Figure 1.

The role of neutrophils in TME. (A) γδ17 T cells which secret IL-17 can recruit neutrophils into TME to stimulate the angiogenesis by producing VEGF and MMP9. In addition, γδ17 T cells can produce G-CSF to expand, and polarize neutrophils to promote metastasis by suppressing cytotoxic CD8 T cells immunity. (B) eIF4E is phosphorylated by MNK1/2 to promote neutrophils survival and accumulation in TME due to increased expression of BCL2 and MCL1, which then promote metastasis. (C) Estradiol (E2) promotes N2 polarization of neutrophils via TGF-β1, thus causing cancer cells to be highly metastatic. (D) TNFα-activated MSCs promote metastasis via production of CXCL1, CXCL2, and CXCL5 to recruit CXCR2⁺ neutrophils, and then neutrophils activate tumor cells to express higher levels of metastasis-related genes including CXCR4, CXCR7, MMP12, MMP13, IL-6 and TGFβ. In addition, tumor cells secreted GM-CSF can induce neutrophils to produce HGF, which binds to c-Met on tumor cells to promote metastasis. (E) Tumor-derived GM-CSF induces PD-L1 expression on neutrophil via JAK-STAT3signaling pathway, and cancer-associated fibroblasts (CAFs) induce PD-L1 expression on neutrophils by IL6—STAT3 signaling pathway, both of which inhibit T-cell immunity. In addition, c-Kit⁺ neutrophils use fatty acid oxidative metabolism to support ROS production to mediate T cell suppression.