ArticleFrontiers in immunology2023
Lenvatinib improves anti-PD-1 therapeutic efficacy by promoting vascular normalization via the NRP-1-PDGFRβ complex in hepatocellular carcinoma.
Article in Frontiers in immunology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed.
- A phase II peri-operative study of pembrolizumab plus lenvatinib for mucosal melanoma.Nature communications · 2026Trial
- CyberKnife SBRT plus lenvatinib and tislelizumab versus doublet systemic therapy for hepatocellular carcinoma with macrovascular invasion: A real-world IPTW-adjusted study.Clinical and translational radiation oncology · 2027Article
- Sequential axitinib and survivin vaccination unlock curative PD-1 immunotherapy in renal carcinoma.Oncoimmunology · 2026Article
- Potential of Nanoparticle-Based Phototherapies for Future Treatment of Uveal Melanoma.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- T cell-nanodrug conjugates synchronize vascular normalization and immune activation for solid tumor therapy.Science advances · 2026Article
- Renal toxicity during VEGF-pathway inhibition in cancer: a practical review of proteinuria, hypertension, and kidney-limited thrombotic microangiopathy.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2026Review
- Lenvatinib plus hepatic arterial infusion chemotherapy of oxaliplatin, fluorouracil, and leucovorin versus lenvatinib alone for advanced hepatocellular carcinoma: a multicenter retrospective cohort study.Journal of gastroenterology · 2026Article
- TACE, lenvatinib, and PD-1 inhibitors in unresectable advanced hepatocellular carcinoma: an exploratory retrospective cohort study.BMC gastroenterology · 2026Article
- Multi-tyrosine kinase inhibitors: exploring immunomodulatory effects on various immune cell types in cancer.Cancer cell international · 2026Review
- Transarterial infusion chemotherapy combined with lenvatinib and tislelizumab versus intravenous chemotherapy for unresectable pancreatic ductal adenocarcinoma: a retrospective propensity score matching analysis.Frontiers in oncology · 2026Article
- FOLFOX-HAIC Plus Lenvatinib and Tislelizumab in Advanced Hepatocellular Carcinoma with Arteriovenous Fistulae: A Real-World Study.Journal of hepatocellular carcinoma · 2026Article
- Efficacy and safety analysis of D-TACE combined with lenvatinib in the treatment of hepatocellular carcinoma refractory to C-TACE.BMC gastroenterology · 2025Article
- Tumour-associated vasculature in T cell homing and immunity: opportunities for cancer therapy.Nature reviews. Immunology · 2025Review
- Turning cold tumors into hot tumors to ignite immunotherapy.Molecular cancer · 2025Review
- Nanopuerarin Improves Doxorubicin Therapeutic Efficacy by Inhibiting Angiogenesis via Regulating NSUN2 in Hepatocellular Carcinoma.ACS omega · 2025Article
- Interaction of neuropilin-1 and hepatocyte growth factor/C-Met pathway in liver fibrosis progression in hepatocyte-specific NRP-1 knockout mice.Journal of gastroenterology · 2025Article
- Lenvatinib Plus Pembrolizumab Versus Chemotherapy in Advanced Endometrial Cancer: Efficacy and Safety Insights.Cureus · 2025Review
- Single-Cell Transcriptomic Analysis Unveils Key Regulators and Signaling Pathways in Lung Adenocarcinoma Progression.Biomedicines · 2025Article
- Divergent Functions of Rap1A and Rap1B in Endothelial Biology and Disease.International journal of molecular sciences · 2025Review
- The Efficacy and Safety of Hepatic Artery Infusion Chemotherapy Combined with Lenvatinib and Programmed Death (PD)-1 Inhibitors for Unresectable Intrahepatic Cholangiocarcinoma: A Retrospective Study.Current oncology (Toronto, Ont.) · 2025Article
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Authors and funding
19 authors.
Funding
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Abstract
Introduction: The limited response to immune checkpoint blockades (ICBs) in patients with hepatocellular carcinoma (HCC) highlights the urgent need for broadening the scope of current immunotherapy approaches. Lenvatinib has been shown a potential synergistic effect with ICBs. This study investigated the optimal method for combining these two therapeutic agents and the underlying mechanisms. Methods: The effect of lenvatinib at three different doses on promoting tissue perfusion and vascular normalization was evaluated in both immunodeficient and immunocompetent mouse models. The underlying mechanisms were investigated by analyzing the vascular morphology of endothelial cells and pericytes. The enhanced immune infiltration of optimal-dose lenvatinib and its synergistic effect of lenvatinib and anti-PD-1 antibody was further evaluated by flow cytometry and immunofluorescence imaging. Results: There was an optimal dose that superiorly normalized tumor vasculature and increased immune cell infiltration in both immunodeficient and immunocompetent mouse models. An adequate concentration of lenvatinib strengthened the integrity of human umbilical vein endothelial cells by inducing the formation of the NRP-1-PDGFRβ complex and activating the Crkl-C3G-Rap1 signaling pathway in endothelial cells. Additionally, it promoted the interaction between endothelial cells and pericytes by inducing tyrosine-phosphorylation in pericytes. Furthermore, the combination of an optimal dose of lenvatinib and an anti-PD-1 antibody robustly suppressed tumor growth. Conclusions: Our study proposes a mechanism that explains how the optimal dose of lenvatinib induces vascular normalization and confirms its enhanced synergistic effect with ICBs.
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