Neuronal activity promotes high-grade glioma progression via secreted proteins and neuron-to-glioma synapses, and glioma cells boost neuronal activity to further reinforce the malignant cycle. Whereas strong evidence supports that the activity of neuron-to-glioma synapses accelerates tumor progression, the molecular mechanisms that modulate the formation and function of neuron-to-glioma synapses remain largely unknown. Our recent findings suggest that a proton (H + ) signaling pathway actively mediates neuron-to-glioma synaptic communications by activating neuronal acid-sensing ion channel 1a (Asic1a), a predominant H + receptor in the central nervous system (CNS). Supporting this idea, our preliminary data revealed that local acid puff on neurons in high-grade glioma-bearing brain slices induces postsynaptic currents of glioma cells. Stimulating Asic1a knockout (Asic1a -/- ) neurons results in lower AMPA receptor-dependent excitatory postsynaptic currents (EPSCs) in glioma cells than stimulating wild-type (WT) neurons. Moreover, glioma-bearing Asic1a -/- mice exhibited reduced tumor size and survived longer than the glioma-bearing WT mice. Finally, pharmacologically targeting brain Asic1a inhibited high-grade glioma progression. In conclusion, our findings suggest that the neuronal H + -Asic1a axis plays a key role in regulating the neuron-glioma synapse. The outcomes of this study will greatly expand our understanding of how this deadly tumor integrates into the neuronal microenvironment.