Mannose enhances anti-PD-1 therapy efficacy in ovarian cancer via modulating gut microbial metabolite.

The gut microbiome serves as a crucial mediator for improving the efficacy of immune checkpoint blockade (ICB) therapy. Here, we show that oral supplementation with prebiotics (mannose) retarded tumor growth in immunocompetent mice in a gut microbiota dependent manner, correlating with the enrichment of Faecalibaculum. Mannose generates an immune-stimulatory tumor microenvironment (TME) characterized by an increase percentage of effector and memory CD8+T cells, accompanied by a prominent immunoreactivegeneexpressionsignature. Most importantly, mannose modulates the stemness program of CD8+T cells and facilitates the generation of progenitor exhausted CD8+T cells (Tpex). Mechanistically, mannose increases gut microbial production of the short-chain fatty acids (SCFA) propionate and butyrate. Administration of propionate and butyrate suppresses tumor progression and stimulates the expansion and differentiation of Tpex both in vivo and in vitro. Mannose synergized with PD-1 blockade in tumor regression and augmented intratumoral Tpex differentiation into intermediate exhausted CD8+T cells (Tex-int) and terminally exhausted CD8+T cells (Tex-term). Moreover, we identified a mannose-therapy related gene signature associated with favorable responses to ICB in pan-cancer. Overall, our findings support the rationale for combining dietary supplementation of mannose with anti-PD-1 immunotherapy in ovarian cancer, and its clinical translation.