Zhan TA, Xia F, Huang HW, Zhan JC, Liu XK, Cheng Q. Fibroblast growth factor 19-fibroblast growth factor receptor 4 axis: From oncogenesis to targeted-immunotherapy in advanced hepatocellular carcinoma. World J Gastrointest Oncol 2025; 17(9): 108649 [DOI: 10.4251/wjgo.v17.i9.108649]
Corresponding Author of This Article
Qi Cheng, MD, PhD, Professor, Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Wuhan 430030, Hubei Province, China. chengqi@hust.edu.cn
Research Domain of This Article
Gastroenterology & Hepatology
Article-Type of This Article
Review
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (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: http://creativecommons.org/licenses/by-nc/4.0/
Tian-Ao Zhan, Feng Xia, Hong-Wei Huang, Jun-Cheng Zhan, Xin-Kang Liu, Qi Cheng, Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
Jun-Cheng Zhan, Department of Clinical Medicine, Bengbu Medical College, Bengbu 233004, Anhui Province, China
Qi Cheng, Key Laboratory of Organ Transplantation, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Ministry of Education, Chinese Academy of Medical Sciences, Wuhan 430030, Hubei Province, China
Co-first authors: Tian-Ao Zhan and Feng Xia.
Author contributions: Cheng Q carried out study conception and design; Zhan TA, Xia F and Huang HW collected and organized the data and wrote the manuscript; Zhan JC and Liu XK carried out data collection, assembly, analysis, and interpretation, and final proofreading and revision of the manuscript.
Supported by Chen Xiao-Ping Foundation for the Development of Science and Technology of Hubei Province, No. CXPJJH124001-2406; and National Natural Science Foundation of China, No. U23A20483.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
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: Qi Cheng, MD, PhD, Professor, Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Wuhan 430030, Hubei Province, China. chengqi@hust.edu.cn
Received: April 21, 2025 Revised: May 25, 2025 Accepted: July 18, 2025 Published online: September 15, 2025 Processing time: 148 Days and 16.7 Hours
Abstract
Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality globally, with limited therapeutic progress for advanced stages. The aberrant fibroblast growth factor 19 (FGF19)-fibroblast growth factor receptor 4 (FGFR4) axis promotes oncogenesis and is linked to targeted-immunotherapy of HCC. Multi-kinase inhibitors (MKIs) enhance anti-tumor effects by targeting this axis and FGF19 overexpression upregulates programmed cell death ligand 1 in tumor microenvironment. Clinical studies have demonstrated the efficacy of selective FGFR4 inhibitors in HCC treatment, with enhanced anti-tumor effects when combined with MKIs or immune checkpoint inhibitors. Phase I clinical trials of Irpagratinib (ABSK-011) demonstrated an objective response rate of 43.5%, which increased to 55.6% combined with atezolizumab. FGF19 also serves as a biomarker for HCC. This review systematically summarizes the literature retrieved from PubMed and other databases using search terms “HCC”, “fibroblast growth factor 19”, “fibroblast growth factor receptor 4”, “FGFR4 inhibitor”, “targeted therapy”, “multi-kinase inhibitor”, “immunotherapy”, “immune checkpoint inhibitor”, and “biomarker”. It also firstly synthesizes combination strategies and underlying mechanisms between FGFR4 inhibitors and targeted-immunotherapy, addressing critical gaps in existing reviews. Additionally, we discuss the potential of FGF19 as a predictive biomarker, integrating mechanistic and clinical evidence to advance precision HCC therapeutics.
Core Tip: The aberrant Fibroblast growth factor 19 (FGF19)-fibroblast growth factor receptor 4 (FGFR4) axis plays a crucial role in progression of hepatocellular carcinoma. Multi-kinase inhibitors enhance anti-tumor effects by targeting the FGF19-FGFR4 axis and FGF19 overexpression contributes to the development of immune suppression. These findings highlight the association between FGF19 and targeted-immunotherapy in hepatocellular carcinoma (HCC). Selective FGFR4 inhibitors, either alone or combining with targeted-immunotherapy, have demonstrated therapeutic potential for advanced HCC, although the clinical application is hindered by challenges such as adverse effects and drug resistance. Furthermore, FGF19 serves as a promising biomarker for HCC, underscoring its potential for precision treatment.
