EPHA2 is a receptor tyrosine kinase that regulates cell migration, adhesion, and growth factor signaling across multiple tissues. The receptor mediates ephrin ligand binding and activates downstream signaling cascades including ERK1/2, PI3K/AKT, and SRC pathways that control cell motility, focal adhesion dynamics, and lamellipodium assembly. EPHA2 also serves as a receptor for human cytomegalovirus entry in glioblastoma cells. EPHA2 is substantially overexpressed across diverse human malignancies including glioblastoma, colorectal cancer, hepatocellular carcinoma, and osteosarcoma, where high expression correlates with poor prognosis 1. In glioblastoma, EPHA2 mediates platelet-derived growth factor A signaling independently of its canonical receptor PDGFRA and contributes to resistance against single-agent PDGFRA inhibitors 2. In colorectal cancer, EPHA2 promotes vasculogenic mimicry through m6A-dependent mRNA stabilization and supports cancer stemness via interaction with claudin-1 34. In hepatocellular carcinoma, the ephrin-A3/EphA2 axis drives metabolic rewiring and self-renewal under hypoxic conditions 5. EPHA2 silencing sensitizes osteosarcoma cells to cisplatin chemotherapy 6. Clinically, dual EPHA2/EGFR-targeting bispecific antibodies show preclinical efficacy in overcoming EGFR inhibitor resistance 7. Dasatinib, an FDA-approved SRC/EPHA2 inhibitor, reduces tumor progression in PTEN-deficient cancers by disrupting EPHA2/SRC/PI3Kβ complexes 8. Novel approaches including EphA2-targeting bicyclic peptides for radiotheranostics and EphA2-BiTE immunotherapy in pediatric gliomas are in preclinical development 910.