The role of FPR3 in remodeling the immune microenvironment and lung metastasis of colon adenocarcinoma.

Colon cancer is a prevalent and deadly malignancy on a global scale, with metastasis being the primary cause of mortality associated with this disease. Immune dysregulation plays a critical role in tumor cell metastasis. Formyl-peptide receptor 3 (FPR3), a family of G protein-coupled receptors, plays an important regulatory role in the process of leukocyte activation and chemotaxis. However, the role of FPR3 in colon adenocarcinoma remains unclear. Through bioinformatics and immunohistochemistry staining analysis, we found that FPR3 protein was significantly up-regulated in colon adenocarcinoma tissues and associated with shorter overall survival (OS) and relapse-free survival (RFS) of patients. GSEA revealed a correlation between high FPR3 expression and cancer cell metastasis, as well as immune-related features, including inflammatory response, extracellular cell matrix degradation, and Wnt/β-catenin pathway activation. Compared with normal tissue, higher FPR3 expression in colon adenocarcinoma was more likely to be associated with high M2 phase macrophage markers and T-cell exhaustion markers, this, in turn, facilitated the formation of an immunosuppressive microenvironment. Knockdown of FPR3 suppressed the migration and invasive potential of colon adenocarcinoma cells in vitro and reduced the number of lung metastatic foci in vivo. Moreover, FPR3 silencing also impeded nuclear translocation of β-catenin, thereby suppressing canonical Wnt/β-catenin signaling and the expressions of proteins associated with EMT. Taken together, our data elucidate the clinical value and function of FPR3 in immune suppression and Wnt/β-catenin pathway activation, suggesting that FPR3 may be a novel therapeutic target for interventions against colon adenocarcinoma metastasis.