Background While hypoxia is a well-established driver of glioblastoma progression, its role in IDH-mutant gliomas, characterized by localized hypoxic microenvironments rather than overt necrosis, remains poorly understood. Here, we investigate how hypoxia and microenvironmental-adaptations shape cellular heterogeneity and transcriptional plasticity in these tumors. Methods We integrated bulk, single-cell, and spatial-transcriptomics datasets from IDH-mutant glioma patients (Astrocytomas and Oligodendrogliomas) to characterize cellular-states and map the localization of hypoxic niches. To uncover tumor microenvironment effects, we established co-culture models using primary IDH-mutant glioma cells with human microglia and astrocytes, maintained under hypoxic and normoxic conditions, followed by bulk RNA-sequencing. Results We identified a hypoxia-associated astrocyte-like (AC-like) program that defines a quiescent, non-cycling population with a distinct transcription factor profile indicative of functional plasticity in IDH-mutant gliomas. These cells harbor glioma stem cell (GSC)-like features and are poised for a quiescent-to-activated (Q-to-A) transition that drives tumor progression. Mechanistically, co-culture models reveal that microglia promote this Q-to-A transition by enhancing HBEGF/EGFR paracrine signaling. Spatial transcriptomics uncovers the co-localization of hypoxic niches within quiescent AC-like cells, whereby the activated subpopulation forms discrete niches defined by localized HBEGF/EGFR communication gradients. Notably, tumors exhibiting elevated EGFR-driven activation signatures correlate with higher histological grade and poorer patient survival, implicating the Q-to-A transition as a critical driver of malignant progression. Conclusion Q-to-A transition within the hypoxic niche represents a critical driver of malignant progression in IDH-mutant gliomas, providing a microenvironment-driven mechanism for the transition to higher-grade disease and identifying targetable-vulnerabilities for therapeutic intervention.
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