Tian_2026_Transl.Cancer.Res_15_437

High-grade gliomas (HGGs), particularly isocitrate dehydrogenase (IDH)-wild-type glioblastoma (GBM), remain highly lethal despite increasingly complex, tumor-intrinsic therapies. Converging evidence from models and human studies now positions neuronal activity as a core driver of glioma growth, invasion and epileptogenesis. This review synthesizes data on a mechanistically defined neuro-glioma circuit that links activity-dependent neuroligin-3 (NLGN3) shedding by the sheddase a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) ADAM10 with the formation and strengthening of neuron-glioma alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor synapses. Neuronal and oligodendroglial firing activates ADAM10, generating soluble NLGN3 (sNLGN3) that reprograms glioma cells toward a highly neural, synapse-competent state through kinase, epigenetic and mechanosensory pathways, including LYN proto-oncogene, Src family tyrosine kinase (LYN), phosphoinositide 3-kinase (PI3K)-mechanistic target of rapamycin (mTOR) and chondroitin sulfate proteoglycan 4 (CSPG4)-Piezo-type mechanosensitive ion channel component 1 (PIEZO1) signaling. Reprogrammed tumor cells then assemble calcium-permeable AMPA receptors and bona fide neuron-glioma synapses, receive excitatory input and propagate calcium waves across tumor networks, which in turn amplify peritumoral hyperexcitability and seizures, closing a positive feedback loop of activity-dependent growth. On this basis, we outline an "actionable circuit" spanning neuronal activity, NLGN3-ADAM10 shedding, intracellular signaling, synaptic integration and network remodeling, and we organize emerging pharmacologic and device-based strategies into a circuit-breaking framework that includes activity dampening, inhibition of NLGN3 shedding, blockade of downstream signaling and AMPA synapses, and network-level modulation. Finally, we highlight key translational challenges and opportunities in target selectivity, brain delivery, biomarker development and adaptive trial design, arguing that multidimensional, circuit-informed interventions may complement standard surgery, radiochemotherapy and molecular targeting in selected patients with activity-driven glioma.