NETO2 (neuropilin and tolloid like 2) is a multifunctional protein with distinct roles in neurotransmission and oncogenic signaling. In the central nervous system, NETO2 functions as an accessory subunit of kainate-sensitive glutamate receptors (GRIK2 and GRIK3) 1. It modulates receptor pharmacology by slowing desensitization and deactivation kinetics, increasing recovery from desensitization, and enhancing agonist sensitivity 2. Structurally, NETO2 binds variable stoichiometries to kainate receptors, accessing multiple receptor faces and regulating gating kinetics through interactions with the M1-M2 linker cap domain 1. This modulation directly influences synaptic transmission through altered excitatory postsynaptic current kinetics 3. Beyond synaptic function, NETO2 exhibits oncogenic properties across multiple cancer types. In esophageal squamous cell carcinoma, NETO2 overexpression promotes proliferation and metastasis via PI3K/AKT and ERK/Nrf2 pathways 4. Similarly, in gastric and nasopharyngeal cancers, elevated NETO2 correlates with advanced clinical stage and metastasis, activating PI3K/AKT/NF-κB signaling 56. NETO2 knockdown suppresses epithelial-mesenchymal transition and enhances radiotherapy efficacy through Caspase-3-mediated apoptosis 6. In lung adenocarcinoma, NETO2 partners with α5-nicotinic acetylcholine receptors to promote stress-induced tumorigenesis 7. These findings establish NETO2 as both a synaptic modulator and cancer-associated biomarker with therapeutic potential.