Glioblastoma-secreted C1QL1 orchestrates tumor microtube expansion and neural synaptic pruning to drive malignant synapse formation and recurrence

Glioblastoma (GBM) cells form neuron-to-glioma malignant synapses on neurite-like tumor microtubes (TMs), driving infiltrative growth and recurrence. The mechanisms underlying coordinated crosstalk among GBM cells and with neurons to favor malignant over normal synapses remain largely unknown. Here, we demonstrate that glioma-secreted C1QL1 is a key messenger for glioma-neuron and glioma-glioma crosstalk to drive TM expansion and malignant synapse formation. C1QL1 binds to its receptor BAI3 on neighboring neurons and GBM cells, activating Rac1-mediated cytoskeleton rearrangement to prune normal synapses and outgrow TMs, promoting malignant synapse and glioma network formation. Targeted treatment with a non-GEF-targeting, first-in-class Rac1 inhibitor rescues C1QL1-mediated synaptic pruning, inhibiting TMs and malignant synapses to impede glioma recurrence. Our findings elucidate how crosstalk among GBM cells and neurons allows infiltrating GBM cells to sculpt and integrate into the existing neural network, highlighting a therapeutic strategy against GBM recurrence through simultaneous inhibition of TMs and glioma-induced synaptic pruning.