Jul 2026· Journal of Immunology· Vol 215· 0 citations
TL;DR
Deletion of Satb1 specifically in Tregs impaired the function of Satb1+ pro-tumorigenic Tregs, leading to enhanced CD8+ T cell antitumor immune responses, and complete tumor eradication without any systemic autoimmune conditions.
Abstract
Rigorous research over the years has revealed that the cellular composition of the tumor microenvironment (TME) matters, and a major constituent that facilitates tumor progression is the regulatory T cell (Treg). Tregs are essential for maintaining immune homeostasis and preventing autoimmune conditions but can also be a detriment via their suppression of immune responses against cancer. The significance of Treg research is far-reaching as supported by the 2025 Nobel Prize in Physiology or Medicine awarded to Drs. Mary Brunkow, Fred Ramsdell and Shimon Sakaguchi, “for their discoveries concerning peripheral immune tolerance”. However, identifying differences in Treg subtypes to specifically disrupt the activities of tumor-promoting Tregs, without affecting Tregs that maintain immune homeostasis remain elusive. Here, we sought to discover how to blunt pro-tumorigenic Tregs without compromising the abilities of Tregs in mediating self-tolerance.
To this end, we used state-of-the-art methods in immunology, including high dimensional flow cytometry, lineage-specific loss-of-function studies and single-cell RNA sequencing, as well as multiple tumor models in animals to investigate these fundamental gaps in the field.
In doing so, we discovered that expression of the genome organizer special AT-rich sequence binding protein 1 (Satb1) could readily separate two Treg subtypes: pro-tumorigenic Tregs (termed Satb1+) and immune-regulatory Tregs (termed Satb1-). Deletion of Satb1 specifically in Tregs impaired the function of Satb1+ pro-tumorigenic Tregs, leading to enhanced CD8+ T cell antitumor immune responses, and complete tumor eradication without any systemic autoimmune conditions. Notably, Satb1- Tregs remained intact in knockout mice and were necessary for maintaining immune homeostasis and preventing autoimmunity.
Our results reveal a key mechanism to safely and potently enhance cancer immunity without causing systemic autoimmune diseases.
Pelotonia Institute for Immuno-Oncology
Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)
The imbalance of pro-inflammatory and immunosuppressive constituents in the tumor microenvironment (TME) significantly dictates cancer progression, immune invasion, and treatment response. Immunosuppressive regulatory T cells (Tregs) are associated with decreased disease-free survival due to their ability to suppress anti-tumor immunity. Notably, in response to environmental cues, Tregs display functional and phenotypic plasticity with inflammatory helper T cell subsets. Given their predominant role in sustaining immune suppression, it is remarkable that multiple developmental pathways converge to regulate Treg development and function. In this study, we designed, validated, and employed a novel genetically modified mouse model to conditionally ablate the Hedgehog (Hh) gene, Gli2, specifically in Tregs. Ablation of Gli2 activity in Tregs significantly reduced tumor burden, impaired Treg suppressive function, and shifted the transcriptional balance of Foxo3 and Rorγt, transcription factors essential for Tregs and Th17 cells. Spatial mapping highlighted that Gli2 ablation in Tregs enhances the immunogenicity of the tumor and promotes a pro-inflammatory milieu of the TME. This was underscored by a higher tumor immune signature score and enhanced infiltration of cytotoxic CD8+ T cells into the tumor. These findings highlight Hh/Gli2 signaling in Tregs as a mechanistic regulator of immunogenicity in the TME and a potential therapeutic target to prime tumors for enhanced responsiveness for adjuvant treatments.
Courtney A. Swain, D. Hinshaw, Ian D. Miranda et al.· Cell Death and Disease· 0 citations
The study depicts an epigenetic polarity governing Treg-mediated immune tolerance, highlighting a fundamental asymmetry at the epigenetic level that differentially regulates Treg and conventional T cells.
Wenjun Huang, Yongqiang Feng, Jun Li et al.· Journal of Immunology· 0 citations
Bladder cancer is characterized by a highly dynamic tumor microenvironment (TME) that critically influences tumor progression, immune evasion, and therapeutic responsiveness. Among the immune populations in the TME, regulatory T cells (Tregs) play a central role in maintaining immune tolerance but also suppress effective antitumor immunity. Increasing evidence suggests that Tregs accumulate in bladder tumors and are associated with disease progression and reduced response to immunotherapies. The bladder cancer TME provides multiple signals that promote Treg recruitment, expansion, and functional stabilization, including chemokine-mediated trafficking, metabolic adaptation, and cytokine-driven differentiation. Interactions between Tregs and other microenvironmental components, such as cancer-associated fibroblasts, tumor-associated macrophages, endothelial cells, and extracellular matrix elements, further reinforce the immunosuppressive niche that facilitates tumor survival and therapy resistance. Recent advances in single-cell transcriptomics, spatial profiling, and multiomics analyses have revealed substantial heterogeneity among tumor-infiltrating Tregs, suggesting the existence of specialized subsets with distinct functional and metabolic properties in the bladder TME. These emerging insights highlight the importance of understanding Treg–TME crosstalk in shaping the immune landscape of bladder cancer. Targeting the mechanisms regulating Treg recruitment, stability, or suppressive function may represent a promising strategy to enhance the efficacy of immunotherapies including Bacillus Calmette–Guérin therapy. This review summarizes recent advances in Treg biology in bladder cancer and highlights potential therapeutic strategies to modulate Treg-mediated immunosuppression in the TME.
Yusuke Fukiage, Nodoka Okubo, M. Taga et al.· Frontiers in Molecular Biosc...· 0 citations
Regulatory T cells (Tregs) are essential mediators of immune tolerance that maintain tissue homeostasis by restraining excessive immune activation. In cancer, these regulatory mechanisms are reinforced within malignant tissues and contribute to suppression of endogenous anti-tumor immunity. Tumor-infiltrating Tregs (TI-Tregs) represent a specialized activation state shaped by chronic antigen exposure, inflammatory cytokines, stromal cues, and metabolic stress imposed by the tumor microenvironment (TME). Rather than functioning as a static suppressive lineage, intratumoral Tregs integrate receptor-mediated signaling, FOXP3-centered transcriptional stabilization, and metabolic licensing, and spatial niche formation to maintain suppressive fitness under hypoxic and nutrient-restricted conditions. This review synthesizes current understanding of the molecular and metabolic programs that stabilize tumor-associated Tregs and organizes them into an integrated framework linking antigen-driven activation, regulatory identity, metabolic adaptation, tissue-contextual reprogramming, and therapeutic resistance. We further discuss emerging therapeutic strategies aimed at selectively modulating tumor-associated regulatory states while preserving systemic immune tolerance, with explicit attention to preclinical versus clinical evidence, tumor-type specificity, and toxicity risks.
Haewon Song, Jihyun Kim, S. Hwang· International Reviews of Imm...· 1 citation
T regulatory cell (Treg) infiltration and accumulation within solid tumors leads to tumor immune evasion and is a major barrier to immunotherapy efficacy. Thus, immunotherapeutic strategies aimed at reducing Treg abundance and/or suppressive function hold significant promise for cancer treatment. Efforts to modulate Tregs have largely relied on non-specific molecular or cellular approaches; however, targeting Forkhead box protein 3 (FoxP3), the master transcription factor for Tregs holds significant promise. Here, we report the first FoxP3-specific small molecule degrader which promotes proteasomal degradation of FoxP3 and partially reduces Treg suppressive function.
To identify potential hits, we used high content imaging to screen a 640 small, electrophilic compound library. The top hits were resynthesized and validated by flow cytometry in human Treg-like MT-2 cells, leading to identification of our lead compound, termed FD03. To explore the mechanism by which FD03 mediated FoxP3 reduction, we employed co-immunoprecipitation and immunoblotting techniques. We then evaluated therapeutic efficacy of our compound in ex vivo and in vivo settings using flow cytometry as a readout.
After identifying FD03 as the lead compound, we further characterized its efficacy finding that FD03 had a EC50 of ∼5-10 uM in primary murine and human Tregs. Mechanistically, FD03 degrades FoxP3 in part through facilitating FoxP3 interaction with its E3 ligase, STUB1, to promote FoxP3 ubiquitination-mediated proteasomal degradation. Finally, we characterized the therapeutic potential of FD03: we illustrated that FD03 can reduce Treg suppressive function. Importantly, we demonstrated that FD03 treatment in tumor-bearing mice can decrease tumor burden and skew the immune cell landscape towards an inflammatory phenotype.
Overall, we demonstrated proof-of-concept and feasibility of targeting FoxP3, which has been known to be “undruggable”, in a chemical manner by small molecules.
1F31CA287701-01, T32GM15538-10, 1T32GM149439-01
Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)
Amy Y. Tang, Zhaomeng Cai, Kun Liu et al.· Journal of Immunology· 0 citations
Regulatory T cells (Treg) act as a powerful barrier to effective antitumor immunity. Although manipulating Treg is a promising anticancer strategy, doing so while sparing general immune tolerance has been a challenge. Identifying factors specifically expressed in tumor-infiltrating Treg is therefore important for better understanding cancer pathogenesis and identifying novel therapeutic targets that enhance antitumor immunity. We show that T cell Immunoglobulin and Mucin 3 (Tim-3) expression on tumor Treg is required for the function and survival of these cells, in part through Akt and FOXO1 signaling. Deleting Tim-3 in Treg leads to delayed tumor-specific T-cell exhaustion and lower tumor burden, without altering peripheral homeostasis. Similar effects were noted when Tim-3 was only deleted from half of the Treg or when deletion was delayed until after tumor inoculation. Moreover, Treg-specific deletion of Tim-3 cooperated with PD-1 checkpoint blockade to sensitize an immunotherapy-resistant tumor model. In addition, a decrease in Tim-3+ tumor Treg correlated with responsiveness to PD-1/LAG-3 combination checkpoint blockade in a human clinical trial. Overall, our data provide evidence that Tim3-expressing Treg are a promising target to modulate tumor-specific immune responses.
Hridesh Banerjee, Onyedikachi V Onyekachi, Hector M Nieves-Rosado et al.· Cancer immunology research· 0 citations