SATB1 preserves CD4+ T-cell fidelity and establishes Treg function in antitumor immunity.

The genome organizer special AT-rich sequence binding protein 1 (SATB1) is critical for the development of T lymphocyte subsets by regulating Foxp3 and Pdcd1 expression. However, its physiological role in mature peripheral T cells has remained obscured by the severe developmental defects caused by early-stage gene knockout models. Here, we used a Thpok-cre driver to specifically delete Satb1 after CD4 lineage commitment. We demonstrate that SATB1 is continuously required to suppress Foxp3 expression in conventional CD4+ T cells; however, this aberrant derepression does not confer Treg suppressive activity. In contrast, FoxP3+CD25+ Tregs isolated from SATB1-deficient mice exhibit functional defects in immune suppressive function. Although SATB1 deletion does not cause severe global defects in the Treg transcriptome, it disrupts essential FoxP3-mediated gene regulation, resulting in a targeted failure to silence transcripts detrimental to Treg fitness. Physiologically, this Treg-specific functional defect significantly enhances antitumor immunity in a melanoma model. Our findings reveal a dual requirement for SATB1, preserving lineage fidelity by repressing Foxp3 in conventional T cells, while enforcing foundational programming required for Treg suppressive function.