The anterior insular cortex (AIC) is a critical hub integrating exteroceptive and interoceptive information into high-order cognition, yet its neural basis remains incompletely understood. Here, by combining whole-cell-based single-cell transcriptomics with Patch-seq recordings, we resolved and characterized 78 detailed cell types in the macaque AIC, revealing the diversity and specialization of this region in cell type, connectivity profile, signal-processing strategy and metabolic characteristics. Among these, we identified two transcriptomically and morphoelectrically defined von Economo neuron (VEN) subtypes, DSG2 -expressing VEN-L and POC5 -expressing VEN-S, transcriptomically relating to extratelencephalic and corticothalamic projection neurons, respectively. We also uncovered a previously underappreciated signal-processing strategy by VENs, whereby the geometry of the dendrite-originating axon reshapes action potential dynamics and enhances somatic responsiveness to deep-layer synaptic inputs. Our multimodal atlas establishes a molecular and functional framework for investigating the circuit principles underlying cognitive processes in the primate AIC.

Tumour–neuron interactions and malignant synapse formation drive glioblastoma progression, recurrence and neurological dysfunction, but systemic inhibition of synaptic signalling causes unacceptable neurotoxicity. Here we defined the spatial and molecular determinants of malignant synapses by analysing intact human glioblastoma specimens, revealing enrichment of synapse-like structures and synapse-associated gene programmes at the tumour–brain interface. Spatial and transcriptomic analyses highlighted the neurotrophic receptor TrkB as a candidate therapeutic target at the tumour–brain interface. Guided by this target, we developed an intracavitary, multiresponsive hydrogel that locally delivers small interfering RNA to silence TrkB in residual tumour cells after surgery. In syngeneic and patient-derived glioblastoma models, treatment suppressed tumour regrowth and prolonged survival; in the syngeneic GL261 model, median survival increased from 32 to 67 days, with more than 30% of treated animals surviving beyond 90 days. TrkB silencing reduced excitatory synaptic input to tumour cells and alleviated tumour-associated anxiety and memory deficits without impairing motor function. Combination with radiotherapy further reduced invasive growth at the tumour–brain interface and extended survival. Together, these findings establish a spatially restricted, mechanism-guided therapeutic strategy for glioblastoma.