Sea cucumber polysaccharides overcome immunotherapy resistance in tumor-bearing mice via modulation of the gut microbiome†

Cancer immunotherapy has been successful in patients with different types of cancers, but its efficacy in treating certain types of colorectal cancer (CRC) is limited. The aim of this study was to explore whether sea cucumber polysaccharides (SCP) could impact resistance to anti-programmed cell death-1 (anti-PD1) immunotherapy of CRC and the role of microbiota in mediating their effects. Mice inoculated with immunotherapy resistant CT-26 CRC cells were pretreated with SCP, followed by treatment with/without the anti-PD1 antibody. SCP alone exhibited no inhibitory effect on tumor growth, but they drastically enhanced the efficacy of anti-PD1 treatment, which alone showed minimal effect on tumor development. Compared to anti-PD1 only treatment, a combination of SCP and anti-PD1 increased CD8⁺ T cells, especially IFN-γ⁺ cytotoxic CD8⁺ T cells, and decreased regulatory CD4⁺ T cells. SCP modulated gut microbiota and increased the relative abundance of bacteria including Bifidobacterium and Faecalibaculum. A fecal microbiota transplantation experiment showed that the sensitizing effect of SCP was at least partly mediated by microbiota. Furthermore, oral supplementation of Bifidobacterium pseudolongum or Faecalibaculum rodentium recapitulated the beneficial effect of SCP in potentiating anti-PD1 efficacy. Altogether, these findings demonstrated that SCP could be potentially developed as a dietary adjuvant to increase the efficacy of immunotherapy in CRC.