Neuron-glioma synaptic transmission amplified by free 19S proteasome-mediated AMPAR deubiquitination promotes tumor progression.

Glioma progression is closely linked to neuronal activity. Glutamatergic neurons form functional synapses with glioma cells (neuron-glioma synapses, NGS), directly promoting tumor growth via electrophysiological signaling. However, the key molecular regulators of NGS remain unclear. This study aims to investigate the pivotal role of free 19S proteasomes in NGS and their underlying molecular mechanisms. Combining a murine orthotopic glioma model with an in vitro NGS model, we demonstrate specific enrichment of free 19S proteasomes within tumor-infiltrated regions. These proteasomes maintain the stability of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors (AMPARs) through their deubiquitination activity, thereby enhancing synaptic signal transmission and fostering tumor progression. Functionally, inhibition of free 19S deubiquitinase activity significantly attenuates postsynaptic potentials and suppresses tumor proliferation and invasion. Interestingly, radiotherapy further activates the free 19S-AMPAR axis, suggestive of a promising strategy to enhance radiosensitivity by targeting this pathway. In therapeutic experiments using mouse models, combined inhibition of the 19S-AMPAR axis and radiotherapy markedly suppressed growth of glioma. These findings elucidate a novel mechanism of glioma-neuron interaction via proteasome-mediated synaptic regulation and provide a crucial foundation for developing combination therapies targeting synaptic pathways. This study uncovers a new function of proteasomes in intercellular communication, offering a potential target to overcome glioma treatment resistance.