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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月8日

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  • Bo Yuan,
  • Xiaolin Zhang,
  • Dongying Zheng,
  • Haoran Wang,
  • Xiran Jiang,
  • Bin Zhang,
  • Feng Wan

摘要

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.