Glypican-3-targeted therapy in hepatocellular carcinoma: biological insights and therapeutic strategies.

Glypican-3 (GPC3) is an oncofetal cell surface proteoglycan that is highly expressed in hepatocellular carcinoma (HCC) and largely absent from normal adult tissues, making it an attractive target for gene and cell therapies. A broad range of GPC3-directed strategies has been explored, including antibody-based agents, bispecific engagers, chimeric antigen receptor (CAR) and T cell receptor (TCR)-engineered immune cells, vaccine platforms, and emerging radiopharmaceutical approaches. However, durable clinical responses have remained limited. Here, we synthesize biological and translational evidence to examine factors that may constrain the clinical efficacy of GPC3-targeted therapies, including antigen-related features, tumor microenvironment-associated barriers, and platform-specific challenges. Finally, we discuss emerging therapeutic modalities and outline design principles for the rational optimization of next-generation GPC3-directed strategies.