Tumor microenvironment in glioblastoma: The central role of the hypoxic-necrotic core

Glioblastoma (GBM), the most aggressive and lethal primary brain tumor, is characterized by profound intratumoral heterogeneity and a hostile tumor microenvironment (TME) that drives immune evasion, therapeutic resistance, and relentless progression. Among its defining pathological features is the development of a hypoxic-necrotic core, long recognized as a hallmark of poor clinical outcome. This review synthesizes current insights into how hypoxia and necrosis act not merely as pathological markers, but as a spatiotemporal evolution engine of the GBM TME, driving metabolic adaptation, extracellular matrix (ECM) remodeling, and immune evasion. We examine how oxygen and nutrient deprivation activate hypoxia-inducible factors (HIFs), triggering cascades that promote angiogenesis, altered metabolism, and accumulation of immunosuppressive metabolites. These stressors also contribute to the recruitment and polarization of tumor-associated macrophages (TAMs) and neutrophils (TANs), expansion of myeloid-derived suppressor cells (MDSCs), and infiltration of regulatory T cells (Tregs), collectively creating an immune-excluded niche. Furthermore, hypoxia-induced ECM stiffening and degradation enhance tumor invasiveness while limiting immune cell access. By exploring the dynamic interplay between physicochemical stressors and immune modulation within the necrotic core, this review highlights the need for targeting the hypoxia-necrosis axis to overcome current therapeutic limitations. A deeper understanding of these processes will be crucial for the development of precision-targeted therapies in this highly refractory malignancy.