Mannose Enhances Immunotherapy Efficacy in Ovarian Cancer by Modulating Gut Microbial Metabolites

Abstract The gut microbiome significantly influences the effectiveness of immune checkpoint blockade (ICB) therapy. However, its clinical application is hindered by the absence of cost-effective production methods. In this study, we demonstrated that oral mannose supplementation inhibits ovarian tumor growth in immunocompetent mice through the enrichment of Faecalibaculum rodentium (F. rodentium). Administration of F. rodentium not only suppressed tumor progression but also enhanced anti-tumor immune responses. Mannose supplementation fostered an immune stimulatory tumor microenvironment, characterized by the expansion and differentiation of progenitor exhausted CD8+ T cells (Tpex). Metabolomics analysis identified propionate and butyrate as critical metabolites driving the mannose-mediated tumor-suppressive effects, which was validated in vivo. Mechanistically, propionate and butyrate enhanced histone acetylation to promote Tpex cell expansion. Moreover, a mannose-related gene signature was associated with favorable response to ICB therapy across multiple cancer types. Supplementation with mannose also improved the efficacy of anti-PD-1 therapy and PARP inhibitor (PARPi) treatment. These findings highlight the role of F. rodentium-derived metabolites propionate and butyrate as key stimulators of Tpex cell expansion, thereby activating anti-tumor immune responses. This underscores the therapeutic potential of mannose supplementation in enhancing cancer immunotherapy outcomes in high-grade serous ovarian cancer.