Tle3, short for Transducin-like enhancer of split 3, is a transcriptional co-factor and corepressor that plays a crucial role in multiple biological processes. It is involved in various signaling pathways and is important for maintaining cell lineage identity, immune homeostasis, and has implications in cancer development and metabolism [1-10]. Genetic models, such as KO/CKO mouse models, have been valuable in studying its functions.

In CD8+ T cells, genetic ablation of Tle3 promoted CD8+ TCM cell formation at the expense of CD8+ TEM cells, indicating its role in controlling T cell fates [1]. In luminal breast cancer, TLE3 actively repressed the gene-expression signature of basal-like breast cancers, preventing a hybrid epithelial-mesenchymal state and reducing metastasis [2]. In myeloid cells lacking Tle3, there was an increase in regulatory T and TH17 cells, affecting intestinal immune homeostasis [3]. Loss of Tle3 in prostate cancer cells conferred resistance to AR inhibitors [4]. In mesenchymal stem cells, adipogenic TLE3 is selectively removed by chaperone-mediated autophagy to promote osteogenesis [5]. In colorectal cancer, down-regulation of TLE3 was associated with poorer patient survival, and overexpression of TLE3 repressed cancer cell proliferation by inhibiting MAPK and AKT signaling pathways [6]. In beige adipocytes, conditional deletion of TLE3 promoted mitochondrial oxidative metabolism and improved glucose control [7].

In conclusion, Tle3 is essential for maintaining cell lineage fidelity in T cells and breast cancer cells, regulating immune homeostasis in the intestine, influencing prostate cancer response to treatment, and playing roles in mesenchymal stem cell differentiation, colorectal cancer progression, and beige adipocyte-related metabolism. The KO/CKO mouse models have significantly contributed to understanding Tle3's role in these disease-related biological processes, providing insights for potential therapeutic strategies.