<scp>FN1</scp> Immunoregulation in Glioblastoma: Insights From Neutrophil‐Centric Studies

Neutrophils, as key components of the tumor microenvironment, play a crucial role in cancer progression and prognosis. This study aimed to identify a neutrophil-related gene signature to improve prognostic predictions and explore potential immunotherapy targets for glioblastoma multiforme (GBM) patients. Through co-expression analysis, 60 neutrophil-associated genes were identified, showing significant enrichment in 159 Gene Ontology terms and eight KEGG pathways. Among these, 10 genes were significantly associated with patient survival, leading to the development of a six-gene risk model termed the Neutrophil-Related Gene Prognostic Index (NRGPI). The NRGPI predicted overall survival (OS) in both training and validation cohorts (p < 0.05), with enhanced prognostic accuracy when combined with clinicopathological factors. Higher NRGPI scores were correlated with worse OS, increased mortality, and more aggressive disease progression. Immune profiling linked NRGPI to immune cell infiltration, immune checkpoint expression, and tumor mutation burden, suggesting its potential in identifying candidates for immunotherapy. Among the identified genes, FN1 emerged as a central regulator, associated with immune cell composition and poor prognosis. Pan-cancer analysis revealed consistent upregulation of FN1 across cancer types, underscoring its broad clinical relevance. Additionally, tissue microarray analysis using multiplex immunofluorescence on 84 GBM samples confirmed co-expression of FN1, SDC1, and TWIST1, with higher levels associated with reduced survival. These findings establish NRGPI as a valuable prognostic biomarker for GBM, offering novel insights into the immune landscape and positioning FN1 as a promising therapeutic target for further investigation in GBM treatment.