Decoding glioblastoma's diversity: Are neurons part of the game?

Glioblastoma multiforme (GBM, WHO Grade 4) is a highly aggressive primary brain tumor with limited treatment options and a poor prognosis. A key challenge in GBM therapy lies in its pronounced heterogeneity, both within individual tumors (intratumoral) and between patients (intertumoral). Historically, neurons have been underexplored in GBM research; however, recent studies reveal that GBM development is closely linked to neural and glial progenitors, often mimicking neurodevelopmental processes in a dysregulated manner. Beyond damaging neuronal tissue, GBM actively engages with neurons to promote pro-tumorigenic signaling, including neuronal hyperexcitability and seizures. Single-cell RNA sequencing (scRNA-seq) has revolutionized our understanding of the tumor microenvironment (TME), uncovering the critical roles of immune cells, endothelial cells, and astrocytes in tumor progression. However, technical limitations of scRNA-seq hinder its ability to capture the transcriptomes of neurons, necessitating the use of single-nucleus RNA sequencing (snRNA-seq) to study these interactions at single-cell resolution. This work collects the emerging insights of glioblastoma-neuron interactions, focusing on how GBM exploits neurodevelopmental pathways and reshapes neuronal networks. Moreover, we perform bioinformatic analysis of publicly available snRNA-seq datasets to propose putative cell-cell interactions driving glioma-neuronal dynamics. This study delineates key signaling pathways and underscores the need for further investigation to evaluate their potential as therapeutic targets.