Juzentaihoto modulates gut microbiota and potentiates the anti-tumor effect of anti-PD-1 antibody in an immunogenic mouse melanoma model.

Immune checkpoint blockade (ICB) therapy has been extensively employed across various cancer types. However, unresponsiveness to ICB remains a major obstacle; therefore, novel strategies to improve its efficacy are required. Juzentaihoto (JTT) is a Japanese Kampo medicine widely used in clinical practice as supportive care to improve the overall condition of cancer patients, particularly those with compromised immune function. Although the immunomodulatory effects of JTT have been suggested, it remains unclear whether JTT can enhance the efficacy of ICB. In this study, we demonstrated that JTT enhances the anti-tumor efficacy of anti-PD-1 antibody therapy in a B16-OVA model, accompanied by modulation of gut bacterial composition and the production of their metabolites in tumor-bearing mice.　In line with these changes in gut microbiota and metabolite production, the combination of JTT and anti-PD-1 antibody therapy inhibited Treg expansion in tumor-draining lymph nodes and enhanced the activation of tumor-infiltrating CD8+ T cells, resulting in greater diversity of the TCR repertoire. These results suggest that the immunomodulatory mechanism of JTT may involve alterations in the gut microbiome and the immunological tumor microenvironment.