Beyond synapses non-synaptic neural microenvironment interactions remodel circuits and drive glioma progression

Genomic and epigenomic alterations alone cannot fully account for glioma infiltration, therapeutic resistance, or symptom severity. This review proposes a shift toward viewing the neural microenvironment as an active driver of glioma progression through diverse non-synaptic mechanisms, including metabolic coupling, ionic and volume transmission, gap junction signaling, and tumor microtube connectivity. We systematically map the contributions of astrocytes, oligodendrocyte precursor cell programs, microglia/macrophages, and the neurovascular unit, highlighting how their interactions contribute to local excitation-inhibition imbalances and disruptions in large-scale neural connectivity. These circuit-level disturbances closely correspond with clinically significant manifestations such as glioma-related epilepsy, cognitive deficits, and mood disorders, and also demonstrate correlations with patient survival outcomes. To rigorously connect molecular mechanisms to observable circuit disruptions, we integrate advanced methodologies including single-cell and spatial multi-omics analyses, human brain organoids and organotypic slice models, in vivo calcium imaging, and causal neuromodulation approaches. Emerging translational strategies identified by this approach include disrupting tumor microtube networks and gap junction-mediated signaling, functionally reprogramming glial cells, and employing targeted neuromodulation therapies. Additionally, we explore biomarker-driven combination therapies involving anti-angiogenic treatments and immunomodulatory agents as promising avenues for enhancing clinical outcomes.