Regulatory T cells in cancer and inflammation

Signal Transduction and Targeted Therapy REVIEW ARTICLE www.nature.com/sigtrans OPEN Regulatory T cells in cancer and inflammation Haoyi Yang1,2,3,4, Huafeng Zhang1,5, Ni Xia1,2,3,4 ✉ and Xiang Cheng1,2,3,4 ✉ 1234567890();,: As immunoregulatory cells, regulatory T cells (Tregs) play pivotal roles in maintaining immune tolerance and preventing autoimmunity. However, Tregs exhibit distinct functions across different diseases. In cancer, Tregs are most likely to suppress antitumor immune responses and promote tumor immune evasion, whereas in inflammatory diseases, functionally competent Tregs mitigate excessive immune activation and facilitate tissue repair. Notably, dysfunctional Tregs lead to persistent inflammation and progression to chronic disease. Therefore, targeting Tregs has emerged as an attractive immunotherapeutic strategy for both cancer and inflammatory disorders. Recent studies have shown that Tregs exhibit instability and plasticity under specific conditions, allowing them to shift between functional and dysfunctional states. A comprehensive understanding of the dynamic changes in Tregs and their regulatory mechanisms in diverse pathological contexts is highly important. In this review, we summarize the dual roles of Tregs in cancer and various inflammatory diseases. We explore the signaling pathways and molecular mechanisms underlying their biological characteristics, with a particular focus on how microenvironmental cues shape Treg behavior. Additionally, we discuss recent advances in Treg-targeted therapies in these disease contexts. Overall, this review greatly advances our understanding of the roles of Tregs in cancer and inflammation and helps inform the development of more precise and effective therapeutic strategies. Signal Transduction and Targeted Therapy (2026)11:205 INTRODUCTION Tregs constitute a subset of CD4+ T lymphocytes characterized by high expression of interleukin-2 receptor alpha (IL2RA, CD25) and the lineage-defining transcription factor forkhead box protein P3 (Foxp3).1,2 Tregs are conventionally identified as a group of T cells that perform immunosuppressive functions. Under physiological conditions, they are crucial for maintaining immune tolerance to self-antigens and controlling excessive immune responses that might be harmful to the host.3,4 In addition to their conventional immune regulatory functions, Tregs also perform tissue-specific functions, such as facilitating tissue repair following injury and regulating metabolism.5,6 However, under certain pathological conditions, Tregs display marked heterogeneity and may exert detrimental effects. For example, in tumors, Tregs frequently accumulate within the tumor microenvironment (TME), where they suppress antitumor immune responses, and may correlate with poor prognosis and reduce the efficacy of various anticancer therapies.7 In contrast, in many inflammatory diseases, Tregs play crucial roles in controlling aberrant immune activation and promoting tissue repair, but their dysfunction or instability may lead to uncontrolled inflammation and disease progression.8–10 These contrasting roles underscore the need to understand Tregs in a disease-specific manner. Rather than being a functionally stable population, Tregs exhibit significant plasticity and instability modulated by intrinsic and extrinsic factors. This is characterized by either downregulated or unchanged Foxp3 expression, accompanied by the expression of ; https://doi.org/10.1038/s41392-026-02584-w transcription factors and effector molecules associated with other T-cell subsets.11 This dynamic behavior presents both challenges and opportunities for Treg-related research. On the one hand, understanding the roles of Tregs across various diseases is complex; on the other hand, this finding offers potential targets for therapeutic intervention by modulating Treg stability: destabilizing Tregs in tumors may enhance antitumor immunity, while stabilizing Tregs in inflamed tissues may restore immune tolerance and resolve pathology.12,13 Over the past decade, the rapid advancement of emerging technologies—particularly single-cell sequencing and multiomics approaches—has provided significant insights into the fine details of Treg phenotypes, functions, and their dynamic changes, particularly regarding Treg heterogeneity in different disease microenvironments.14,15 This review begins with a brief introduction of Treg classification, differentiation, and the molecular biology underlying their functions. We then focus on recent discoveries concerning Tregs in cancer and inflammatory diseases, along with the signaling pathways and regulatory mechanisms involved. These insights are instrumental in informing and refining future Treg-targeted immunotherapeutic strategies. BASIC CONCEPTS OF TREGS Classification and differentiation of Tregs Tregs are classified into two main types according to their origin: thymus-derived Tregs (tTregs) and peripheral-derived Tregs 1 Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; 2Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; 3Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; 4 Key Laboratory of Biological Targeted Therapy (Huazhong University of Science and Technology), Ministry of Education, Wuhan, Hubei, China and 5Department of Pathology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China Correspondence: Ni Xia () or Xiang Cheng () Received: 23 February 2025 Revised: 12 January 2026 Accepted: 12 January 2026 © The Author(s) 2026 Regulatory T cells in cancer and inflammation Yang et al. 2 Fig. 1 Differentiation of tTregs and pTregs. The peripheral Treg pool comprises tTregs and pTregs, which undergo different differentiation processes. a Bone marrow–derived lymphoid progenitor cells migrate to the thymus, where they differentiate into CD3⁺CD4⁺CD8⁻ SP lymphocytes. A subset of SP cells that recognize self-antigens further differentiates into tTregs under the influence of multiple signaling cues. The hypomethylated state of the CNS2 region, also known as the TSDR, is crucial for stabilizing Foxp3 expression and tTreg lineage commitment. b In the periphery, CD4⁺ naïve T cells enter the circulation and, upon encountering APCs in mucosal tissues such as the gut, are induced into pTregs in the presence of cytokines, including IL-2 and TGF-β. TGF-β signaling promotes Smad3 binding to the CNS1 region of the Foxp3 locus, a process essential for pTreg differentiation. This figure was created with Biorender.com (pTregs), both of which typically express Foxp3.16 However, distinguishing tTregs from (...truncated)