Gut microbial fucosidase unlocks the immunotherapy-enhancing potential of polysaccharides

Immune checkpoint blockade with anti-PD-1 (αPD1) antibodies has transformed cancer therapy, yet most patients remain non-responsive. Safe and effective adjuvants that overcome resistance are urgently needed. Traditional Chinese medicine polysaccharides exhibit immunomodulatory potential, but their mechanisms in enhancing immunotherapy remain poorly defined. By screening polysaccharide-enriched extracts from six traditional medicines, we identified Wolfiporia cocos polysaccharide (WCP) as a potent enhancer of αPD1 efficacy across multiple subcutaneous tumor models without inducing overt systemic toxicity. The activity of WCP was microbiota-dependent and was associated with increased Turicibacter abundance in the WCP + αPD1 treatment context. Functional validation showed that T. sanguinis FUC2-associated α-L-fucosidase activity could liberate L-fucose from WCP. Serum metabolomics, targeted L-fucose quantification, microbial add-back, and engineered bacterial experiments supported a contributory role for fucosidase-mediated L-fucose release in the therapeutic benefit of WCP. Supplementation with T. sanguinis or engineered E. coli expressing FUC2 partially rescued the WCP-enhanced αPD1 response under microbiota-depleted conditions. Both WCP and L-fucose increased intratumoral IFNγ⁺CD8⁺ T-cell accumulation, and CD8⁺ T-cell depletion abolished the antitumor effect. Notably, WCP further enhanced αPD1 efficacy in mice colonized with fecal microbiota from non-responding cancer patients. These findings identify a gut microbial fucosidase-associated pathway that contributes to WCP-derived L-fucose release and supports enhanced αPD1 immunotherapy. This work provides a mechanistic rationale for integrating structurally defined dietary polysaccharides with immune checkpoint blockade to improve therapeutic responses. Video Abstract