SUMOylation is destined for regulatory T cell-related immune dysregulation.

Regulatory T (Treg) cells perform immunosuppressive functions in rapid response to genetic and environmental stress for maintaining the immune balance, which play a physiological role in preventing autoimmune and inflammatory diseases. Given the highly dynamic and reversible nature of small ubiquitin-like modifier (SUMO) modification, along with the predominant nuclear localization of SUMO paralogs and their associated enzymes, SUMOylation is essential for the flexible regulation of key nuclear processes in Treg cells, such as membraneless organelle formation, genome integrity, and cell cycle progression. Notably, SUMO:SUMO-interacting motif (SIM) interactions facilitate the formation of regulatory complexes that govern cellular processes, and enable crosstalk with other post-translational modifications (PTMs), particularly ubiquitination, phosphorylation, acetylation, and methylation, which are globally harnessed by Treg cells in various contexts to regulate key processes of protein stability, signaling pathways, transcriptional reprogramming, and epigenetic modifications, thereby fine-tuning their immune-regulatory responses. This review explores the multifaceted roles of SUMOylation in Treg cell biology, emphasizing its influence on differentiation, maturation, transcriptional and epigenetic regulation, and metabolic reprogramming. By delineating these pathways, we aim to uncover how dysregulation of SUMOylation may be destined to Treg cells mediated immune disorders, providing a foundation for therapeutic interventions.