Chinese yam polysaccharide enhances anti-PD-1 immunotherapy in colorectal cancer through alterations in the gut microbiota and metabolites

Immune checkpoint inhibitors (ICIs) have shown limited efficacy in colorectal cancer (CRC). Chinese yam polysaccharide (CYP), a naturally derived plant polysaccharide, demonstrates immunomodulatory and antitumour activities. This study investigated whether CYP enhances the antitumour effects of αPD-1 monoclonal antibody (mAb) by modulating gut microbiota and metabolites. In MC38 and CT26 xenograft models, CYP synergistically inhibited tumour growth when combined with αPD-1 mAb. 16S rRNA sequencing revealed that the combination therapy enriched beneficial bacteria (such as Clostridia_UCG-014 and Actinobacteria) while reducing pathogenic bacteria (including Enterorhabdus and Desulfovibrionaceae). Antibiotic-mediated gut microbiota ablation abolished therapeutic benefits, confirming microbiota-dependent mechanisms. Cytometry by Time-Of-Flight indicated that the combination therapy reshaped the tumour microenvironment by inhibiting immunosuppressive M2 macrophages (CD206⁺ subset) and enhancing infiltration of cytotoxic CD8⁺ T cells. Metabolomics analysis demonstrated that the combination therapy effectively rectified tumour-induced metabolic dysregulation, particularly in pathways related to linoleic acid, tryptophan, and purine metabolism. Significantly, the purine-associated metabolite deoxyguanosine was identified to promote M2 macrophage polarization and tumour progression in vitro, whereas its levels were markedly attenuated following combined therapeutic intervention. The results suggest that CYP enhances the efficacy of αPD-1 mAb through remodeling gut microbiota, reducing pro-tumour metabolite (deoxyguanosine), and reprogramming the tumour immune microenvironment. This provides a novel strategy for enhancing CRC patients' response to anti-PD-1 immunotherapy response.