Detwiler Zachary, Chaudhari Snehal N
Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI, USA.
Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, USA.
Immunometabolism (Cobham). 2025 May 9;7(2):e00062. doi: 10.1097/IN9.0000000000000062. eCollection 2025 Apr.
In this renaissance era of gene therapy, a new study published by the Susan Kaech lab in demonstrates the use of CRISPR-Cas9 technology to selectively deplete conjugated bile acids in the liver by targeting the bile acid-CoA:amino acid -acyltransferase () gene to improve responsiveness to immunotherapy. This study highlights the role of conjugated bile acids in impairing intratumoral T cell function by directly accumulating in resident liver T cells and driving mitochondrial dysfunction. Knockout of reduced hepatic conjugated bile acid production, thus improving immunotherapy potency and reducing tumor burden. Subsequently, liver knockout reduced levels of microbially produced secondary bile acids such as lithocholic acid, a known carcinogen and T cell toxin. This study mechanistically links bile acids to liver cancer immunotherapy success, setting the stage for bile acid-based screening approaches and pharmacologic manipulations for improved patient outcomes.
在这个基因治疗的复兴时代，苏珊·凯奇实验室于[具体年份]发表的一项新研究表明，利用CRISPR-Cas9技术通过靶向胆汁酸辅酶A：氨基酸酰基转移酶（[具体基因名称]）基因，选择性消耗肝脏中的结合胆汁酸，以提高对免疫疗法的反应性。这项研究突出了结合胆汁酸通过直接在驻留肝脏T细胞中积累并导致线粒体功能障碍，从而损害肿瘤内T细胞功能的作用。敲除[具体基因名称]可减少肝脏结合胆汁酸的产生，从而提高免疫治疗效力并减轻肿瘤负担。随后，[具体基因名称]肝脏敲除降低了微生物产生的次级胆汁酸水平，如石胆酸，一种已知的致癌物和T细胞毒素。这项研究从机制上把胆汁酸与肝癌免疫治疗的成功联系起来，为基于胆汁酸的筛查方法和药物操作奠定了基础，以改善患者预后。
