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Glioblastomas are malignant tumors of the central nervous system hallmarked by subclonal diversity and dynamic adaptation amid developmental hierarchies. The source of dynamic reorganization within the spatial context of these tumors remains elusive. Here, we characterized glioblastomas by spatially resolved transcriptomics, metabolomics, and proteomics. By deciphering regionally shared transcriptional programs across patients, we infer that glioblastoma is organized by spatial segregation of lineage states and adapts to inflammatory and/or metabolic stimuli, reminiscent of the reactive transformation in mature astrocytes. Integration of metabolic imaging and imaging mass cytometry uncovered locoregional tumor-host interdependence, resulting in spatially exclusive adaptive transcriptional programs. Inferring copy-number alterations emphasizes a spatially cohesive organization of subclones associated with reactive transcriptional programs, confirming that environmental stress gives rise to selection pressure. A model of glioblastoma stem cells implanted into human and rodent neocortical tissue mimicking various environments confirmed that transcriptional states originate from dynamic adaptation to various environments. [Display omitted] • Five spatially distinct transcriptional programs are identified in glioblastomas • Hypoxia induces defined transcriptional and genomic responses, including CNAs • Immunosuppressive tumor-myeloid cell interactions are enhanced in segregated niches • Non-stress environments support subtype transition towards developmental stages Ravi et al. employ spatially resolved multi-omics in glioblastoma samples and identify segregated niches hallmarked by immunological and metabolic stress factors. These spatial niches are influenced by the tumor microenvironment and reflect transcriptional adaptations to inflammatory or metabolic stimuli and recapitulate neural developmental stages. [ABSTRACT FROM AUTHOR]