Neutrophils in glioblastoma: orchestrators of the tumor microenvironment and immune evasion

Glioblastoma (GBM) is the most aggressive primary brain tumor in adults and remains refractory to current therapies. Beyond profound immunosuppression, GBM is characterized by a complex tumor microenvironment (TME) in which neutrophils have emerged as critical yet understudied regulators of tumor progression and immune evasion. Tumor-associated neutrophils (TANs) display marked functional plasticity, acquiring pro-tumor or anti-tumor phenotypes depending on microenvironmental cues. GBM recruits and reprograms infiltrating neutrophils through chemokine-driven trafficking, hypoxia, and tumor-derived cytokines, promoting angiogenesis, glioma stem-like cell support, and immune suppression via vascular endothelial growth factor (VEGF), matrix metalloproteinase-9 release (MMP-9), arginase-1, and neutrophil extracellular traps (NETs). Conversely, under inflammatory or therapeutically modulated conditions, neutrophils can exert cytotoxic and antibody-dependent anti-tumor functions and enhance T-cell responses. Clinically, elevated neutrophil-to-lymphocyte ratios and intratumoral neutrophil transcriptional signatures correlate with poor prognosis and resistance to immunotherapy. Emerging therapeutic strategies aim to modulate neutrophil recruitment, metabolism, polarization, and NET formation, often in combination with immune checkpoint blockade. This review synthesizes current knowledge of neutrophil biology in GBM, highlights their dualistic roles within the TME, and outlines translational opportunities for neutrophil-targeted therapies.