山东大学徐云飞团队宣布他们的研究认为胆汁酸激活癌相关成纤维细胞并诱导胆管癌免疫抑制微环境。该项研究成果发表在2025年6月26日出版的《癌细胞》上。

在这项研究中，该研究团队发现过量的BAs特异性激活GPBAR1在癌症相关成纤维细胞（CAFs）上表达高水平的CXCL10，增强CCA细胞的上皮-间质转化（EMT）和转移，并通过在CCA中募集中性粒细胞创造免疫抑制肿瘤微环境（TME）。有趣的是，单细胞RNA测序分析表明，CCA中的CAFs特异性表达GPBAR1，这是一种BAs受体，而其他癌症类型则没有。GPBAR1-CXCL10轴抑制增强了派姆单抗在多种CCA临床前模型中的疗效。高BA水平和GPBAR1表达上调预示着不良预后和较差的免疫治疗反应。总之，他们的研究揭示了BAs的免疫抑制机制，并确定GPBAR1和CXCL10是CCA的潜在免疫治疗靶点。

据悉，胆管癌（CCA）是一种起源于胆道的高度致命的恶性肿瘤，其特征是暴露于高水平的胆汁酸（BAs）。免疫疗法已证明对CCA的疗效有限，但潜在的机制仍不清楚。

附：英文原文

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

Author: Fan Huang, Zengli Liu, Yan Song, Ganyu Wang, Anda Shi, Tianli Chen, Shaohui Huang, Shuo Lian, Kangshuai Li, Yongchang Tang, Lijie Zheng, Guoli Sheng, Nuoqi Zhang, Fan Yang, Chang Pan, Weiqiang Jing, Zongli Zhang, Yunfei Xu

Issue&Volume: 2025-06-26

Abstract: 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.

DOI: 10.1016/j.ccell.2025.05.017

Source: https://www.cell.com/cancer-cell/abstract/S1535-6108(25)00226-0