Regulatory T Cells and FOXP3: Milestones and Cutting-edge Breakthroughs in Peripheral Immune Tolerance

The 2025 Nobel Prize in Physiology or Medicine was awarded to Mary E. Brunkow, Fred Ramsdell and Shimon Sakaguchi in recognition of their groundbreaking contributions to unraveling the mechanisms of peripheral immune tolerance. Regulatory T cells (Treg cells), as the core components maintaining peripheral immune tolerance, exhibit high plasticity and heterogeneity. Dysregulation of Treg function is closely associated with autoimmune diseases, tumor progression, and transplant rejection. Forkhead box protein P3 (FOXP3) is a key transcription factor that controls the development and function of Tregs. This review discusses the classification of Tregs into thymic-derived Tregs (tTregs), peripherally induced Tregs (pTregs), and <italic>in vitro</italic>-induced Tregs (iTregs). It also elaborates on how Treg cells exert their inhibitory functions through multiple pathways, including the secretion of inhibitory factors, metabolic interference <italic>via</italic> competitive uptake of IL-2, and direct cell-cell contact. In recent years, significant advances have been made in Treg and FOXP3 research, progressively deepening our understanding of Treg plasticity. Investigations have revealed their capacity to adapt and acquire features of effector T helper cell subsets—such as Th1, Th2, and Th17—under specific microenvironmental cues. This plasticity also poses challenges for therapeutic interventions, as Tregs can potentially lose their suppressive function and acquire pro-inflammatory properties, thereby exacerbating disease pathology. Furthermore, the concept of tissue-specific Treg specialization has emerged, highlighting distinct functional subsets resident in organs such as the gut, adipose tissue, and tumors. For instance, gut-resident Tregs maintain tolerance to commensal bacteria and dietary antigens, while tumor-infiltrating Tregs promote immune evasion by suppressing anti-tumor immunity. Concurrently, studies on the metabolic and epigenetic regulation of Tregs, including post-translational modifications of FOXP3 such as acetylation and ubiquitination, have uncovered intricate layers of control over their stability and function. Building upon these fundamental insights, this review synthesizes FOXP3-targeted therapeutic strategies. These encompass approaches to enhance Treg function in autoimmune diseases and transplantation, including adoptive cell therapies and pharmacological interventions. Conversely, strategies to antagonize Treg-mediated immunosuppression in oncology, such as immune checkpoint blockade, are discussed. Notably, the development of programmable engineered Tregs represents a particularly promising frontier for achieving antigen-specific immune modulation with enhanced precision and efficacy. However, the field of Treg research continues to grapple with several complex challenges. The deeper, underlying regulatory networks governing Treg biology remain incompletely understood. A comprehensive resolution of Treg heterogeneity is still lacking, and significant hurdles exist in maintaining the stability and function of Tregs during <italic>in vitro</italic> expansion and culture. Furthermore, the precision and efficacy of translating these findings into clinical applications require substantial improvement. Consequently, both the development of Treg-targeting pharmacological agents and the refinement of Treg-based cellular therapies demand more profound exploration. The ultimate goal is to overcome these obstacles and achieve transformative, breakthrough clinical outcomes in the foreseeable future.