TFDP3 is an X-linked transcription factor that functions as a competitive inhibitor of E2F-mediated transcriptional activity. Unlike its paralogues TFDP1 and TFDP2, TFDP3 binds E2F proteins but the resulting heterodimers fail to interact with E2F consensus DNA sequences, thereby suppressing E2F-driven gene expression and impairing G1/S cell cycle progression 1. Four critical amino acids in TFDP3's DNA-binding domain are responsible for this functional conversion from E2F activation to suppression 1. TFDP3 plays opposing roles across different biological contexts. In hepatocellular carcinoma, HIF-2α suppresses TFDP3 expression, and reintroduction of TFDP3 inhibits E2F1-mediated transcriptional activity through p53-dependent and -independent apoptotic pathways 2. In prostate and breast cancer, however, TFDP3 is upregulated and suppresses E2F1-induced apoptosis while promoting autophagy, contributing to chemotherapy resistance 3, 4, 5. Clinically, TFDP3 is a cancer-testis antigen expressed in malignant tissues and normal testicular tissue. TFDP3 variants cause oligoasthenoteratozoospermia through E2F1-induced spermatogonial apoptosis, highlighting its essential role in primate spermatogenesis 6. In myelodysplastic syndromes, TFDP3 reactivation after azacitidine treatment correlates with complete remission and elicits specific cytotoxic immune responses 7.