Polysaccharides-gut microbiota interaction: mechanisms regulating the hepatocellular carcinoma immune microenvironment.

Hepatocellular carcinoma (HCC) has a poor prognosis, and the clinical responses to immune checkpoint inhibitors (ICIs) remain limited. Increasing evidence suggests that gut microbiota dysbiosis plays an important role in HCC progression through the gut-liver axis. This review summarizes the mechanisms by which polysaccharide-gut microbiota interactions reshape the immunosuppressive tumor microenvironment (TME) in HCC, and discusses the translational potential and challenges of this emerging therapeutic axis. Specifically, gut microbiota dysbiosis promotes chronic hepatic inflammation and immunosuppression through metabolites such as lipopolysaccharide, short-chain fatty acids, and bile acids. As biocompatible prebiotics, natural polysaccharides can selectively enrich beneficial gut bacteria, including Bacteroides and Akkermansia, promote the production of immunoregulatory metabolites, and regulate key signaling pathways such as TLR/NF-κB, bile acid-FXR, and PD-1/PD-L1. Nanopolysaccharides designed to improve tumor-targeting efficiency are also being explored in preclinical studies for HCC. Despite the therapeutic potential of the gut microbiota-polysaccharide-liver TME axis, several challenges remain, including polysaccharide structural heterogeneity, unclear microbiota-immune causal relationships, and undefined safe dose windows. Overall, this review provides an integrated overview of polysaccharide-based modulation of the HCC immune microenvironment and may offer insights for the development of more precise therapeutic strategies according to HCC etiological heterogeneity.