BAAT away liver cancer: conjugated bile acids impair T cell function in hepatocellular carcinoma immunotherapy

In this renaissance era of gene therapy, a new study published by the Susan Kaech lab in <i>Science</i> demonstrates the use of CRISPR-Cas9 technology to selectively deplete conjugated bile acids in the liver by targeting the bile acid-CoA:amino acid <i>N</i>-acyltransferase (<i>Baat</i>) 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 <i>Baat</i> reduced hepatic conjugated bile acid production, thus improving immunotherapy potency and reducing tumor burden. Subsequently, <i>Baat</i> 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.