Decoding the spatial architecture of integrated electrophysiological and transcriptomic diversity in malignant brain tumors

Neuronal integration is a hallmark of many brain tumors, yet the mechanisms underlying synaptogenesis and tumor-neuron interactions remain poorly understood. Here, we combine integrative spatial electrophysiology and transcriptomics (ElectroGenOmics) to uncover a STAT3-driven inflammatory microglial program that promotes BDNF-mediated synaptogenesis within the tumor ecosystem. Through alignment of retrograde tracing and spatially resolved transcriptomics in human cortical slice models and murine systems, we demonstrate that inflammatory microglia are essential for neuron-tumor connectivity. Pharmacological STAT3 inhibition or microglia depletion significantly reduced neuron-tumor connectivity. Our findings identify inflammatory microglia as a central driver of neuronal integration in brain tumors, establishing a generalizable mechanism for tumor-induced neuronal connectivity and offering potential therapeutic avenues to disrupt these interactions.神经元整合是多数脑肿瘤的标志性特征，但突触形成与肿瘤-神经元互作的潜在机制仍未得到充分阐明。本研究结合整合空间电生理学与转录组学技术（ElectroGenOmics），揭示了一套由STAT3驱动的炎症性小胶质细胞程序，该程序可在肿瘤生态系统内促进BDNF（Brain-Derived Neurotrophic Factor）介导的突触形成。研究通过在人类皮层切片模型与小鼠实验体系中，对逆行示踪数据与空间分辨转录组学数据进行整合比对，证实炎症性小胶质细胞是神经元-肿瘤连接建立的必要条件。采用药物抑制STAT3或清除小胶质细胞，可显著降低神经元-肿瘤连接的形成效率。本研究发现炎症性小胶质细胞是脑肿瘤中神经元整合的核心驱动因素，确立了肿瘤诱导神经元连接形成的普适性机制，并为阻断这类肿瘤-神经元互作提供了潜在治疗途径。