Changmei Wu, Jinjin Dou, Xiwu Zhang
Hepatocellular carcinoma (HCC) is a leading cause of cancer‑related morbidity and mortality worldwide. HCC pathogenesis is predominantly associated with chronic liver disease, driven by a vicious cycle of persistent hepatic injury, chronic inflammation and aberrant hepatocyte regeneration. Within this complex pathological landscape, remodeling of the tumor immune microenvironment (TIME), metabolic dysregulation and gut‑liver axis imbalance collectively contribute to HCC initiation and progression. Given the limited efficacy of conventional therapeutic modalities against such multifaceted pathologies, there is an urgent need to explore novel strategies that are safe, effective and capable of multi‑target regulation. Natural polysaccharides, a class of bioactive macromolecules, have emerged as promising candidates for prevention and treatment. Polysaccharides not only directly suppress malignant phenotypes in HCC cells by modulating cell cycle progression, inducing apoptosis, and inhibiting invasion and metastasis, but also exert potent immunomodulatory effects. Specifically, they activate key immune effectors, including cytotoxic T lymphocytes, dendritic cells, natural killer cells and tumor‑associated macrophages, thereby reversing immunosuppression and reshaping the TIME. Furthermore, polysaccharides can modulate the gut microbiota and its metabolites, enrich beneficial bacterial taxa, and reinforce intestinal barrier integrity. These actions subsequently influence intrahepatic immune responses and inflammatory status, achieving systemic intervention via the 'gut‑liver‑immune' axis. The present review provides a systematic overview of the multifaceted mechanisms by which polysaccharides combat HCC, including direct antitumor effects, modulation of the TIME and regulation of the gut microbiota. By synthesizing current evidence, the present review aims to offer critical perspectives to advance the mechanistic understanding and facilitate the clinical translation of polysaccharides for HCC treatment.