Neuronal precursor cell persistence in Ganglioglioma is associated with ECM remodeling and immune cell infiltration

Abstract 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. Key Points Spatial transcriptomics identifies reproducible transcriptional programs that define the ganglioglioma microenvironment. Tumor-associated regions show transcriptional programs consistent with immature neuronal states together with ECM remodelling and immune activity. Single-cell reference data indicate that immature neuronal programs in ganglioglioma resemble radial glia-derived developmental states. Importance of the Study Ganglioglioma is a low-grade glioneuronal tumor that combines benign growth with pronounced epileptogenicity, yet the molecular basis of this dual behavior remains poorly understood. Through spatial transcriptomics integrated with single-cell analysis, we reveal that ganglioglioma architecture is defined by two interacting transcriptional axes: a residual glioneuronal network and a tumoral niche enriched for extracellular-matrix, vascular, and immune programs. Within these niches, immature neuronal-like tumor cells persist in a developmentally arrested state maintained by ECM-immune signaling. This spatially organized interplay between physiological and pathological programs explains both the low oncologic aggressiveness and high excitability of these lesions. Our findings provide molecular signatures that may refine diagnostic classification within the LEAT spectrum, delineate epileptogenic zones, and identify candidate pathways for therapeutic modulation of the ganglioglioma microenvironment.