Lenvatinib targets STAT-1 to enhance the M1 polarization of TAMs during hepatocellular carcinoma progression

• Published in: BMC cancer Vol. 24; no. 1; pp. 922 - 14
• Main Authors: Sun, Peng, Li, Zhenfeng, Yan, Zaojun, Wang, Zhaofeng, Zheng, Peng, Wang, Mingliang, Chang, Xu, Liu, Zihao, Zhang, Jianxin, Wu, Huiyong, Shao, Wenbo, Xue, Dewen, Yu, Jinming
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 30.07.2024; BioMed Central; BMC
• Subjects: Animals; Antibodies; Cancer therapies; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - immunology; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell Line, Tumor; Cell Movement - drug effects; Cell proliferation; Cell Proliferation - drug effects; Combination therapy; Development and progression; Disease Progression; Drug therapy; FDA approval; HCC; Health aspects; Hepatocellular carcinoma; Hepatocytes; Hepatoma; Hospitals; Humans; Immunomodulation; Kinases; Lenvatinib; Leukocyte migration; Liver cancer; Liver Neoplasms - drug therapy; Liver Neoplasms - immunology; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Macrophage Activation - drug effects; Macrophages; Macrophages - drug effects; Macrophages - immunology; Macrophages - metabolism; Male; Medical prognosis; Medical research; Metastases; Metastasis; Mice; Phenylurea Compounds - pharmacology; Phenylurea Compounds - therapeutic use; Physiological aspects; Polarization; Quinolines - pharmacology; Quinolines - therapeutic use; STAT-1; STAT1; Stat1 protein; STAT1 Transcription Factor - metabolism; TAMs; Tumor-Associated Macrophages - drug effects; Tumor-Associated Macrophages - immunology; Tumor-Associated Macrophages - metabolism; Tumors; Vascular endothelial growth factor; China; Beijing China; United States > US; STAT-1; HCC; Lenvatinib; TAMs
• ISSN: 1471-2407; 1471-2407
• DOI: 10.1186/s12885-024-12680-1

Lenvatinib, a multitarget kinase inhibitor, has been proven to be effective in the treatment of advanced hepatocellular carcinoma. It has been previously demonstrated that tumour associated macrophages (TAMs) in tumour tissues can promote HCC growth, invasion and metastasis. Furthermore, lenvatinib has certain immunomodulatory effects on the treatment of HCC. However, the role of lenvatinib in macrophage polarization during HCC treatment has not been fully explored. In this study, we used a variety of experimental methods both in vitro and in vivo to investigate the effect of lenvatinib on TAMs during HCC progression. This study is the first to show that lenvatinib can alter macrophage polarization in both humans and mice. Moreover, macrophages treated with lenvatinib in vitro displayed enhanced classically activated macrophages (M1) activity and suppressed liver cancer cell proliferation, invasion, and migration. Furthermore, during the progression of M1 macrophage polarization induced by lenvatinib, STAT-1 was the main target transcription factor, and inhibiting STAT-1 activity reversed the effect of lenvatinib. Overall, the present study provides a theoretical basis for the immunomodulatory function of lenvatinib in the treatment of HCC.