EGFRvIII-positive glioblastoma contributes to immune escape and malignant progression via the c-Fos-MDK-LRP1 axis

PMCID: PMC12174314

PMID: 40527884

DOI: 10.1038/s41419-025-07771-1

Journal: Cell death & disease

Publication Date: 2025-6-17

Authors: Yuan F, Wang Y, Yuan L, Tang T, Ye L, et al.

Key Points

• EGFRvIII mutation is associated with higher WHO grade 4 gliomas (93.3% vs. 53.6%, p=0.044)
• M2 macrophages comprise 19.39% of cell types in EGFRvIII-positive GBM, compared to 6.78% in EGFRvIII-negative tumors
• Blocking MDK signaling pathway could inhibit macrophage polarization and potentially interrupt tumor progression

Summary

This study investigates the molecular mechanisms by which epidermal growth factor receptor variant III (EGFRvIII) mutation drives immune escape in glioblastoma multiforme (GBM). Through comprehensive molecular and single-cell analysis, researchers discovered that EGFRvIII-positive GBM exhibits a unique tumor microenvironment characterized by significantly higher proportions of immunosuppressive M2 macrophages, accounting for nearly 19.39% of cell types compared to 6.78% in EGFRvIII-negative tumors.

The research elucidates a novel signaling pathway where EGFRvIII-mutated GBM cells secrete midkine (MDK) via the ERK-c-Fos pathway, which activates macrophage LRP1 receptors and drives M2 macrophage polarization. This mechanism promotes the secretion of CXCL1, a chemokine associated with tumor invasiveness, thereby creating an immunosuppressive microenvironment that facilitates tumor progression. Mechanistically, this study provides insights into how genetic mutations can reshape tumor immunity and potentially offers a new therapeutic target for precision immunotherapy in GBM.