FOXP3 as a therapeutic target in autoimmune diseases: Molecular regulation, regulatory T cells, and emerging precision immunotherapies

Forkhead box protein P3 (FOXP3) is a key transcription factor responsible for the development and function of regulatory T cells (Tregs), which play a crucial role in maintaining immune tolerance and preventing autoimmune responses. Defects in FOXP3 expression or function can impair Treg activity, leading to immune dysregulation and the development of autoimmune diseases. While complete loss of FOXP3 results in immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, altered FOXP3 expression and Treg dysfunction have also been reported in common autoimmune disorders such as systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes mellitus, multiple sclerosis, and inflammatory bowel disease. Recent advances have significantly improved our understanding of the molecular mechanisms regulating FOXP3, including transcriptional control, epigenetic modifications, metabolic pathways, and environmental influences that affect Treg stability and function. These discoveries have led to the development of novel therapeutic approaches aimed at restoring immune tolerance through enhancement of FOXP3 activity and Treg-mediated suppression. Strategies such as low-dose interleukin-2 therapy, adoptive Treg cell transfer, antigen-specific Treg therapy, chimeric antigen receptor regulatory T cells (CAR-Tregs), and gene-editing technologies have shown promising results in preclinical and early clinical studies. This review summarizes the current understanding of FOXP3 biology, its role in autoimmune disease pathogenesis, and recent advances in FOXP3-directed therapeutic strategies. In addition, emerging concepts including Treg plasticity, epigenetic regulation, immunometabolism, and precision immunotherapy are discussed. A better understanding of FOXP3-mediated immune regulation may facilitate the development of targeted therapies capable of achieving long-term immune tolerance and improved clinical outcomes in patients with autoimmune diseases.