Glioma-on-a-Chip: Microengineering Platforms for Unraveling Tumor-Induced Epileptogenesis and Personalized Neuro-Oncology

Gliomas are the most common primary malignant brain tumors and are frequently associated with severe neurological comorbidities, most notably tumor-associated epilepsy. Seizures affect 40% of all patients and up to 80% of patients with IDH-mutant low-grade gliomas, while more than half of these cases are refractory to standard antiseizure medications. Despite significant advances in molecular profiling, the mechanistic interplay between infiltrating glioma cells and peritumoral neuronal circuits remains poorly understood, largely due to the lack of adequate in vitro models that recapitulate both the cytoarchitecture and the electrophysiological complexity of the tumor microenvironment. In this Perspective, we discuss the use of microfluidic Glioma-on-a-Chip platforms as a transformative tool for studying glioma-neuron interactions. These compartmentalized devices, when integrated with multi-electrode arrays and patient-derived cells (including human iPSC-derived neurons), enable real-time monitoring of the interaction of neurons and cancer cells, tumor invasion, network hyperexcitability, and pharmacological responses. The integration of these advanced platforms offers the potential to generate more physiologically relevant disease models. Recent studies have demonstrated that glioma-on-a-chip platforms are valuable for unraveling fundamental mechanisms of network hyperexcitability and may facilitate personalized drug screening, improving clinical outcomes.