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Abstract

Regulatory T cells (Tregs) establish dominant immune tolerance but obstruct tumor immune surveillance, warranting context-specific mechanistic insights into the functions of tumor-infiltrating Tregs (TIL-Tregs). We show that enhanced posttranslational O-linked N-acetylglucosamine modification (O-GlcNAcylation) of cellular factors is a molecular feature that promotes a tumor-specific gene expression signature and distinguishes TIL-Tregs from their systemic counterparts. We found that altered glucose utilization through the glucose transporter Glut3 is a major facilitator of this process. Treg-specific deletion of Glut3 abrogates tumor immune tolerance, while steady-state immune homeostasis remains largely unaffected in mice. Furthermore, by employing mouse tumor models and human clinical data, we identified the NF-κB subunit c-Rel as one such factor that, through Glut3-dependent O-GlcNAcylation, functionally orchestrates gene expression in Tregs at tumor sites. Together, these results not only identify immunometabolic alterations and molecular events contributing to fundamental aspects of Treg biology, specifically at tumor sites but also reveal tumor-specific cellular properties that can aid in the development of Treg-targeted cancer immunotherapies.