CNSC-19. Glioma-Associated Neurons Potentiate Glioma Radioresistance by Facilitating the Transfer of Fresh Mitochondria From Peripheral Macrophages to Glioma Cells via Tumor Microtubes

The tumor microenvironment (TME), including mitochondrial dynamics, plays a pivotal role in the initiation and progression of glioblastoma. Beyond the traditional components of the TME, neurons have recently been identified as key regulators of glioma behavior. However, the role of glioma-associated neurons in mediating mitochondrial transfer and contributing to radiation resistance remains largely unexplored. Here, using neuronal ablation and chemogenetic techniques and in vivo mitochondrial tracking, we identified that radiation-exposed neurons in glioma secret unique exosomes that facilitate physical connections between glioma cells and tumor-infiltrating macrophages via tumor microtubes (TMs). These TMs enable the transfer of healthy mitochondria from newly recruited macrophages to irradiated glioma cells, thereby restoring glioma cell mitochondrial function. Mechanistically, neuronal exosomal FABP7 protein is transferred to glioma cells and facilitates the formation of tumor TMs by modifying palmitoylation and subsequent plasma membrane localization of TMs proteins. Importantly, combined inhibition of neuronal activity and peripheral immune cell infiltration, followed by hypofractionated radiotherapy, significantly enhances the radiation efficacy in damaging glioma cells and improves the prognosis of glioma-bearing mice.