ArticleHepatology international2024
Fibroblast growth factor inhibition by molecular-targeted agents mitigates immunosuppressive tissue microenvironment in hepatocellular carcinoma.
Article in Hepatology international, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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12 citing papers in PubMed, 19 citations in OpenAlex.
- SLC25A39 Upregulation Is Associated with DNA Methylation, Immune Cell Infiltration, and Poor Prognosis in Hepatocellular Carcinoma.International journal of molecular sciences · 2026Article
- Strategic drug sequencing in hepatocellular carcinoma in the era of chemo-diversity: maximizing the therapeutic benefit of lenvatinib.Journal of liver cancer · 2026Review
- Lenvatinib as Second-Line Regimen after Atezolizumab plus Bevacizumab Combination Therapy.Liver cancer · 2026Article
- Distinct tumor immune microenvironment modulation by anti-PD-1/PD-L1, VEGF, and CTLA-4 blockade provides a rationale for triplet therapy in hepatocellular carcinoma.Clinical and molecular hepatology · 2026Article
- Protein-Ligand Interactions in Cardiometabolic Drug Targets: Focus on Weight Loss and Cardioprotection.Molecules (Basel, Switzerland) · 2025Review
- Immune checkpoint molecules signal regulatory protein alpha in the development of hepatocellular carcinoma.World journal of gastrointestinal oncology · 2025Review
- Surgical Outcomes of Lenvatinib Treatment Followed by Liver Resection for Advanced Hepatocellular Carcinoma Larger than 10 cm.Cancers · 2025Article
- Anti-Angiogenic Agents for Advanced Hepatocellular Carcinoma Induce Liver Atrophy.Cancer medicine · 2025Article
- New insights into biomarkers and risk stratification to predict hepatocellular cancer.Molecular medicine (Cambridge, Mass.) · 2025Review
- Association between cancer-associated fibroblasts and prognosis of neoadjuvant chemoradiotherapy in esophageal squamous cell carcinoma: a bioinformatics analysis based on single-cell RNA sequencing.Cancer cell international · 2025Article
- Advances in Lipid-Based Nanomedicine: Pathway Specific siRNA Therapy and Optimizing Delivery for Hepatocellular Carcinoma.International journal of nanomedicine · 2025Review
- Lenvatinib and immune-checkpoint inhibitors in hepatocellular carcinoma: mechanistic insights, clinical efficacy, and future perspectives.Journal of hematology & oncology · 2024Review
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Authors and funding
10 authors at 2 institutions in 2 countries.
Funding
Abstract
BACKGROUND &
aimsCombination immunotherapy refers to the use of immune checkpoint inhibitors (ICI) and molecular-targeted agents (MTA), which have recently been approved for the treatment of advanced hepatocellular carcinoma (HCC). Owing to its relatively low antitumor effect (up to 30%), sequential therapy following ICIs treatment is required in patients with HCC. This study aimed to determine the impact of MTAs on the tumor immune microenvironment (TIME).
methodsWe established immune syngeneic orthotopic HCC mouse models using Hep-55.1C and Hep-53.4, and treated them with MTAs (lenvatinib, sorafenib, regorafenib, cabozantinib, and DC101 as anti-vascular endothelial growth factor receptor-2 antibodies, and AZD4547 as a fibroblast growth factor receptor (FGFR)-1/2/3/4 inhibitor) for 2 weeks. Subsequently, alterations in the TIME caused by MTAs were evaluated using immunohistochemistry (antibodies for CD3, CD8, Foxp3, Granzyme B, Arginase-1, NK1.1, F4/80, CD11c, PD-1, and PD-L1). We conducted RNA-seq analysis using lenvatinib- and AZD4547-treated tumors. To confirm the clinical relevance of these findings, we analyzed the transcriptome data of human HCC cells (MHCC-97H) treated with various concentrations of lenvatinib for 24 h using RNA-seq data from the Gene Expression Omnibus database.
resultsThe number of Foxp3- and F4/80-positive cells in the TIME was decreased in many MTAs. Cabozantinib increased the numbers in NK1.1-, Granzyme B, and CD11c-positive cells. Lenvatinib and AZD4547 increased the number of CD8, Granzyme B, and PD-L1-positive cells. Gene ontology enrichment analysis revealed that lipid metabolism-related genes were downregulated by lenvatinib and AZD4547. In total, 161 genes downregulated by FGFR inhibition in rodent models overlapped with those downregulated by lenvatinib in human HCC cells.
conclusionsIn this study, we showed that cabozantinib activated the innate immune system, and lenvatinib and AZD4547, which commonly inhibit FGFR signaling, altered TIME to a hot immune state by downregulating lipid metabolism-related genes. These findings support the therapeutic use of combination immunotherapies.
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