Therapeutic potential of natural product polysaccharides in hepatocellular carcinoma: from microenvironment modulation to combination strategies

Natural-product polysaccharides are being investigated in hepatocellular carcinoma (HCC) as modulators of immune, inflammatory, metabolic and treatment-response pathways. Preclinical studies describe effects on tumor-associated macrophages, gut–liver signaling, hypoxia-associated angiogenesis and tumor-cell survival, including apoptosis, autophagy and ferroptosis. These findings motivate combination strategies with locoregional treatment, kinase inhibitors, chemotherapy and immune checkpoint blockade, but enhanced combination activity does not by itself demonstrate pharmacological synergy. This narrative review integrates material identity, mechanistic evidence and clinical outcomes, distinguishing purified polysaccharides, incompletely characterized preparations, composite extracts or granules, and formulation-enabled systems. Randomized evidence for fucoidan with transarterial chemoembolization and Huaier granule after resection provides product- and setting-specific signals; observational studies and immune-marker analyses offer less certain evidence of patient benefit. Clinical findings for composite products cannot establish the efficacy of isolated polysaccharides. Translation requires reproducible composition and dosing, exposure and interaction studies, safety assessment in impaired liver function, and controlled trials with clinically meaningful endpoints. Natural-product polysaccharides offer an experimental adjunctive framework, while definitive clinical utility for chemically defined products remains to be established.