N2 neutrophils induce cell stemness reprogramming to promote gastric cancer progression via exosomal miRNAs.

Exosomes mediate cellular communications and have a profound impact on cancer progression. N2 neutrophils, which are polarized by factors from cancers, extensively infiltrate into tumor tissues and promote cancer progression via distinct mechanisms. However, the role and underlying mechanism of exosomes derived from N2 neutrophils (N2-EXO) in cancer remain to be investigated. Herein, we reported that N2-EXO enhanced the proliferation and metastasis of gastric cancer (GC) cells by promoting their stemness. In addition, miR-223-3p and miR-425-5p, which were highly expressed in N2-EXO from GC patients, promoted cancer metastasis and reduced cancer sensitivity to oxaliplatin. The cancer-promoting effect of N2-EXO was abolished by the addition of miRNA inhibitor both in vitro and in vivo. Mechanically, miR-223-3p and miR-425-5p directly targeted FOXO3 and PTEN genes, respectively, which synergistically promoted GC progression by regulating PI3K/AKT signaling pathway. Taken together, our results reveal a novel mechanism by which N2-EXO promotes GC progression, providing new insights into the function of exosomes from N2 neutrophils in cancer.