Sanghuangporus vaninii polysaccharide potentiates anti-PD-1 antibody in colorectal cancer associated with gut microbiota and immune modulation

Objective This study aimed to investigate the antitumor efficacy of Sanghuangporus vaninii polysaccharides (SHP) against colorectal cancer (CRC) and to explore the correlative relationships among SHP treatment, gut microbiota remodeling, short-chain fatty acids (SCFAs) elevation, and immune activation, with the aim of generating hypotheses for future mechanistic studies. Methods The effects of SHP were studied in syngeneic MC38 orthotopic mouse model of CRC. Based on the determined optimal dose, four groups were established: Sham, SHP monotherapy, anti-PD-1 antibody monotherapy, and combination therapy. The antitumor efficacy was measured by tumor counts, histological staining, RT-qPCR and western blot. Gut microbiota and SCFAs were analyzed by 16S rRNA sequencing and targeted metabolomics. The change of immune was evaluated by flow cytometry, immunohistochemical staining and ELISA. And the related signaling pathway was examined by western blot. Results SHP monotherapy (optimal dose: 400 mg/kg) significantly inhibited tumor growth, reduced tumor numbers, alleviated intestinal inflammation, and improved intestinal barrier function. It remodeled the gut microbiota structure and increased levels of beneficial SCFAs, including acetic acid and propionic acid. In immune modulation, SHP showed a trend toward normalization of the splenic CD4 + /CD8 + T cell balance and elevated serum IFN-γ concentrations. Combination therapy produced enhanced antitumor effects and further enriched CD8 + PD-1 + T cells in the spleen. Mechanistically, the combined treatment showed greater inhibition of the PI3K/Akt signaling pathway. Conclusion SHP treatment was associated with alterations in gut microbiota composition, increased SCFA production, and enhanced systemic and intratumoral immune responses. This study provides experimental evidence for developing natural polysaccharide to potentiate tumor immunotherapy.