TMED3 (transmembrane emp24 domain-containing protein 3) functions primarily in vesicular protein trafficking within the early secretory pathway. Under normal conditions, TMED3 contributes to coupled localization of TMED2 and TMED10 in the cis-Golgi network 1. Under ER stress, TMED3 forms a heteromeric complex with TMED2, TMED9, and TMED10 that recognizes ER core-glycosylated protein cargos and mediates their Golgi-independent unconventional secretion, including trafficking-deficient mutants like ΔF508-CFTR associated with cystic fibrosis and p.H723R-pendrin associated with Pendred syndrome 1. Beyond protein trafficking, TMED3 exhibits significant oncogenic functions across multiple cancer types. TMED3 is highly overexpressed in glioma, chordoma, non-small cell lung cancer, and prostate cancer, where elevated expression correlates with poor prognosis, higher tumor grades, and reduced survival 2345. TMED3 knockdown inhibits cancer cell viability, migration, and proliferation while enhancing apoptosis 3. Mechanistically, TMED3 promotes malignant progression through the Wnt/β-catenin and ZBTB7A signaling axes 46. Conversely, TMED3 functions as a metastatic suppressor in colon cancer, modulating WNT-TCF signaling 7. These contrasting roles suggest TMED3's function may be context-dependent across different malignancies.