Abstract: Hepatocellular carcinoma (HCC) remains one of the most aggressive malignancies, with poor prognosis and limited treatment options, particularly due to the immunosuppressive tumor immune microenvironment (TIME). Hydrogels have emerged as a promising biomaterial platform for local and controlled delivery of immunomodulatory agents, offering a novel strategy to remodel the TIME and enhance the efficacy of existing therapies. This review explores hydrogel-based strategies for immunomodulation in HCC, focusing on their potential to localize immune regulation, improve immune cell infiltration, and overcome immune evasion. Hydrogels can be engineered to encapsulate a range of therapeutic agents, including immune checkpoint inhibitors, cytokines, tumor antigens, and adjuvants, allowing for sustained release and targeted action within the tumor. The integration of hydrogels with therapies such as ablation, CAR-T cell therapy, and tumor vaccines has demonstrated synergistic effects, significantly enhancing antitumor immunity and reducing tumor recurrence. However, challenges remain in optimizing hydrogel composition, biocompatibility, degradation rates, and the efficiency of agent delivery. Personalized hydrogel-based therapies, tailored to individual patient’s TIME, hold great potential for precision immunotherapy in HCC. This review highlights the current advances, challenges, and future directions for hydrogel-based immunomodulation strategies in HCC treatment, underscoring their transformative potential in cancer therapy. Keywords: hepatocellular carcinoma, tumor immune microenvironment, hydrogels, immunotherapy, precision medicine, ablation, CAR-T
Zhang et al. (2026) studied this question.