Concentric spatial architecture of GBM and enrichment of developmental malignant programs and niches. Schematic of a glioblastoma section rendered as five concentric territories (L1–L5), integrating developmental malignant programs (NPC-like, OPC-like, AC-like, and mesenchymal variants), immune–vascular niches, and example markers. This five-layer scaffold is recapitulated across cohorts, but exact state boundaries vary between patients and are constrained by current spatial resolution. L1 Necrotic/Hypoxic core: Acidotic tissue with extensive necrosis, enriched for MES-like tumour cells, including injury-response MES-transition and neural-crest/perivascular MES-NCperiV, together with inflammatory myeloid cells and stress-response signatures; checkpoint proteins such as B7-H3/CD276 and metabolic features such as MCT1/lactate are highlighted. L2 Hypoxic rim: Perinecrotic territory with stronger hypoxia signals (HIF-1) and ECM remodelling (TGF-β). We propose that MES-transition programs are more frequent here, consistent with links between hypoxia, inflammation, and mesenchymal reprogramming. L3 Angiogenic/immune belt: A viable ring with proliferative NPC-like and OPC-like programs adjacent to aberrant vessels and pericytes; this zone functions as a perfusion hub and an immune-checkpoint corridor where PD-L1 and CTLA-4 are often elevated. Perivascular stromal features compatible with MES-NCperiV may appear near vessels. L4 Neuro-developmental zone: Oxygenated territory enriched for NPC-like and OPC-like developmental programs that mirror embryonic lineages (illustrative oncogenic drivers MYC/KRAS shown). L5 Infiltrative margin: Tumour–brain interface containing reactive glia, neurons, and scattered NPC-like cells; mature neurons at the edge explain the historical “Neural” bulk signal. Marker key: MES-transition (e.g., CHI3L1/YKL-40, CD44), MES-NCperiV (e.g., COL5A2, NES), AC like (GFAP, AQP4), NPC like (ASCL1, SOX2), OPC like (OLIG2, NG2/CSPG4). Together, the layers depict a reproducible, hypoxia-graded organisation that ties developmental malignant programs to microenvironments and helps explain region-specific therapy response. (The details are shown in Video 1 at the bottom of the article as this speculation.)