Targeting glypican-3 as a new frontier in liver cancer therapy

doi:10.4254/wjh.v17.i9.107671

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Sep 27, 2025 (publication date) through Sep 25, 2025

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World Journal of Hepatology

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1948-5182

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Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA

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World J Hepatol. Sep 27, 2025; 17(9): 107671
Published online Sep 27, 2025. doi: 10.4254/wjh.v17.i9.107671

Targeting glypican-3 as a new frontier in liver cancer therapy

Chen-Shiou Wu, Teng-Yu Lee, Hsu-Wen Chao

Chen-Shiou Wu, Department of Medical Research, Taichung Veterans General Hospital, Taichung 407219, Taiwan

Teng-Yu Lee, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 407219, Taiwan

Teng-Yu Lee, School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan

Hsu-Wen Chao, Department of Physiology, School of Medicine, Taipei Medical University, Taipei 110301, Taiwan

Hsu-Wen Chao, Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110301, Taiwan

Hsu-Wen Chao, Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung 807378, Taiwan

Author contributions: Wu CS wrote the original draft; Lee TY and Chao HW provided guidance and critically reviewed the manuscript. All authors read and approved the final manuscript.

Conflict-of-interest statement: The authors declare no conflict of interest related to this manuscript.

Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/

Corresponding author: Hsu-Wen Chao, PhD, Associate Professor, Department of Physiology, School of Medicine, Taipei Medical University, Wuxing St, Xinyi District, Taipei 110301, Taiwan. chaohw3619@tmu.edu.tw

Received: March 28, 2025
Revised: May 23, 2025
Accepted: August 1, 2025
Published online: September 27, 2025
Processing time: 181 Days and 23 Hours

Abstract

Glypican-3 (GPC3) is a tumor-associated antigen that is specifically expressed in hepatocellular carcinoma (HCC) and having relatively low levels in normal tissues. This unique expression pattern positions GPC3 as a potential target for precision therapy and drug development in HCC. Recent studies have shown significant advancements in GPC3-targeted therapies and immunotherapies, particularly for patients with advanced or treatment-resistant HCC. Although certain clinical trials have yielded suboptimal results, numerous ongoing studies continue to explore its therapeutic efficacy. This mini-review focuses on the latest research developments regarding GPC3 as a therapeutic target across various HCC treatment strategies, including monoclonal antibodies, bispecific antibodies, chimeric antigen receptor-T-cell therapies, and other innovative approaches. In addition, the limitations of GPC3-targeted therapies and their future application prospects in HCC treatment are discussed. The review particularly emphasizes the unmet need for future research directions, such as combination immunotherapy strategies and novel drug designs. Through the integration of innovative technologies and clinical validation, GPC3 holds strong potential as a promising breakthrough in the treatment of HCC, offering new opportunities for enhancing patient outcomes and improving therapeutic efficacy.

Keywords: Glypican-3; Hepatocellular carcinoma; Chimeric antigen receptor T-cell; Wnt; Immunotherapy

Core Tip: This review provides a comprehensive overview of glypican-3 (GPC3)-targeted strategies in hepatocellular carcinoma (HCC), including monoclonal and bispecific antibodies, chimeric antigen receptor-T cell therapies, vaccines, and photodynamic approaches. It further explores GPC3’s role in molecular imaging, radiomics, and liquid biopsy. Despite challenges in clinical translation, ongoing trials and novel combination therapies highlight the potential of GPC3-based approaches to improve treatment specificity, overcome resistance, and guide personalized therapy in HCC.