Multidimensional Regulation and Therapeutic Conversion of Regulatory T Cell Function

In the environment of regulatory T cells, traditional research has mainly focused on the master transcription factor FOXP3 and its epigenetic modifications in determining the Treg phenotype, whereas more recent studies suggest that Treg functional homeostasis is shaped by dynamic microenvironmental signals, among which mechanosensation and neuroimmune signaling may represent emerging regulatory dimensions. This article reviews recent advances in the functional regulation of Tregs systematically from four perspectives, emphasizing a shift from single-molecule regulation toward a multidimensional regulatory framework that encompasses epigenetic regulation, metabolic reprogramming, mechanosensation, and neuroimmune interaction; it also notes that the available evidence and the extent of validation differ across these regulatory dimensions. First, it explores the fundamental mechanisms underlying the FOXP3 gene network and epigenetic regulation. Second, it discusses the roles of mitochondrial dynamics and metabolites in shaping Treg heterogeneity and in maintaining functional stability under different biological environment. Third, it discusses emerging advances in the regulation of Tregs by the physical microenvironment, with particular focus on Piezo1-mediated mechanosensation as a potential regulatory mechanism. Finally, it discusses neuroimmune interactions relevant to Treg regulation, including the potential direct effects of neurotransmitters as well as indirect effects mediated through neurons, glial cells, endocrine pathways, and the broader inflammatory microenvironment. In addition, this review summarizes emerging therapeutic strategies related to Treg engineering and functional stabilization, including CDK8/19 inhibition and epigenetic reprogramming (e.g., S/F-iTreg), which remain at the experimental stage, and CAR-Treg, which has entered early-phase clinical investigation; these strategies address the key challenges encountered in Treg therapeutic development, including the loss of Treg identity or function during in vitro expansion, epigenetic instability, and insufficient antigen specificity. On the basis of the advances described above, this article proposes the conceptual framework of a “neuroimmune–mechano-force coupling axis” to integrate the potential links among the tissue microenvironment, mechanosensation, metabolic state, and Treg epigenetic regulation. Currently, several of these key mechanistic links lack direct experimental evidence in Tregs and remain to be validated. This article aims to provide a systematic perspective for understanding the multidimensional integrative regulation of Treg function, to summarize potential therapeutic directions, and to highlight the key mechanisms within current multidimensional regulatory models that still await experimental validation.