The Zeb1-Cxcl1 axis impairs the antitumor immune response by inducing M2 macrophage polarization in breast cancer I

Zeb1, a classic epithelial-mesenchymal transition (EMT) regulator, has recently been found to be involved in M2 macrophage polarization in the tumor immune microenvironment, thereby promoting tumor development. However, the underlying mechanism of Zeb1-induced M2 macrophage polarization remains largely unexplored. To identify the potential role of Zeb1 in remodeling the tumor immune microenvironment in breast cancer, we crossed the floxed Zeb1 allele homozygously into PyMT mice to generate PyMT;Zeb1cKO (MMTV-Cre; PyMT;Zeb1fl/fl) mice. We found that the recruitment of M2 macrophages was significantly reduced in tumors from PyMT;Zeb1cKO mice, along with weakening of the tumor suppressive effect. Mechanistically, Zeb1 plays a crucial role in transcriptionally promoting the expression of Cxcl1 in tumor cells and enhancing the secretion of Cxcl1 in serum. Eventually, Cxcl1 activated the JAK-Stat3 signature via Cxcr2 and then induced the M2 polarization of macrophages, which leads to T cell inactivation and impairs the antitumor immune response in breast cancer. Our results revealed the important role of Zeb1 in the remodeling of the breast cancer tumor microenvironment, suggesting a novel therapeutic intervention for the treatment of advanced cancers. Overall design: To identify the molecular mechanism that mediates Zeb1-induced M2-like TAM polarization, shZeb1/231 and shCtrl/231 cell lines was obtained to perform RNA sequencing.