Polysaccharide-based nanomedicines remodel the immunosuppressive tumor microenvironment to enhance hepatocellular carcinoma immunotherapy: mechanisms and advances

Hepatocellular carcinoma (HCC) remains one of the most lethal malignancies worldwide, and although immune checkpoint inhibitors (ICIs) have reshaped its systemic treatment, most patients still derive little benefit because the hepatic tumor microenvironment (TME) is profoundly immunosuppressive. Polysaccharide-based nanomedicines have emerged as a versatile strategy to break this barrier by combining the intrinsic immunomodulatory activity of natural polysaccharides with the pharmacokinetic advantages of nanoscale carriers. This review first dissects the cellular and molecular architecture of the immunosuppressive HCC TME and the mechanisms that limit ICI efficacy. We then summarize the design principles of polysaccharide-based nanomedicines—chemical modification, nano-assembly, active targeting, and stimuli-responsive release—together with the intrinsic immunostimulatory functions of polysaccharides as pattern-recognition-receptor ligands. The core of this review addresses the convergent mechanisms by which these systems remodel the TME, including reprogramming tumor-associated macrophages (TAMs) from the M2 to the M1 phenotype, activating innate immune signaling (TLR/NF-κB and cGAS–STING), promoting effector T cell infiltration while reversing exhaustion, and inducing immunogenic cell death (ICD) to enhance antigen presentation. We further outline therapeutic strategies spanning monotherapy, combination with ICIs and other modalities, and adoptive cell therapy, as well as polysaccharide-based theranostics and companion diagnostics. Finally, we discuss the principal obstacles to clinical translation—structural heterogeneity, ill-defined pharmacokinetics, and preclinical model fidelity—and propose future directions toward intelligent and precision polysaccharide nanomedicines.