Targeting LY6E Inhibits Neuroblastoma Progression and Suppresses M2 Macrophage Polarization

Neuroblastoma is a pediatric malignancy characterized by significant clinical heterogeneity. Although MYCN amplification is a well-established marker of high-risk disease, its interplay with the tumor immune microenvironment-particularly tumor-associated macrophages (TAMs)-remains poorly understood. In this study, we developed an integrated gene signature incorporating genes associated with both MYCN amplification status and TAM infiltration, leading to the identification of 16 differentially expressed genes implicated in both biological processes. Six of these genes (CMBL, LY6E, KLRB1, CTSH, CD3d, and PTGDS) were utilized to construct a risk-scoring model that effectively stratified neuroblastoma patients into high- and low-risk groups with significantly distinct clinical outcomes (p < 0.001). Notably, LY6E emerged as the most prognostically significant gene within the signature. More importantly, we revealed that LY6E modulates M2-type macrophage polarization in neuroblastoma for the first time, suggesting a novel mechanism through which it may contribute to shaping an immunosuppressive tumor microenvironment.