in vitro-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 via 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 in vitro 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.]]> 2025/12/7 10:07:30 JIANG Huang-Hao,FAN Jing-Yuan,PENG Cheng and LI Bin 4true +CD25⁺ suppressive T cells by Shimon Sakaguchi and the subsequent discovery of the lineage-defining transcription factor forkhead box P3 (Foxp3) by Mary E. Brunkow and Fred Ramsdell, Treg cells have been recognized as indispensable guardians of immune homeostasis. These advances collectively clarified that central tolerance alone is insufficient to eliminate all self-reactive lymphocytes, and peripheral tolerance—critically mediated by Treg cells—serves as a second barrier preventing pathological autoimmunity. Contemporary research has therefore expanded the functional and therapeutic significance of Treg cells across the fields of autoimmunity, cancer, transplantation, and tissue repair. Treg cells originate from two major developmental pathways: thymus-derived Treg (tTreg) cells, which arise from high-affinity self-reactive TCR interactions in the thymus, and peripheral Treg (pTreg) cells, which are induced in mucosal and other peripheral tissues via antigen stimulation under tolerogenic cytokine cues such as IL-2 and TGF-β. Their differentiation is orchestrated by a multilayered transcriptional and epigenetic network within the Foxp3 locus, including CNS0-CNS3 elements that integrate TCR, cytokine and environmental signals to support lineage stability. Treg cells are identified by a combination of surface and intracellular markers——CD25, CD127^low/-, CTLA-4, GITR, TNFR2, CD39/CD73, and Foxp3——although marker specificity varies with context, activation state, and species. Their notable heterogeneity enables Treg cells to adopt Th1-, Th2-, Th17- or Tfh-like programs through transcription factors such as T-bet, GATA3, RORγt and Bcl6, thereby permitting precise suppression of corresponding effector responses. Tissue-resident Treg subsets in adipose tissue, skin, skeletal muscle and the CNS have emerged as highly specialized regulators that integrate local metabolic and stromal signals, contributing not only to immunosuppression but also to tissue regeneration. Mechanistically, Treg cells maintain tolerance through three synergistic strategies: (1) secretion of suppressive cytokines (IL-10, TGF-β, IL-35) and cytotoxic mediators (granzyme B, perforin); (2) cell-contact-dependent interactions via CTLA-4, PD-1/PD-L1, and LAG-3 to limit dendritic cell maturation and T-cell activation; and (3) metabolic regulation including IL-2 consumption, adenosine production via CD39/CD73, cAMP transfer through gap junctions, and adaptation to hypoxic or nutrient-restricted microenvironments. Dysregulation of Treg cell quantity or function contributes directly to pathogenesis across a spectrum of diseases. In autoimmune diseases such as type 1 diabetes, systemic lupus erythematosus, rheumatoid arthritis and multiple sclerosis, impaired Foxp3 stability, epigenetic abnormalities, defective IL-2 signaling or inflammatory cytokine exposure undermine Treg suppressive capacity, facilitating excessive autoreactive T- and B-cell activation. In contrast, within the tumor microenvironment, Treg cells are often enriched through chemokine axes such as CCL22-CCR4 and reinforced by interaction with myeloid-derived suppressor cells and tumor-associated macrophages. Their enhanced metabolic fitness and suppressive phenotype enable tumors to evade immune destruction. In transplantation, Treg cells are essential for promoting graft tolerance, restraining effector T-cell activation, and facilitating tissue repair after injury. Rapid therapeutic progress has been driven by Treg-based immunomodulation. Polyclonal Treg adoptive transfer has demonstrated safety and preliminary efficacy in type 1 diabetes, autoimmune disorders, solid-organ transplantation, and graft-versus-host disease. Gene-engineered Treg therapies, including antigen-specific CAR-Treg and TCR-Treg platforms, offer superior precision and stability, enabling targeted suppression at disease sites. Additional strategies——including low-dose IL-2 therapy, small-molecule modulation, and selective depletion of intratumoral Treg using antibodies against CCR4, CCR8, CTLA-4 or CD25×TIGIT bispecifics——further expand the translational landscape. Collectively, advances in Treg biology——from lineage ontogeny and molecular regulation to specialized functions and therapeutic engineering——highlight Treg cells as central orchestrators of immune equilibrium. Continued integration of single-cell multi-omics, systems immunology and gene-editing technologies is expected to accelerate the development of highly specific, durable and safe Treg-centered therapies, ultimately enabling precision control of immune tolerance in autoimmunity, transplantation and cancer.]]> 2025/12/5 10:24:29 XIAO Teng,CHEN Meng-Yu,YI Lei,XIONG Wei and WANG Fu-Yan 3true + T cells defined by expression of the lineage-specifying transcription factor FOXP3 and a potent capacity to maintain peripheral immune tolerance. The modern concept of Tregs was catalyzed by Shimon Sakaguchi’s identification of CD4⁺CD25⁺ suppressive T cells and subsequent work establishing FOXP3 as a central determinant of Treg cell development and function; together with landmark FOXP3 genetic discoveries by Mary E. Brunkow and Fred Ramsdell, these advances transformed understanding of immune homeostasis and were recognized by the 2025 Nobel Prize in Physiology or Medicine. Under normal physiological conditions, FOXP3⁺ Treg cells restrain autoreactive lymphocytes, prevent excessive inflammation, and shape antigen-presenting cell activity through contact-dependent pathways and suppressive cytokines, thereby protecting tissues from immune-mediated damage. Disruption of Treg abundance, stability, or suppressive capacity can therefore lead to immune dysregulation and disease. Over the past two decades, Treg cells have become a major focus of immunology because their roles are highly context-dependent. In autoimmune and chronic inflammatory diseases, impaired Treg cell function or insufficient Treg activity contributes to loss of tolerance and persistent tissue injury, supporting therapeutic approaches designed to enhance Treg cell number, stability, and suppressive potency. In contrast, many cancers exploit Treg cells by promoting their expansion, activation, and recruitment into the tumor microenvironment (TME), where they blunt antitumor immunity by suppressing cytotoxic T-cell priming and effector function, limiting dendritic cell activation, and fostering immune escape. In both settings, immune checkpoint pathways critically influence Treg cell biology. Beyond PD-1/PD-L1 and CTLA-4, emerging checkpoints and costimulatory receptors, including TIGIT, TIM-3, LAG-3, and OX40, modulate Treg cell generation, stability, and suppressive functions, thereby shaping the balance between tolerance and immunity. Meanwhile, immunometabolic adaptations further tune Treg cell fitness and function in inflamed tissues and tumors; lipid utilization and mitochondrial programs, among other metabolic axes, enable Treg cells to persist in nutrient- and oxygen-restricted microenvironments, while microenvironmental stress can drive functional remodeling or fragility in a subset-dependent manner. In this review, we summarize the discovery and defining biological features of Treg cells, highlight core suppressive mechanisms and regulatory circuits, and synthesize evidence for the dual roles of Treg cells in preventing autoimmunity yet enabling tumor immune evasion. We further outline current and emerging therapeutic strategies aimed at augmenting Treg cell activity to restore tolerance in autoimmune disease, or selectively depleting, functionally inhibiting, and reprogramming tumor-resident Treg cells to enhance cancer immunotherapy. Overall we discuss how deeper insight into Treg heterogeneity, checkpoint control, and immunometabolic regulation may enable more precise Treg cell-directed interventions and inform next-generation immunotherapeutic combinations across immune-mediated and malignant diseases.]]> 2025/12/18 16:11:21 RIAZ Farooq,LIANG Ming-Wei,LI Yi-Kui,JIANG An-Mei,ZHANG Zhen-Zhen,ZHOU Zhi-Yi,FAN Zu-Sen and PAN Fan 2true in vitro diagnosis, various MOF-based biomarker detection methods have been developed, providing technical means for the precise early diagnosis of diseases. Meanwhile, this paper deeply analyzes the key challenges that MOFs still face in clinical translation, including large-scale preparation, long-term stability, and biological safety assessment, and prospects the future development directions and application prospects.]]> 2025/12/15 15:46:35 GENG Fu-Kang,FANG Xiao-Cui,LEI Sheng-Bin and WANG Chen 1true