Gliomas as network diseases: Neuron-tumor interactions, connectome disruption, and clinical implications

Gliomas are increasingly understood as disorders of distributed brain networks rather than focal lesions confined within radiographic margins. Emerging evidence suggests that glioma cells interact with neural circuits, alter structural and functional connectivity, and contribute to cognitive, neuropsychiatric, and functional decline through network-level mechanisms.

This structured narrative review synthesizes preclinical, molecular, neuroimaging, and clinical evidence on how gliomas disrupt the brain connectome. Evidence is organized into sections on neuron-glioma interactions, white matter-guided invasion, functional network disruption, grade- and subtype-specific vulnerability, prognostic biomarkers, recurrence detection, network-guided surgery, and exploratory neuromodulatory strategies.

Glioma-related connectome disruption is mediated by activity-dependent neuron-glioma synaptic coupling, paracrine signaling, tumor microtubule networks, gap junction communication, tumor microenvironment remodeling, and white matter tract-guided invasion. These mechanisms enable gliomas to integrate into and remodel neural circuits, producing structural disconnection and functional network instability beyond the visible tumor core. Large-scale cognitive and affective networks, including the default mode, salience, and central executive networks, are frequently altered and may contribute to early neuropsychiatric symptoms, cognitive impairment, seizures, and functional decline. Disruption patterns vary by tumor biology: low-grade gliomas often show compensatory plasticity, whereas high-grade gliomas and glioblastomas exhibit extensive bilateral network disruption and reduced interhemispheric connectivity. Connectome-derived metrics have been associated with tumor grade, molecular subtype, recurrence, cognitive outcomes, and survival. In selected glioblastoma cohorts, preserved intratumoral functional connectivity may correlate with improved outcomes, suggesting a marker of local tumor aggressiveness and preserved host tissue architecture. Translational applications include connectome-informed surgical planning, noninvasive prognostication, recurrence monitoring, and network-based rehabilitation or neuromodulation, although these approaches remain investigational.

Glioma biology reflects dynamic interactions between tumor cells and distributed neural networks. A connectome-informed framework may complement conventional imaging and molecular classification by identifying global brain vulnerability, functional risk, and therapeutic targets. Clinical implementation will require standardized imaging pipelines, prospective multicenter validation, and integration with patient-centered outcomes. Only then can connectome-guided strategies be routinely incorporated into glioma care.