingly, single-cell RNA sequencing analysis demonstrates that CAFs in CCA, but not other cancer types examined, specifically express GPBAR1, a receptor for BAs. GPBAR1-CXCL10 axis inhibition enhances the efficacy of pembrolizumab in multiple CCA preclinical models. High BA levels and upregulated GPBAR1 expression predict poor prognosis and inferior immunotherapy response. In summary, our study reveals an immunosuppressive mechanism of BAs and identifies GPBAR1 and CXCL10 as potential immunotherapeutic targets in CCA.