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

Abstract

Abstract Lenvatinib, a multi-target kinase inhibitor, has been proven to be effective in the treatment of advanced hepatocellular carcinoma. It has been previously demonstrated that tumor associated macrophages (TAMs) in tumor tissues could promote HCC growth, invasion and metastasis. Furthermore, the lenvatinib has certain immunomodulatory activity in the treatment of HCC. However, the role of lenvatinib to the macrophages polarization in the HCC treatment has not been fully explored. In this article, we used a variety of experimental methods both in vitro and in vivo, to investigate the effect of lenvatinib on tumor-associated macrophages in HCC progression. The results showed for the first time that the lenvatinib could alter the macrophages polarization status both in human and mice. Meanwhile, Macrophages which treated with lenvatinib in vitro displayed the enhanced M1 activity and suppressed the proliferation, invasion, migration of liver cancer cells. Furthermore, in the progression of M1 polarization induced by lenvatinib, STAT-1 was the main target transcription factor and STAT-1 activity inhibition could reverse the effect caused by lenvatinib. Altogether, the present study provided a theoretical basis for the immunomodulatory function of lenvatinib in the treatment of HCC.