CXCL8-dependent recruitment of neutrophils by the tumor microenvironment drives poor prognosis in glioblastoma patients

Abstract Glioblastoma remains a therapeutic challenge due to its immunosuppressive tumor microenvironment and resistance to immunotherapy. This study investigates the role of CXCL8 signaling in recruiting immunosuppressive neutrophils and driving poor prognosis in glioblastoma. Analysis of TCGA data revealed significant upregulation of CXCL8 in glioblastoma tissues, correlating with reduced survival and neutrophil chemotaxis pathway activation. We identified a distinct low-density neutrophil subpopulation (L-NEUs) in GBM patient blood, characterized by immature markers (CD16low, CD13low, CD10low) and CXCL8-dependent migration. Integrative bioinformatics identified RNASE2 and THBD as L-NEU-specific markers, both upregulated in GBM and associated with poor prognosis. Functional studies demonstrated that CXCL8 overexpression in macrophages enhanced L-NEU recruitment. RNASE2 (secretory) and THBD (transmembrane) emerged as dual biomarkers and therapeutic targets, with pan-cancer survival analysis linking their overexpression to adverse outcomes in glioblastoma, renal carcinoma, and others. These findings define CXCL8-driven neutrophil recruitment as a key immunosuppressive mechanism in glioblastoma and propose RNASE2/THBD-targeted strategies to improve immunotherapy efficacy.