Chimeric antigen receptor T (CAR-T) cell therapy has revolutionized the treatment of hematologic malignancies, offering remarkable therapeutic efficacy and new hope in the field of cellular immunotherapy. However, challenges remain, including improving the durability of therapeutic responses, minimizing adverse effects, and overcoming the limited efficacy observed in solid tumors and various other cancer types.

Recent studies have revealed that metabolites derived from the human microbiome play critical roles in regulating immune cell functions, including inflammation, immune tolerance, and cellular metabolism. This study evaluated the effects of over 200 microbiome-derived metabolites on CAR-T cell functionality, identifying four candidates that augmented CAR-T cell activity. Notably, a lead metabolite significantly improved CAR-T cell short-term proliferation (120h) and long-term persistence following repeated antigen stimulation (>12 days), without altering short-term cytotoxicity or cytokine secretion profiles compared to controls. Furthermore, this metabolite demonstrated potential to improve CAR-T cell efficacy not only in the challenging context of solid tumors but also for CAR-T cells targeting BCMA, indicating its broad utility.

In conclusion, our study provides evidence that this lead microbiome-derived metabolite may represent a novel and broadly applicable strategy to enhance the therapeutic performance of CAR-T cells across diverse tumor types and antigen targets.