GPX2 induces macrophage M2 polarization through the MIF signaling pathway to promote colorectal cancer progression

Abstract

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, yet the precise mechanistic role of M2 macrophages in the tumor microenvironment during CRC progression remains poorly characterized. In this study, we elucidate a novel molecular pathway whereby glutathione peroxidase 2 (GPX2) orchestrates M2 macrophage polarization via macrophage migration inhibitory factor (MIF) signaling to drive CRC progression. Integrated analysis of single-cell RNA sequencing, bulk RNA sequencing, and spatial transcriptomics revealed that high expression of GPX2 was significantly associated with advanced CRC stages and unfavorable clinical outcomes. Furthermore, tumor cells with elevated expression of GPX2 showed notable spatial colocalization with activated MIF pathway and M2 macrophages. Functional assays demonstrated that GPX2 upregulation enhanced CRC cell proliferation, migration, and invasion. Mechanistically, we established that GPX2 stabilizes MIF expression through USP7-mediated deubiquitination, thereby promoting macrophage M2 polarization. In vivo animal studies demonstrated accelerated tumor growth associated with GPX2 overexpression, correlating strongly with increased MIF signaling and M2 macrophage. Collectively, our results delineate a previously unrecognized GPX2-MIF-M2 macrophage axis that critically promotes CRC progression, positioning GPX2 as a potential therapeutic target for CRC intervention.

Keywords: Colorectal cancer; GPX2; MIF; Macrophage polarization; Single cell RNA-sequencing; Spatial transcriptomics.