HOMER3 is a postsynaptic density scaffolding protein that cross-links cytoplasmic regions of glutamate receptors (GRM1, GRM5) with intracellular calcium-release channels (ITPR1), coupling surface receptor activation to intracellular calcium signaling and supporting glutamatergic synaptic plasticity. It also negatively regulates T cell activation by competing with calcineurin for NFAT binding, thereby inhibiting the calcineurin-NFAT pathway. Beyond its canonical synaptic role, HOMER3 has emerged as an oncogenic driver across multiple cancer types. In prostate cancer, HOMER3 overexpression promotes YAP1 activity by facilitating SRC kinase-mediated YAP1 phosphorylation, driving tumor growth and immunosuppression via CD274 upregulation 1. In glioma, ELK4-induced HOMER3 expression activates the Wnt/β-catenin/epithelial-mesenchymal transition pathway, promoting proliferation and metastasis 2. HOMER3 elevation in non-small cell lung cancer sustains mitochondrial biogenesis through GABPB1, supporting tumor growth and metastatic potential 3. In oral squamous cell carcinoma, HOMER3 integrates calcium influx and microtubule dynamics via distinct scaffolding complexes, driving proliferation and docetaxel resistance 4. Elevated HOMER3 in hepatocellular carcinoma and colorectal cancer correlates with poor prognosis and associates with protumoral immune infiltration 5, 6. Additionally, HOMER3 interacts with amyloid precursor protein and suppresses amyloid-β production 7, 8, suggesting a protective role in Alzheimer's disease pathology. In triple-negative breast cancer, HOMER3 facilitates growth factor-mediated β-catenin activation, promoting metastasis 9. SRC kinase inhibition may offer therapeutic benefit in HOMER3-overexpressing cancers.