EFEMP2 Is Associated with Shelterin-Related DNA Damage Repair, Immune Microenvironment Features, and Prognosis in Glioblastoma

Background: Glioblastoma (GBM) carries a median overall survival below 15 months despite aggressive multimodal therapy. Treatment resistance reflects the interplay of genomic instability, dysregulated DNA damage repair (DDR), and an immunosuppressive tumor microenvironment (TME). The shelterin complex maintains telomere integrity, yet its broader role in coordinating DDR, TME remodeling, and clinical outcomes in GBM remains unclear. Methods: We integrated transcriptomic and clinical data from four public cohorts (TCGA, CGGA1, CGGA2, and REMBRANDT, n = 583) and an institutional cohort (CSUXY, n = 65). A composite shelterin score was computed by ssGSEA and correlated with DDR activity, immune infiltration, and checkpoint expression. Ten machine-learning algorithms generated 101 candidate model configurations; the final shelterin-related signature (SRS) was trained in TCGA and evaluated in external public cohorts and the institutional cohort. EFEMP2, the top-weighted gene in the SRS, was further examined using public transcriptomic datasets, an exploratory anti-PD-1 cohort, immunohistochemistry, and in vitro assays. Results: Higher shelterin scores were associated with enhanced DDR pathway activity, greater immune and stromal infiltration, and elevated checkpoint expression. The SRS achieved moderate discrimination, with a mean C-index of 0.60, and stratified patients into prognostically distinct risk groups across cohorts. EFEMP2 was consistently associated with inferior overall survival. High EFEMP2 correlated with an immunosuppressive TME enriched for MDSCs and exhausted T cells alongside reduced enrichment of several DDR pathways. Silencing EFEMP2 suppressed proliferation, migration, and invasion while inducing DNA double-strand break markers. In the small anti-PD-1 cohort, high EFEMP2 showed non-significant trends toward longer OS and PFS, which should be interpreted as hypothesis-generating. Conclusion: This study provides a biologically interpretable prognostic framework that was externally evaluated across multiple independent cohorts and links shelterin-related biology to GBM outcomes. EFEMP2 may connect genomic stress and immune suppression, but its mechanistic and immunotherapy-predictive roles require further validation.