Opposing Functions of Gut Immunomodulatory Metabolites on CAR-T Therapy

Chimeric antigen receptor (CAR)-T cell therapy has transformed hematological cancer treat-ment, yet nearly half of patients still relapse or progress. Increasing evidence implicates the gut microbiome and antibiotic exposure as key modulators of clinical outcomes. In a cohort of 129 patients across three German centers, shotgun metagenomics and targeted mass spectrometry revealed that reduced short-chain fatty acids, particularly valeric acid prior to CAR-T cell thera-py correlated with increased risk of disease progression. Conversely, high levels of indole me-tabolites, including indole-3-carboxyaldehyde and indole-3-acetic acid as well as the branched chain fatty acid isovaleric acid, were linked to adverse outcomes. Functional validation in hu-man and murine CAR-T cell models demonstrated that valeric acid supplementation enhanced, while indole-3-carboxyaldehyde and isovaleric acid impaired, CAR-T cell efficacy. These find-ings reveal opposing roles of immunomodulatory metabolites on CAR-T cell therapy, carrying significant implications for the design of metabolite-guided, microbiome-based therapeutics.