Regulatory T cells (Treg cells or Tregs), a subset of CD4⁺ T cells with immunosuppressive properties, are essential for immune homeostasis and self-tolerance. Characterized by their immunosuppressive capabilities and reliance on the transcription factor Foxp3 (Forkhead box protein P3), Tregs employ multiple mechanisms, including cytokine secretion, metabolic control, and cell contact inhibition, to restrain excessive immune activation to prevent autoimmunity while maintaining tissue repair processes. However, dysregulation in their frequency or function—whether deficiency or hyperactivity—is implicated in diverse pathologies, spanning autoimmune disorders, cancer progression, transplant rejection, and emerging associations with neurological and cardiovascular diseases. Thus, Treg-targeted strategies represent a promising approach for restoring immune balance under various conditions. This review synthesizes current knowledge on Treg biology, from their discovery and definition of markers to their new regulatory mechanisms. We further explore the roles of Tregs across diseases, emphasizing their context-dependent therapeutic potential. Strategies to deplete or inhibit Tregs in cancer immunotherapy contrast with approaches to expand or stabilize their function in autoimmunity and transplantation. However, challenges persist, including achieving tissue-specific targeting, ensuring the functional stability of engineered Tregs, and minimizing off-target effects. By integrating mechanistic insights with translational innovations, this review provides a roadmap for advancing Treg-based therapies, ultimately aiming to restore immune equilibrium in a disease-specific manner.

Epigenetic mechanisms are processes that affect gene expression and cellular functions without involving changes in the DNA sequence. This abnormal or unstable expression of genes regulated by epigenetics can trigger cancer and other various diseases. The immune cells involved in anti-tumor responses and the immunogenicity of tumors may also be affected by epigenomic changes. This holds significant implications for the development and application of cancer immunotherapy, epigenetic therapy, and their combined treatments in the fight against cancer. We provide an overview of recent research literature focusing on how epigenomic changes in immune cells influence immune cell behavior and function, as well as the immunogenicity of cancer cells. And the combined utilization of epigenetic medications with immune checkpoint inhibitors that focus on immune checkpoint molecules [e.g., Programmed Death 1 (PD-1), Cytotoxic T-Lymphocyte-Associated Protein 4 (CTLA-4), T cell Immunoglobulin and Mucin Domain (TIM-3), Lymphocyte Activation Gene-3 (LAG-3)] present in immune cells and stromal cells associated with tumors. We highlight the potential of small-molecule inhibitors targeting epigenetic regulators to amplify anti-tumor immune responses. Moreover, we discuss how to leverage the intricate relationship between cancer epigenetics and cancer immunology to create treatment regimens that integrate epigenetic therapies with immunotherapies.

Nuclear receptor coactivator 2 (Ncoa2) is a member of the Ncoa family of coactivators, and we previously showed that Ncoa2 regulates the differentiation of induced regulatory T cells. However, it remains unknown if Ncoa2 plays a role in CD8+ T-cell function. Here, we show that Ncoa2 promotes CD8+ T cell–mediated immune responses against tumors by stimulating T-cell activation via upregulating PGC-1α expression to enhance mitochondrial function. Mice deficient in Ncoa2 in T cells (Ncoa2fl/fl/CD4Cre) displayed defective immune responses against implanted MC38 tumors, which associated with significantly reduced tumor-infiltrating CD8+ T cells and decreased IFNγ production. Consistently, CD8+ T cells from Ncoa2fl/fl/CD4Cre mice failed to reject tumors after adoptive transfer into Rag1−/− mice. Further, in response to TCR stimulation, Ncoa2fl/fl/CD4Cre CD8+ T cells failed to increase mitochondrial mass, showed impaired oxidative phosphorylation, and had lower expression of PGC-1α, a master regulator of mitochondrial biogenesis and function. Mechanically, T-cell activation–induced phosphorylation of CREB triggered the recruitment of Ncoa2 to bind to enhancers, thus, stimulating PGC-1α expression. Forced expression of PGC-1α in Ncoa2fl/fl/CD4Cre CD8+ T cells restored mitochondrial function, T-cell activation, IFNγ production, and antitumor immunity. This work informs the development of Ncoa2-based therapies that modulate CD8+ T cell–mediated antitumor immune responses.

Recurrent somatic mutations in spliceosome factor 3b subunit 1 (SF3B1) are identified in hematopoietic malignancies, with SF3B1-K700E being the most common one. Here, we show that regulatory T cell (T _reg )–specific expression of SF3B1-K700E ( Sf3b1 ^K700Efl/+ /Foxp3 ^YFP-Cre ) results in spontaneous autoimmune phenotypes. CD4 ⁺ T cells from Sf3b1 ^K700Efl/+ /Foxp3 ^YFP-Cre mice display defective T _reg differentiation and inhibitory function, which is demonstrated by failed prevention of adoptive transfer colitis by Sf3b1 ^K700Efl/+ /Foxp3 ^YFP-Cre T _regs . Mechanically, SF3B1-K700E induces an aberrant splicing event that results in reduced expression of a cell proliferation regulator Anapc13 due to the insertion of a 231–base pair DNA fragment to the 5′ untranslated region. Forced expression of the Anapc13 gene restores the differentiation and ability of Sf3b1 ^K700Efl/+ /Foxp3 ^YFP-Cre T _regs to prevent adoptive transfer colitis. In addition, acute myeloid leukemia grows faster in aged, but not young, Sf3b1 ^K700Efl/+ /Foxp3 ^YFP-Cre mice compared to Foxp3 ^YFP-Cre mice. Our results highlight the impact of cancer-associated SF3B1 mutation on immune responses, which affect cancer development.

Tudor domain-containing protein 3 (TDRD3) functions as a methylarginine reader that relays posttranslational arginine methylation signals to the transcriptional machinery, thereby regulating cellular functions through modulation of gene expression. Regulatory T cells (T _regs ) are pivotal for establishing and maintaining immune tolerance. In this study, we demonstrate that mice with T _reg -specific deletion of Tdrd3 exhibit severely impaired iT _reg , but not thymic T _reg , differentiation. Moreover, iT _regs , but not thymic T _regs , derived from these mice fail to suppress colitis in adoptive transfer models, indicating compromised inhibitory capacity. Aged Tdrd3 -deficient mice also show spontaneous autoinflammation. Mechanistically, TDRD3 is recruited by the transcription factor FOXO1, presumably in a methylation-dependent manner, to activate Klf2 expression, which is essential for T _reg differentiation. Notably, the enforced expression of Klf2 in Tdrd3 -deficient CD4 ⁺ T cells rescue both iT _reg development and suppressive function. Collectively, our findings identify TDRD3 as a central transcriptional regulator of iT _reg differentiation and immune homeostasis, highlighting it as a potential therapeutic target for modulating immune tolerance.