The chromatin-organizer Satb1 modulates regulatory T cell activity within the tumor microenvironment

Regulatory T cells (Tregs) are essential for maintaining immune homeostasis and preventing autoimmune diseases, but are also a major cellular constituent of the tumor microenvironment (TME) that facilitates cancer progression. Identifying differences in Treg subtypes to specifically disrupt the activities of tumor-promoting Tregs, without affecting Tregs that maintain immune homeostasis remain a challenge. Here, we report that expression of the chromatin-organizer protein special AT-rich sequence binding protein 1 (Satb1), in Tregs is critical for their tumor-promoting functions in the TME, but not strictly required to suppress inflammatory T cells in autoimmune colitis. Satb1 expression differentiated between two Treg subtypes with distinct display of Treg phenotypic markers in lymphoid organs. Using transfer experiments, we discovered a context-specific switch in Satb1 protein expression between the two Treg subtypes. In mice, Treg-specific deletion of Satb1 augmented TCF-1 expression via a signaling axis involving Stat3 and the RNA-binding protein poly(C)-binding protein 1 (PCBP1), impairing the activities of tumor-infiltrating Treg cells. Simultaneous deletion of Satb1 and PCBP1 in Tregs completely restored Treg pro-tumorigenic functions and abolished the potent antitumor immune responses observed in Satb1-deficient mice. Our results reveal a key mechanism that may safely and potently enhance antitumor immunity without causing systemic autoimmune diseases.