Abstract

Sorafenib (SOF) exhibits broad-spectrum antitumor activities in human cancers, including colorectal cancer (CRC). SOF-associated drug resistance and side effects largely limit its clinical application. Tumor-associated macrophages (TAMs) play pivotal roles in the progression and chemoresistance of CRC. Presently, we focus on the functions and mechanisms by which NOTCH4 affects SOF sensitivity in CRC and TAM-mediated immunosuppressive tumor microenvironment (TME). Here, we found that NOTCH4 overexpression promoted cell proliferation and growth, and reduced the sensitivity to SOF, while NOTCH4 downregulation exhibited the opposite functions. NOTCH4 levels were positively associated with “M2” TAM markers. NOTCH4 upregulation contributed to “M2” TAM infiltration in the xenograft model of CRC cells and mediated M2 polarization of THP1 macrophages, while NOTCH4 downregulation promoted “M1” polarization of TAMs. NOTCH4 was upregulated in two CRC cell lines (HCT116 and SW480) cocultured with M2-polarized macrophages (M2-Mø) and SOF-resistant CRC cells (HCT116-SR and SW480-SR). Additionally, NICD and HES1 were markedly upregulated in M2-Mø-treated and SOF-resistant CRC cells. Knocking down NICD or HES1 increased SOF sensitivity in CRC cells and reduced CCL2 expression. Blocking CCL2 markedly enhanced the antitumor effects of SOF, reduced “M2” polarization of THP1 macrophages, and reversed NOTCH4-mediated immunosuppressive TME. In conclusion, this study suggested that NOTCH4 downregulation enhances SOF sensitivity of CRC cells by suppressing CCL2-mediated “M2” macrophage polarization and immunosuppressive TME.