The Tumor-suppressive role of CNTNAP2 in glioma: Dual regulation of the NDN-ERK axis and M2 macrophage polarization

Cancer constitutes a persistent major global health burden, which underscores the urgent demand for innovative biomarkers and therapeutic targets. While the Contactin-associated protein (CNTNAP) family has been associated with tumor development, the pan-cancer role of CNTNAP2 is still poorly characterized. Researchers performed a comprehensive pan-cancer analysis of CNTNAP2 based on The Cancer Genome Atlas (TCGA) datasets to evaluate its expression profile and clinical relevance, and conducted functional experiments in U118MG glioblastoma cells and CNTNAP2-deficient mouse tissues to verify its biological function. The results identified CNTNAP2 as a dual diagnostic (AUC > 0.9) and prognostic biomarker for glioma, with low expression levels correlating to worse overall survival. In vitro assays showed that CNTNAP2 knockdown enhanced the proliferation and migration of U118MG cells, while its overexpression inhibited these malignant phenotypes. Mechanistically, CNTNAP2 deficiency triggered excessive activation of the ERK signaling pathway and downregulated its key downstream target Necdin (NDN), and pharmacological inhibition of ERK reversed the oncogenic effects caused by CNTNAP2 silencing. Further analysis demonstrated elevated M2 macrophage infiltration in glioma, and CNTNAP2 expression was closely correlated with M2 macrophage polarization; high CNTNAP2 expression also corresponded to lower TIDE scores, suggesting improved immunotherapy response. Collectively, CNTNAP2 acts as a tumor suppressor in glioma via the NDN-ERK axis, suppressing tumor progression and M2 macrophage polarization, making it a promising diagnostic, prognostic biomarker and potential therapeutic target for glioma.