The malignant synapse: architecture, signal integration, and therapeutic vulnerabilities in glioma

Emerging evidence has fundamentally reshaped the neuro-oncological paradigm, revealing that gliomas and brain metastases are not isolated cellular masses but synaptically integrated entities within the brain's neural circuitry. This review comprehensively delineates the architecture and multi-modal signaling landscape of the "malignant synapse." We explore how diverse pre-synaptic inputs-encompassing glutamatergic, cholinergic, and GABAergic signals-are structurally anchored by matricellular organizers (like thrombospondins) and proteolytically cleaved factors (like sNLGN3). Post-synaptically, glioma cells deploy a sophisticated array of effectors to translate these neural inputs. Through a convergence of electrochemical (AMPAR-mediated), mechanosensory (CSPG4-PIEZO1 cascade), and metabolic (CHRM3 and TrkB) axes, these diverse signals universally ignite the PI3K-mTOR signaling hub, which is further amplified across the tumor mass via the Connexin-43-coupled tumor microtube (TM) syncytium. Recognizing this profound reliance on neural inputs exposes a critical therapeutic vulnerability. We systematically evaluate pharmacological strategies to disconnect these malignant circuits, highlighting the repurposing of neuroactive drugs-including perampanel, gabapentin, and bumetanide-to effectively stall tumor progression. Finally, we address formidable translational challenges, such as blood-brain barrier penetrance and off-target neurotoxicity. We also outline future frontiers, particularly leveraging spatial multi-omics to decode how synaptic signaling orchestrates the tumor immune microenvironment. Ultimately, dismantling the neuron-glioma axis represents a transformative frontier in conquering intractable brain cancers.