Neuronal precursor cell persistence in ganglioglioma is associated with extracellular matrix remodeling and immune cell infiltration.

Background: Gangliogliomas (GGs) are low-grade glioneuronal tumors that frequently present with drug-resistant epilepsy. Although their indolent course contrasts with their high epileptogenic potential, the oncogenic mechanisms sustaining neuronal precursor-like populations within the tumor microenvironment remain poorly defined. Methods: We performed spatial transcriptomic profiling on eight histologically confirmed GGs and matched healthy cortex to map the cellular and molecular architecture of the tumor microenvironment. Integrated analysis with weighted gene correlation network analysis (WGCNA) defined recurrent oncogenic programs and spatially resolved tumor-stroma interactions. Results: Eight conserved gene modules emerged, encompassing physiological cortical, reactive glial, and oncopathological programs. The latter captured extracellular matrix (ECM) remodeling, vascular-immune signaling, and persistence of immature, proliferative neuronal-like states. Spatial modeling revealed that these oncopathological programs form structured niches at the tumor-brain interface, where radial glia-derived neuronal-like tumor cells coexist with immune and stromal elements engaged in ECM turnover and cytokine signaling. Conclusions: Ganglioglioma represents a hybrid glioneuronal neoplasm in which developmental neuronal programs are co-opted by tumor-associated stromal and immune cues. This convergence establishes a permissive oncogenic niche that sustains precursor-like tumor cells and provides a mechanistic basis for both the tumor's benign growth and its intrinsic epileptogenicity.