Tumor microenvironment shapes the spatial organization of glioblastoma cell states.

Glioblastoma is characterized by heterogeneous and plastic cellular populations that adopt transcriptional programs shaped by genetic alterations and microenvironmental cues. Recent studies have identified at least 4 partially inconvertible cell states-astrocytic-like, neural progenitor-like, oligodendrocyte progenitor-like, and mesenchymal-like-that represent aberrant developmental programs. Expanded analysis further reveals hybrid and intermediate states that form continuous transcriptional and metabolic gradients. These states exhibit spatial organization, assembling into 3 distinct microanatomical niches: a perivascular niche enriched with mesenchymal-like and oligodendrocyte progenitor-like cells, a hypoxic niche harboring quiescent and stressed cells of all states, and an invasive niche containing astrocyte-like or proneural populations. Niches continuously remodel as cell states transition, migrate, and reestablish new programming in response to angiogenesis, hypoxia, immune infiltration, and neuronal activity. This interplay between states and the microenvironment generates a self-renewing spatial architecture, maintaining expansion at the edge and protection within the core. This review integrates single-cell, single-nucleus, and spatial studies to describe a microenvironmental-driven model of cell state organization. Understanding how these multiscale drives converge to generate a continuum of cell state identities may reveal strategies to disrupt the spatial architecture underlying glioblastoma plasticity and recurrence.