TMEFF2 is a transmembrane protein with EGF-like and follistatin domains that functions as a tumor suppressor across multiple cancer types. Mechanistically, TMEFF2 exerts its protective effects through multiple pathways: it suppresses STAT3 phosphorylation via SHP-1 interaction 12, inhibits one-carbon metabolism to reduce cellular invasion 3, and prevents BAX protein degradation by blocking TRIM17-mediated ubiquitination 4. In cancer development, TMEFF2 expression is frequently downregulated through epigenetic silencing via CpG island methylation in non-small cell lung cancer (52.5% of tumors) 5, frameshift mutations in microsatellite-instable gastric and colorectal cancers 6, and miR-323-3p-mediated suppression in lung cancer 7. Notably, TMEFF2 methylation in serum DNA shows promise as a blood-based biomarker for lung cancer 5. The protein undergoes proteolytic shedding via ADAM17, ADAM9, ADAM12, matriptase-1, and hepsin, a process enhanced by oxidative stress and cell crowding in the tumor microenvironment 8. Conversely, TMEFF2 promotes benign prostatic hyperplasia progression through BAX degradation 4, demonstrating context-dependent biological functions.