Tumor-Associated Macrophage-Derived CXCL1 Promotes Endometrial Cancer Progression Through the CXCR2/NF-κB Pathway

Abstract

Advanced-stage and metastatic endometrial cancer (EC) are characterized by markedly poor survival outcomes, necessitating a deeper understanding of the mechanisms driving disease advancement. Tumor-associated macrophages (TAMs), particularly the M2 subtype, are instrumental in remodeling the tumor microenvironment and promoting EC proliferation, migration, and metastasis. However, the specific mediators responsible for TAM-driven EC progression remain inadequately elucidated. In this study, we investigated the role of the C–X–C motif chemokine ligand 1 (CXCL1) and its receptor, chemokine receptor 2 (CXCR2), in TAM-induced EC progression. CXCR2, as the primary receptor for CXCL1, activates the NF-κB signaling pathway upon binding, thereby mediating the epithelial–mesenchymal transition process in EC cells and enhancing metastatic potential. This mechanism can be effectively inhibited by silencing CXCR2 or by employing the NF-κB inhibitor BAY 11-7082. Neutralizing CXCL1 markedly diminished the proliferative and migratory burdens imposed by TAMs on EC in subcutaneous xenograft EC models. Additionally, in EC tissue samples, CXCL1 and CXCR2 expression, as well as the extent of macrophage infiltration, exhibited a significant positive relationship with disease progression, suggesting an unfavorable prognosis. In conclusion, targeting the CXCL1/CXCR2 axis is a potential therapeutic approach for EC treatment.