胆管癌（CCA）是一种非常难以治疗的癌症。化疗效果不佳，对免疫检查点抑制剂的反应也有限。因此，需要确定新的治疗策略。我们将酶蛋白精氨酸甲基转移酶 5 (PRMT5) 定性为 CCA 的新治疗靶点。我们评估了 PRMT5、其功能伙伴 MEP50 和甲硫腺苷磷酸化酶 (MTAP) 的表达调节人 CCA 组织中 PRMT5 对药物抑制剂的敏感性。 PRMT5 靶向药物目前正在针对其他恶性肿瘤的临床试验中进行测试，并在人类 CCA 细胞系和类器官以及两种具有免疫功能的 CCA 小鼠模型中进行了评估。通过转录组学、蛋白质组学和功能分析来探索潜在的抗肿瘤机制。PRMT5 和 MEP50 蛋白在大多数 CCA 组织中相关过度表达。 25% 的肝内 CCA 不存在 MTAP。 PRMT5靶向药物与顺铂和吉西他滨协同作用，显着抑制CCA细胞增殖，并阻碍胆管癌类器官的生长。 PRMT5 抑制会削弱参与染色质重塑和 DNA 修复的致癌基因的表达，持续诱导 RNA 环的形成并促进 DNA 损伤。 PRMT5靶向药物治疗显着抑制了实验性CCA的生长，且没有副作用，同时诱导CD4和CD8 T细胞募集到缩小的肿瘤病灶。PRMT5和MEP50在人类CCA中经常上调，PRMT5靶向药物具有显着的抗肿瘤作用临床相关 CCA 模型中的疗效。我们的研究结果支持在临床试验中评估 PRMT5 抑制剂，包括它们与细胞毒性和免疫疗法的组合。© 作者（或其雇主）2024。在 CC BY-NC 下允许重复使用。禁止商业再利用。请参阅权利和权限。英国医学杂志出版。

Cholangiocarcinoma (CCA) is a very difficult-to-treat cancer. Chemotherapies are little effective and response to immune checkpoint inhibitors is limited. Therefore, new therapeutic strategies need to be identified.We characterised the enzyme protein arginine-methyltransferase 5 (PRMT5) as a novel therapeutic target in CCA.We evaluated the expression of PRMT5, its functional partner MEP50 and methylthioadenosine phosphorylase (MTAP)-an enzyme that modulates the sensitivity of PRMT5 to pharmacological inhibitors-in human CCA tissues. PRMT5-targeting drugs, currently tested in clinical trials for other malignancies, were assessed in human CCA cell lines and organoids, as well as in two immunocompetent CCA mouse models. Transcriptomic, proteomic and functional analyses were performed to explore the underlying antitumoural mechanisms.PRMT5 and MEP50 proteins were correlatively overexpressed in most CCA tissues. MTAP was absent in 25% of intrahepatic CCA. PRMT5-targeting drugs markedly inhibited CCA cell proliferation, synergising with cisplatin and gemcitabine and hindered the growth of cholangiocarcinoma organoids. PRMT5 inhibition blunted the expression of oncogenic genes involved in chromatin remodelling and DNA repair, consistently inducing the formation of RNA loops and promoting DNA damage. Treatment with PRMT5-targeting drugs significantly restrained the growth of experimental CCA without adverse effects and concomitantly induced the recruitment of CD4 and CD8 T cells to shrinking tumourous lesions.PRMT5 and MEP50 are frequently upregulated in human CCA, and PRMT5-targeting drugs have significant antitumoural efficacy in clinically relevant CCA models. Our findings support the evaluation of PRMT5 inhibitors in clinical trials, including their combination with cytotoxic and immune therapies.© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.