IJ

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

conjugated bile acids; secondary bile acids; hepatocellular carcinoma; immunotherapy; T cells; CRISPR-Cas9