Liver cancer remains a leading cause of cancer mortality worldwide. Global Cancer Statistics (GLOBOCAN) reported 865,269 new cases and 757,948 deaths due to liver cancer in 2022, rendering it the sixth most commonly diagnosed cancer and the third leading cause of cancer death worldwide [1]. In the United States, the American Cancer Society projects 42,240 new cases and 30,090 deaths from liver cancer in 2025 [2]. Hepatocellular carcinoma (HCC) is the primary form of liver cancer and accounts for approximately 90 % of cases. Generally, HCC predominantly presents itself in those with underlying hepatic dysfunction, especially chronic liver diseases. The main etiologies include chronic infection with hepatitis B (HBV) and C (HCV) viruses, excessive alcohol consumption, and metabolic dysfunction-associated steatohepatitis (MASH) [3], [4].

Early-stage HCC can be treated with curative approaches such as surgical resection or liver transplantation. However, early detection is difficult because the disease is typically asymptomatic at presentation. Liver transplantation is restricted by donor organ scarcity and stringent selection criteria, and surgical resection carries risks of recurrence in addition to postoperative morbidity [5]. In intermediate to advanced stages, locoregional treatments such as radiofrequency ablation (RFA), microwave ablation (MWA), and transarterial chemoembolization (TACE) offer effective local tumor control. The efficacy of these modalities is limited by factors like incomplete tumor necrosis, injury to adjacent tissues, and high recurrence rates [6]. Systemic therapy, particularly tyrosine kinase inhibitors (TKIs), immune checkpoint inhibitors (ICIs), chemotherapy, and radiotherapy has improved survival and delayed disease progression. However, treatment resistance, toxicities, and heterogeneity of patient response remain significant obstacles. Targeted therapies directed against molecular mechanisms such as angiogenesis and immune evasion represent a promising strategy. These therapies not only reduce toxicity, but also enhance efficacy, underscoring the central position of precision medicine in the treatment of HCC [7].

In the evolving landscape of cancer treatment, the identification and validation of individual biomarkers have played a crucial role in the development of targeted therapies. Glypican-3 (GPC3) has emerged as a central biomarker in HCC [8]. It is a heparan sulfate proteoglycan that is highly expressed on the cell membranes of HCC. In contrast, its expression is virtually absent in normal liver tissue, thereby making it a particular tumor-associated marker. The role of GPC3 in HCC development is closely associated with the activation of multiple key signaling pathways, including Wnt/β-catenin, transforming growth factor-β (TGF-β), Hedgehog, and Hippo/Yes-associated protein (YAP). Through these pathways, GPC3 facilitates tumor cell proliferation, survival, epithelial-to-mesenchymal transition (EMT), angiogenesis, and immune evasion, thereby promoting tumor growth, metastasis, and resistance to therapy [9]. Due to its tumor-exclusive expression profile, GPC3 has emerged as a promising target for various therapeutic strategies, including monoclonal antibodies, bispecific antibodies, chimeric antigen receptor (CAR) T/NK cell therapy, vaccines, immunotoxins, and gene therapies. These emerging strategies aim to enhance the specificity, effectiveness, and overall efficacy of HCC therapies, with the potential for fewer side effects and improved clinical outcomes [10].

While targeted therapies directed at GPC3 have demonstrated promising results, their efficacy often faces limitations including immune evasion, development of resistance, the immunosuppressive tumor microenvironment (TME), and tumor heterogeneity [11]. Studies have shown that combination therapies targeting GPC3 alongside systemic treatments such as TKIs, ICIs, chemotherapy, and radiotherapy can overcome resistance mechanisms, enhance antitumor efficacy, and simultaneously promote immune activation and inhibit angiogenesis in HCC [12]. Based on the strengthened synergistic effect of combination treatment and the GPC3 status as a HCC-specific biomarker, this review attempts to evaluate combination treatment strategies aimed at GPC3. Herein, we emphasize the importance of optimizing therapeutic efficacy in HCC by outlining the current progress in these approaches.