Activation of IL-2/IL-2R pathway by Hedyotis diffusa polysaccharide improves immunotherapy in colorectal cancer

Colorectal cancer (CRC) is a prevalent and highly malignant tumor with a limited response to immune checkpoint inhibitor-based immunotherapy. There is an urgent need for novel immunomodulatory agents to enhance the immunotherapeutic response in CRC. Hedyotis diffusa, known for its immunomodulatory properties, has long been utilized as an adjunct in cancer treatment, positioning it as a potential source for discovering new tumor immunomodulators. In this study, we identified a polysaccharide derived from Hedyotis diffusa (HDP), comprising six monosaccharides: rhamnose, arabinose, galactose, glucose, xylose, and mannose. When combined with PD-1 and CTLA-4 inhibitors, HDP can boost systemic immunity in mice to enhance the effectiveness of immune checkpoint inhibitors in CRC therapy. HDP significantly increases the infiltration of CD4⁺ and CD8⁺ T cells into tumor microenvironment and upregulates the expression of key effector molecules derived from cytotoxic T cells. Mechanistic studies reveal that HDP activates the IL-2/IL-2R axis by upregulating IL-2 production and the expression of IL-2 receptor subunits, thereby promoting T cell proliferation. Collectively, this research introduces an innovative strategy to improve the efficacy of tumor immunotherapy by harnessing the immunomodulatory potential of polysaccharides. It also directs a roadmap for developing HDP as a promising immunomodulator for CRC treatment.