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Given the abundant stroma of the liver and that cirrhosis or hepatic fibrosis is the premalignant condition of most hepatocellular carcinomas (HCC), underscores the critical interaction between extracellular matrix (ECM) stiffness and the tumor microenvironment (TME) in the initiation, progression, and immunotherapy of HCC. This review presents a comprehensive exploration of the factors that regulate matrix stiffness, including the activation of cancer-associated fibroblasts (CAFs), the excessive deposition of ECM proteins, and cross-linking. Furthermore, this review explores the underlying molecular pathways through which matrix stiffness affects the prevalence of tumors and immune cells. Based on these premises, we delve into the potential targets and roles of pharmacological interventions targeting matrix stiffness in HCC and its immunotherapy, and highlight the considerable potential of biomaterials for the development of ECM stiffness-targeted agents. The potential exists for such agents to enhance the efficacy of immunotherapy and prolong the survival of patients diagnosed with HCC.