Tumor‐Derived Prostaglandin <scp>E2</scp> Promotes Colorectal Cancer Progression by Inducing <scp>N2</scp> ‐Type <scp>TAN</scp> Polarization

Tumor-associated neutrophils (TANs) play crucial roles in malignant tumors, and their polarization is considered a determining factor in cancer progression. However, knowledge concerning the molecular mechanisms that regulate the changes in the polarization phenotype of TANs and their impact on tumor biology is limited. Here, we demonstrate that tumor-derived prostaglandin E2 (PGE2) regulates the polarization of TANs toward the N2 phenotype within the tumor microenvironment, promoting tumor cell proliferation and migration. Mechanistically, PGE2 is released from the LDs of CRC cells into the TME, where the stimulation of ROS-mediated methylation increases through binding with the surface receptors prostaglandin E receptor 2 (EP2, PTGER2) and EP4 on TANs, resulting in a reduction in the expression of the transcriptional repressor FOXO3a and thereby eliminating its ability to bind to the promoter region of N2-associated molecules such as ARG1, MMP9, and BV8 in TANs and promote their production. In summary, PGE2-induced N2-type TAN polarization directly affects the malignant progression of tumors. Our research revealed that PGE2 could be a potential effective molecule for targeting TANs in antitumor immunotherapy for CRC.