Tumor Associated Neutrophils Extend NETs To Spatially Drive Necroptosis In Glioblastoma

Background: Glioblastoma is pathologically characterized by extensive pseudopalisading necrosis, a hallmark linked to therapeutic resistance and dismal prognosis. While traditionally viewed as a passive ischemic event, the precise radiogenomic drivers and spatial immune architectures orchestrating active tumor necrosis remain poorly understood. Methods: We integrated macroscopic clinical MRI radiomics with public genomic datasets (n=3,639), single-cell spatial transcriptomics, and high-resolution protein immunofluorescence (IF) assays in a novel co-mutant murine model to map the necrotic microenvironment. Results: Radiomic analysis of patient MRIs demonstrated that high tumoral necrotic volume serves as a powerful independent biomarker for poor long-term survival. This macro-structural necrosis phenotype is radiogenomically driven by cell-intrinsic TP53, PTEN, and NF1 (PPN) co-mutations. Spatial transcriptomic profiling of PPN-deficient tumors revealed distinct cellular topography, separating a proliferative, invasive niche (EGFR+ SOX+, Type Inv ) from a hyper-aggressive necrotic niche (ERBB3+, Type Nec ). Mechanistically, TypeNec cells deploy a prominent CCL5/CXCL2 chemokine milieu that actively recruits and prompts tumor-associated neutrophils to undergo neutrophil extracellular trap (NET) formation. This overactive neutrophil infiltrate drives a feed-forward loop of intrinsic tumor necroptosis mediated by the release of the damage-associated molecular pattern (DAMP) protein HMGB2. This cascade could be therapeutically dismantled using targeted anti-inflammatory compounds. Finally, multi-cohort clinical validation confirmed that an HMGB2 high signature dictates a high-risk, myeloid-rich immunosuppressive microenvironment in glioblastoma patients. Conclusions: Our findings redefine glioblastoma necrosis as an active, mutation-driven immunopathological process. The HMGB2-mediated DAMP necroptosis cascade and associated myeloid chemokines provide robust prognostic biomarkers and immediate therapeutic vulnerabilities to disrupt the immunosuppressive necrotic niche.