IL7R remodels immunosuppression tumor microenvironment and promotes macrophage polarization by regulating NF-κB/CXCL1 axis in ovarian cancer

Abstract

In the ovarian cancer microenvironment, the polarization of tumor-associated macrophages (TAMs) is closely associated with immunosuppressive phenotypes. Although elevated levels of circulating interleukin-7 (IL-7) have been linked to a poor prognosis, the regulatory mechanisms underlying this association remain incompletely understood. This study demonstrated that increased IL7R expression in ovarian cancer is correlated with the polarization of CD206 ⁺ macrophages, the remodeling of the immunosuppressive microenvironment, and unfavorable patient prognosis. By employing 3D bioprinted co-culture systems and mouse models, we showed that the knockdown or knockout of IL7R inhibits tumor progression and intraperitoneal dissemination. Mechanistically, IL7R signaling promotes the polarization of macrophages toward an immunosuppressive phenotype through the NF-κB/CXCL1 axis. This is supported by the upregulated expression of Arg1 and IL-10, as well as the downregulated expression of pro-inflammatory markers. These polarized macrophages further enhance tumor cell proliferation and invasion, thereby forming a tumor-immune feedback loop. In conclusion, this study clarifies how IL7R signaling mediates crosstalk between ovarian cancer cells and macrophages to maintain the homeostasis of the immunosuppressive tumor microenvironment (TME).