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Background Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide. Glypican-3 (GPC3) is overexpressed in approximately 70-80% of advanced HCC and minimally expressed in normal adult tissues, making it a promising therapeutic target. GPC3 contributes to hepatocarcinogenesis through activation of oncogenic signaling pathways and its surface localization enables immune-mediated targeting. Chimeric antigen receptor T-cell (CAR-T) therapy directed against GPC3 has shown early antitumor activity in phase I trials; however, outcomes remain variable and a comprehensive synthesis is lacking. This study systematically evaluated clinical outcomes associated with GPC3-targeted CAR-T therapy in advanced HCC.Methods A systematic search of PubMed and Google Scholar was conducted from database inception to February 2026. Search terms included ‘HCC,’ ‘GPC3,’ and ‘CAR-T.’ Prospective clinical studies evaluating GPC3-directed CAR-T therapy in adults with advanced HCC were included. Preclinical studies and non-GPC3-targeted CAR-T trials were excluded. Objective response rate (ORR) and disease control rate (DCR) were calculated from reported patient-level data when not explicitly provided.Results Five early-phase clinical trials comprising 56 patients met the inclusion criteria. All studies utilized autologous CAR-GPC3 T cells generated from peripheral blood mononuclear cells via leukapheresis, with tumor GPC3 expression confirmed by immunohistochemistry prior to enrollment. Across studies, 16 patients achieved partial response, 6 achieved progressive disease and 16 achieved stable disease. ORR ranged from 15.3% to 50%, while DCR ranged from 23.1% to 90.9%. Median progression-free survival (PSF) ranged from 3.1 to 7.9 months and median overall survival (OS) ranged from 5.1 to 9.1 months, with longer PFS observed in patients showing clinical benefit. Higher CAR-GPC3 transgene copy numbers in peripheral blood were associated with greater tumor shrinkage, suggesting that CAR-T expansion and persistence may correlate with clinical benefit. Cytokine release syndrome was the most common adverse event, predominantly grade 1-2. Neurotoxicity was rare.Conclusions GPC3-directed CAR-T therapy demonstrates encouraging preliminary antitumor activity with an acceptable safety profile in patients with advanced HCC. However, current evidence is limited to small and early-phase with heterogeneous methodologies. Larger, multicenter trials with standardized response assessment and longer follow-up are required to better define the durability of response and long-term survival benefit.