The role of tumor microenvironment in lenvatinib resistance of hepatocellular carcinoma - 04/07/25
, Xiao Xu e, f, g, ⁎ Highlights |
• | Comprehensive Role of TME in Lenvatinib Resistance: The tumor microenvironment components, including immune cells (e.g., CD8+ T cells, M2 macrophages, neutrophils) and non-immune cells (e.g., cancer-associated fibroblasts, vascular endothelial cells), drive lenvatinib resistance through pathways like CCL5/CCR5/CYP1A1, PD-L1 upregulation, and metabolic reprogramming. |
• | Hypoxia as a Key Driver of Resistance: Hypoxia-induced HIF-1α activation promotes LR via mechanisms such as enhanced cancer stemness, angiogenesis, and mitophagy. Targeting hypoxia (e.g., FACT inhibitors, CK2/USP22 inhibitors) improves lenvatinib sensitivity. |
• | Metabolic Reprogramming in Resistance: Dysregulated glucose and lipid metabolism (e.g., lactate shuttling, cholesterol accumulation) in the tumor microenvironment directly impair drug efficacy. Inhibiting metabolic pathways (e.g., SLP2, LCAT) enhances lenvatinib’s anti-tumor effects. |
• | Emerging Combination Therapies: Synergistic strategies, such as combining lenvatinib with PD-1 inhibitors, anti-angiogenics, or metabolic modulators, show promise in overcoming lenvatinib resistance and improving clinical outcomes for advanced HCC patients. |
Abstract |
In 2018, lenvatinib was approved as a first-line treatment of advanced hepatocellular carcinoma (HCC). Despite the initial success, its effectiveness in long-term clinical practice is restricted by the emergence of drug resistance. The tumor microenvironment (TME), comprised of various cellular and non-cellular components,collectively drives HCC growth, invasion, and resistance to treatment. Currently, numerous investigations have elucidated that lenvatinib exerts its influence on a multitude of targets within the TME. Moreover, many components of the TME can affect the sensitivity of lenvatinib either directly through interactions or promoting tumor immune evasion. TME plays a crucial role in the development of lenvatinib resistance (LR) in HCC. This review presents an overview on the role of the TME in LR of HCC. Furthermore, it explores therapeutic strategies targeting the TME for overcoming LR. These may improve the efficacy of lenvatinib and the prognosis of advanced HCC patients.
Le texte complet de cet article est disponible en PDF.Keywords : Lenvatinib, Hepatocellular carcinoma, Tumor microenvironment, Drug resistance
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Vol 49 - N° 7
Article 102642- juillet 2025 Retour au numéro
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