Combination therapy strategies targeting glypican-3 in hepatocellular carcinoma: A comprehensive review

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide. Advanced disease often proves resistant to conventional therapies, thereby driving the intensive search for targeted therapies. Glypican-3 (GPC3), a well-validated, signature tumor antigen in HCC, has emerged as an attractive therapeutic target with high potential for precision oncology. Current research strategies for developing novel GPC3-targeted therapeutics are highly diverse, encompassing cellular immunotherapies (e.g., CAR-T and NK cell therapies), antibody-based agents, immunotoxins, peptide vaccines, gene therapies, and nanoparticle-mediated drug delivery systems. Despite promising preclinical and clinical developments, the clinical translation of GPC3-targeted therapies is limited by challenges such as inadequate tumor penetration, immunosuppressive tumor microenvironment, and heterogeneous antigen expression. Consequently, recent research has increasingly shifted toward combination strategies. A growing body of experimental and early clinical data indicates that GPC3-targeted agents synergize effectively with a broad range of co-treatments, including immune checkpoint inhibitors, antiangiogenics, immune modulators, tyrosine kinase inhibitors, radiotherapy, chemotherapy, and local therapies to enhance antitumoral efficacy. In this review, we examine the potential of these multimodal strategies to develop more effective therapeutic approaches for HCC. Future studies should therefore focus on optimizing these combination regimens by incorporating personalized treatment strategies to achieve durable clinical outcomes.