TBX3 is a T-box transcription factor serving as a transcriptional repressor that binds palindromic DNA sequences 12. During development, TBX3 orchestrates organogenesis by restraining differentiation and is essential for limb patterning, mammary gland development, and inner ear formation 1. TBX3 acts as a negative regulator of PML function in cellular senescence 3. In cancer biology, TBX3 exhibits context-dependent functions. In breast cancer, TBX3 mutations are enriched in endocrine-resistant tumors and associated with shorter treatment response duration 4, while in invasive lobular carcinoma it represents an ILC-enriched mutation 5. Conversely, in cholangiocarcinoma, TBX3 overexpression suppresses tumorigenesis by repressing MAD2L1 expression 6. In bladder cancer, TBX3 promotes immunotherapy resistance by inducing an immunosuppressive microenvironment through TGFβ1-mediated recruitment of cancer-associated fibroblasts and reduction of CD8+ T cell infiltration 7. Mechanistically, during BRAF/MAPK-driven tumorigenesis, the USP15-TBX3 axis is reactivated to promote epithelial dedifferentiation 8. Additionally, TBX3 deletion protects against hepatic steatosis in metabolic liver disease models 9. Mutations in TBX3 are associated with ulnar-mammary syndrome.