Oral microbial metabolite prodrug reprograms T cells to boost cancer immunotherapy
Researchers developed an oral prodrug nano-emulsion of 3,4-dihydroxybenzoic acid (DHB), a gut microbial metabolite, which reprograms CD8+ T cells to a stem-like, memory-prone state by suppressing glycolysis via the Akt-mTORC1-Myc axis and depleting intracellular GSH. The formulation increases DHB bioavailability and half-life, enhances antigen-specific stem-like T cell expansion in mice, and boosts efficacy of anti-PD-1 therapy across multiple tumor models, with evidence of long-term immunity and potential to improve adoptive T cell therapy. This work links gut microbiota metabolites to systemic T cell fitness and presents a translational nano-prodrug strategy for cancer immunotherapy.