Zhan Tian-Ao, Xia Feng, Huang Hong-Wei, Zhan Jun-Cheng, Liu Xin-Kang, Cheng Qi
Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China.
Department of Clinical Medicine, Bengbu Medical College, Bengbu 233004, Anhui Province, China.
World J Gastrointest Oncol. 2025 Sep 15;17(9):108649. doi: 10.4251/wjgo.v17.i9.108649.
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.
肝细胞癌（HCC）仍然是全球癌症相关死亡的主要原因，晚期治疗进展有限。异常的成纤维细胞生长因子19（FGF19）-成纤维细胞生长因子受体4（FGFR4）轴促进肿瘤发生，并与HCC的靶向免疫治疗相关。多激酶抑制剂（MKIs）通过靶向该轴增强抗肿瘤作用，FGF19过表达上调肿瘤微环境中的程序性细胞死亡配体1。临床研究已证明选择性FGFR4抑制剂在HCC治疗中的疗效，与MKIs或免疫检查点抑制剂联合使用时抗肿瘤作用增强。Irpagratinib（ABSK-011）的I期临床试验显示客观缓解率为43.5%，与阿替利珠单抗联合使用时增至55.6%。FGF19还可作为HCC的生物标志物。本综述系统总结了使用检索词“HCC”、“成纤维细胞生长因子19”、“成纤维细胞生长因子受体4”、“FGFR4抑制剂”、“靶向治疗”、“多激酶抑制剂”、“免疫治疗”、“免疫检查点抑制剂”和“生物标志物”从PubMed和其他数据库检索到的文献。它还首次综合了FGFR4抑制剂与靶向免疫治疗之间的联合策略和潜在机制，填补了现有综述中的关键空白。此外，我们讨论了FGF19作为预测性生物标志物的潜力，整合机制和临床证据以推进精准HCC治疗。
