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.