Neuropilin-1 serves as a prognostic marker and a potential target of M2-polarized tumor-associated macrophages in gastric cancer.

Neuropilin-1 (NRP1) has recently emerged as a promising immune checkpoint. However, its prognostic significance in gastric cancer (GC) and its association with the tumor immune microenvironment remain insufficiently understood. In this study, analysis of TCGA data revealed elevated NRP1 expression in GC tissues compared to normal controls. Based on NRP1 expression levels, TCGA GC samples were stratified into high- (n = 185) and low-expression (n = 185) groups. The high-expression group exhibited more advanced TNM and histological grade stages, along with a significantly shorter overall survival. Differential expression analysis between the two groups highlighted enrichment of genes involved in extracellular matrix (ECM)-related signaling pathways and cell chemotaxis. Notably, NRP1 expression showed the strongest positive correlation with the infiltration of M2-polarized tumor-associated macrophages (M2-TAMs) and the expression of the M2-TAMs marker CD163 in the TCGA cohort. Consistently, CD163 expression was higher in the NRP1 high-expression group. Furthermore, immunohistochemical analysis of 20 clinical GC specimens, scored for both NRP1 and CD163, demonstrated co-positivity in 14 cases (70%) and co-negativity in 3 cases (15%). Pearson correlation analysis confirmed a significant association between NRP1 staining intensity and both tumor grade and CD163 score. To explore causality, conditioned medium from GC cell lines with high or low NRP1 expression was used to treat THP-1 monocytic cells. The supernatant from NRP1-high cells promoted both CD163 expression and migration of THP-1 cells, effects that were abolished by the NRP1 inhibitor EG00229. In conclusion, our findings suggest that NRP1 serves as a prognostic biomarker and an immune-regulatory molecule warranting further investigation in GC, possibly through modulating M2-TAMs polarization and recruitment.