TBX3 is a T-box transcription factor functioning as a developmental regulator and transcriptional repressor involved in organogenesis, including heart, mammary gland, limb, and lung development 1. During embryogenesis, it binds T-site DNA sequences to orchestrate tissue patterning, likely by restraining differentiation programs. Loss-of-function mutations cause ulnar mammary syndrome, characterized by hypoplasia of mammary and apocrine glands, limb defects, and cardiac malformations 1. In adult tissues, TBX3 exhibits context-dependent oncogenic and tumor-suppressive roles. TBX3 is frequently mutated and enriched in endocrine-resistant breast cancers, where alterations correlate with shorter duration of hormonal therapy response 2. Similarly, TBX3 mutations are enriched in invasive lobular breast carcinoma 3, and high TBX3 expression in luminal progenitor-derived signatures associates with unfavorable outcomes in HER2+ breast cancer 4. In contrast, TBX3 overexpression suppresses intrahepatic cholangiocarcinoma progression by repressing MAD2L1 5, and deletion of Tbx3 protects against hepatic steatosis in metabolic liver disease 6. Recent evidence suggests that in BRAF/MAPK-driven tumorigenesis, the USP15-stabilized TBX3 axis reactivates developmental dedifferentiation programs, promoting epithelial transformation 7. In bladder cancer, TBX3 shapes an immunosuppressive tumor microenvironment by increasing TGFβ1 secretion and cancer-associated fibroblast infiltration, reducing CD8+ T cell cytotoxicity and predicting immunotherapy resistance; combining TBX3 inhibition with anti-PD-1 treatment enhanced anti-tumor immunity 8.