Partial RAG deficiency (pRD) can manifest with systemic and tissue-specific immune dysregulation, with inflammatory bowel disease (IBD) in 15% of the patients. We aimed at identifying the immunopathological and microbial signatures associated with IBD in patients with pRD and in a mouse model of pRD (Rag1w/w) with spontaneous development of colitis. pRD patients with IBD and Rag1w/w mice showed a systemic and colonic Th1/Th17 inflammatory signature. Restriction of fecal microbial diversity, abundance of pathogenic bacteria, and depletion of microbial species producing short-chain fatty acid were observed, which were associated with impaired induction of lamina propria peripheral Treg cells in Rag1w/w mice. The use of vedolizumab in Rag1w/w mice and of ustekinumab in a pRD patient were ineffective. Antibiotics ameliorated gut inflammation in Rag1w/w mice, but only bone marrow transplantation (BMT) rescued the immunopathological and microbial signatures. Our findings shed new light in the pathophysiology of gut inflammation in pRD and establish a curative role for BMT to resolve the disease phenotype.

Canine pyometra is a suppurative uterine infection associated with immune dysregulation. This study investigated the role of regulatory T cells (Tregs) and associated factors in the pus accumulation within the canine uterus. Sixteen client-owned intact bitches, eight diagnosed with pyometra and the other eight healthy animals undergoing elective ovariohysterectomy, were enrolled. Blood samples were collected into ethylenediaminetetraacetic acid (EDTA)-coated tubes for flow cytometry. Tissue samples were obtained after ovariohysterectomy and used to examine localization of interleukin (IL)-2 and IL-2Rα as key regulators of Treg functions. Gene expression was analyzed by reverse transcription quantitative polymerase chain reaction (RT-qPCR). Results of flow cytometry analysis revealed a significant increase in the population of Tregs in the uterine tissue and their corresponding decrease in the peripheral blood. This shift is likely reflective of the recruitment of Tregs from the peripheral blood to the decidua in pyometra. There was a marked upregulation in the expression of IL-2 in the uterine tissue. There was dysregulation in the expression of anti-inflammatory cytokines produced by Tregs (such as IL-10) and pro-inflammatory factors secreted by effector T cells (such as RORγt and IL-17A), which gave a deeper insight into the mechanism underlying the immune dysfunction in canine pyometra. Taken together, these observations elucidate the dynamic changes in Tregs and related factors during canine uterine pyometra, thus providing a new perspective on the equilibrium of the uterine immune microenvironment.

Head and neck squamous cell carcinoma (HNSCC) ranks as the sixth most common cancer globally. Most studies in HNSCC demonstrated that regulatory T (Treg) cells confine the anti-tumor activity of effector T cells which may contribute to the immune escape and uncontrolled tumor progression. Here, we uncovered that the specific abrogation of Bcl6 in Treg cells resulted in significantly delayed malignant transformation of 4NQO-induced tumorigenesis. Bcl6 deficiency impairs the lineage stability of Treg cells by down-regulating the histone H3K4 trimethylation. Importantly, Bcl6 inhibition repressed the tumor growth of murine HNSCC and exhibited synergistic effects with immune checkpoint blockade therapy. These findings suggest that Bcl6 can be exploited as a promising therapeutic target for HNSCC treatment.

The integration of microbiome research and nanotechnology represents a significant advancement in immuno-oncology, potentially improving the effectiveness of cancer immunotherapies. Recent studies highlight the influential role of the human microbiome in modulating immune responses, presenting new opportunities to enhance immune checkpoint inhibitors (ICIs) and other cancer therapies. Nanotechnology offers precise drug delivery and immune modulation capabilities, minimizing off-target effects while maximizing therapeutic outcomes. This review consolidates current knowledge on the interactions between the microbiome and the immune system, emphasizing the microbiome's impact on ICIs, and explores the incorporation of nanotechnology in cancer treatment strategies. Additionally, it provides a forward-looking perspective on the synergistic potential of microbiome modulation and nanotechnology to overcome existing challenges in immuno-oncology. This integrated approach may enhance the personalization and effectiveness of next-generation cancer treatments, paving the way for transformative patient care.

Monocytes infiltrating tumors acquire various states that distinctly impact cancer treatment. Here, we show that resistance of tumors to radiotherapy (RT) is controlled by the accumulation of monocyte-derived dendritic cells (moDCs). These moDCs are characterized by the expression of CD301b and have a superior capacity to generate regulatory T cells (Tregs). Accordingly, moDC depletion limits Treg generation and improves the therapeutic outcome of RT. Mechanistically, we demonstrate that granulocyte-macrophage colony-stimulating factor (GM-CSF) derived from radioresistant tumor cells following RT is necessary for the accumulation of moDCs. Our results unravel the immunosuppressive function of moDCs and identify GM-CSF as an immunotherapeutic target during RT.

The lymphocyte population must traverse a complex path throughout their journey to the liver. The signals which these cells must detect, including cytokines, chemokines and other soluble factors, steer their course towards further crosstalk with other hepatic immune cells, hepatocytes and biliary epithelial cells. A series of specific chemokine receptors and adhesion molecules drive not only the recruitment, migration, and retention of these cells within the liver, but also their localisation. Perturbation of these interactions and failure of self-recognition drive the development of several autoimmune liver diseases. We also describe check point-induced liver injury. Immune cell internalisation into hepatocytes (emperipolesis) in autoimmune hepatitis and into biliary epithelial cells (intra-epithelial lymphocyte) in primary biliary cholangitis are typical features in autoimmune liver diseases. Finally, we describe emerging immune-based therapies, including regulatory T cell, anti-cytokine and anti-chemokine therapies, cytokine supplementation (e.g. interleukin-2), as well as co-inhibitory molecule manipulation, including T-cell engagers, and discuss their potential application in the treatment of autoimmune liver diseases.

A substantial proportion of patients diagnosed with rheumatologic and musculoskeletal diseases (RMDs) exhibit resistance to conventional therapies or experience recurrent symptoms. These diseases, which include autoimmune disorders such as multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus, are marked by the presence of autoreactive B cells that play a critical role in their pathogenesis. The persistence of these autoreactive B cells within lymphatic organs and inflamed tissues impairs the effectiveness of B-cell-depleting monoclonal antibodies like rituximab. A promising therapeutic approach involves using T cells genetically engineered to express chimeric antigen receptors (CARs) that target specific antigens. This strategy has demonstrated efficacy in treating B-cell malignancies by achieving long-term depletion of malignant and normal B cells. Preliminary data from patients with RMDs, particularly those with lupus erythematosus and dermatomyositis, suggest that CAR T-cells targeting CD19 can induce rapid and sustained depletion of circulating B cells, leading to complete clinical and serological responses in cases that were previously unresponsive to conventional therapies. This review will provide an overview of the current state of preclinical and clinical studies on the use of CAR T-cells and other cellular therapies for RMDs. Additionally, it will explore potential future applications of these innovative treatment modalities for managing patients with refractory and recurrent manifestations of these diseases.

The liver is the human body's largest digestive gland, which can participate in digestion, metabolism, excretion, detoxification and immunity. Chronic liver diseases such as metabolic dysfunction-associated fatty liver disease (MAFLD) or viral hepatitis involve ongoing inflammation and resulting liver fibrosis may ultimately lead to the development of hepatobiliary cancers (HCC). Inflammation is the coordinated reaction of different liver cell types to cell signals and death of inflammation, which are linked to injury pathways within the liver or external agents from the gut-liver axis and the circulation. Regulatory T (Treg) cells play a crucial role in controlling inflammation and are essential for maintaining immune tolerance and balance. In this review, we highlight the recent discoveries related to the function of immune systems in liver inflammation and discuss the role of Treg cells in the different liver diseases (including MAFLD, autoimmune hepatitis and others).

Ten-eleven translocation (TET) proteins are dioxygenases that sequentially oxidize the methyl group of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). All three epigenetic modifications are intermediates in DNA demethylation. In the "passive" (replication-dependent) DNA demethylation pathway, sequential oxidation reactions by TETs are essential and modified cytosines (C) are diluted at each cycle of DNA replication. In the "active" (replication-independent) DNA demethylation pathway, both thymine DNA glycosylase (TDG) and TETs play important roles. TDG removes 5fC and 5caC from 5fC:G and 5caC:G base pairs and these modified bases are replaced by unmodified C via base excision repair. Through epigenetic regulation of DNA demethylation, TETs and TDG are involved in cell development, differentiation, and homeostasis. The interplay between TDG and TETs is involved in embryo development, stem cell differentiation, neural development, immune responses, and tumorigenesis. Loss-of-function mutations of TET proteins in immune cells are associated with a variety of abnormalities, including inflammation, cancer, and clonal hematopoiesis, a condition related to aging. Loss of TETs also has a significant impact on the plasticity and differentiation of T cells, which contributes to inflammation and cancer. In this review, we describe recent findings in functions of TETs in T cell plasticity and differentiation and the TET-TDG axis in selected biological processes.

Inflammatory bowel disease (IBD), encompassing ulcerative colitis and Crohn's disease, is characterized by chronic intestinal inflammation and immune dysregulation, driven mainly by Th1 and Th17 cells and sustained by pro-inflammatory cyto-chemokines. This inflammatory milieu is associated with visceral pain, a key symptom affecting patient quality of life. Addressing both gut inflammation/immunity and visceral pain is crucial for improving IBD therapy. This study assessed the therapeutic potential of Mangifera indica L. extract (MIE), a mangiferin-rich formulation, in a DNBS-induced colitis model in rats. MIE treatment administered either simultaneously or post-DNBS induction, significantly reduced pathogenic Th1 and Th17 cell infiltration, along with pro-inflammatory cytokines (IL-1β, TNF-α) and chemokines (CXCL1, CXCL2), though histopathology showed no significant improvements in tissue healing. Additionally, MIE restored microbiota-derived short-chain fatty acids (acetate and butyrate) in colon and faecal samples. Importantly, MIE alleviated post-inflammatory visceral hypersensitivity, reducing the abdominal withdrawal reflex (AWR) to colorectal distension (CRD), after either acute or repeated treatment. These findings suggest that MIE, in the context of nutraceuticals and functional foods, shows promise as a dual-action therapeutic strategy for complementary and/or adjuvant therapy in IBD.

Suppressing immune responses promotes allograft survival but also favours tumour progression and recurrence. Selectively suppressing allograft rejection while maintaining or even enhancing antitumor immunity is challenging. Here, we show loss of allograft-related rejection in mice deficient in Setdb1, an H3K9 methyltransferase, while antitumor immunity remains intact. RNA sequencing shows that Setdb1-deficiency does not affect T-cell activation or cytokine production but induces an increase in Treg-cell-associated gene expression. Depletion of Treg cells impairs graft acceptance in Setdb1-deficient mice, indicating that the Treg cells promote allograft survival. Surprisingly, Treg cell-specific Setdb1 deficiency does not prolong allograft survival, suggesting that Setdb1 may function prior to Foxp3 induction. Using single-cell RNA sequencing, we find that Setdb1 deficiency induces a new Treg population in the thymus. This subset of Treg cells expresses less IL-1R2 and IL-18R1. Mechanistically, during Treg cell induction, Setdb1 is recruited by transcription factor ATF and altered histone methylation. Our data thus define Setdb1 in T cells as a hub for Treg cell differentiation, in the absence of which suppressing allograft rejection is uncoupled from maintaining antitumor immunity.

Regulatory T cells (Tregs), previously referred to as suppressor T cells, represent a distinct subset of CD4+ T cells that are uniquely specialized for immune suppression. They are characterized by the constitutive expression of the transcription factor FoxP3 in their nuclei, along with CD25 (the IL-2 receptor α-chain) and CTLA-4 on their cell surface. Tregs not only restrict natural killer cell-mediated cytotoxicity but also inhibit the proliferation of CD4+ and CD8+ T-cells and suppress interferon-γ secretion by immune cells, ultimately impairing an effective antitumor immune response. Treg cells are widely recognized as a significant barrier to the effectiveness of tumor immunotherapy in clinical settings. Extensive research has consistently shown that Treg cells play a pivotal role in facilitating tumor initiation and progression. Conversely, the depletion of Treg cells has been linked to a marked delay in tumor growth and development.

Treg dysfunction in ischemic cardiomyopathy (ICM) remains mechanistically unclear. We investigated ICM plasma small extracellular vesicles (ICM-sEVs) in Treg regulation and post-MI remodeling. Flow cytometry assessed Treg frequency. ICM-sEV miRNA sequencing revealed miR-223-3p enrichment, validated using miR-223-/- and Foxp3GFP/+ mice. ICM patients and mice exhibited elevated Treg numbers but suppressed Foxp3. miR-223-3p was upregulated in ICM-sEVs and inversely correlated with functional Tregs. ICM-sEVs administration aggravated ventricular remodeling post myocardial infarction (MI) in mice while reducing Treg frequency and elevating miR-223-3p in vitro. miR-223 knockdown increased Treg cell number and Foxp3 expression, whereas miR-223 overexpression reversed the phenotype. ICM-sEVs aggravate ventricular remodeling post-MI and promote miR-223-3p-mediated Treg cell dysfunction.

Multiple sclerosis (MS) is a chronic neurological disorder derived from autoreactive immune system attacking the protective myelin sheath that surrounds nerves in the central nervous system (CNS). Here, a tolerogenic nanovaccine for generating an antigen-specific immune tolerance for treating MS is proposed. It consisted of a mesoporous polydopamine (mPDA) nanoparticle, characterized by high reactive oxygen species (ROS)-scavenging property, loaded with MS-derived autoantigen. Intravenous vaccination of autoantigen-loaded mPDA could induce tolerogenic dendritic cells (DCs) with low expression of co-stimulatory molecules while presenting peptide epitopes. The tolerogenic DCs induced peripheral regulatory T-cells (Tregs), thereby reducing infiltration of autoreactive CD4+ T-cells and inflammatory antigen-presenting cells (APCs) into the CNS. In MS-mimicking mouse model, the tolerogenic nanovaccine prevented MS development in the early therapeutic setup and exhibited an enhanced recovery from complete paralysis in the late therapeutic model. The current platform could be exploited to treat other autoimmune diseases where disease-dependent autoantigen peptides are delivered.

Regulatory T cells (Tregs) are critical for maintaining the stability of the immune system and facilitating tumor escape through various mechanisms. Resting T cells are involved in cell-mediated immunity and remain in a resting state until stimulated, while effector T cells promote immune responses. Here, we investigated the roles of two gene signatures, one for resting Tregs (FOXP3 and IL2RA) and another for effector Tregs (FOXP3, CTLA-4, CCR8 and TNFRSF9) in pan-cancer. Using data from The Cancer Genome Atlas (TCGA), The Cancer Proteome Atlas (TCPA) and Gene Expression Omnibus (GEO), we focused on the expression profile of the two signatures, the existence of single nucleotide variants (SNVs) and copy number variants (CNVs), methylation, infiltration of immune cells in the tumor and sensitivity to different drugs. Our analysis revealed that both signatures are differentially expressed across different cancer types, and correlate with patient survival. Furthermore, both types of Tregs influence important pathways in cancer development and progression, like apoptosis, epithelial-to-mesenchymal transition (EMT) and the DNA damage pathway. Moreover, a positive correlation was highlighted between the expression of gene markers in both resting and effector Tregs and immune cell infiltration in adrenocortical carcinoma, while mutations in both signatures correlated with enrichment of specific immune cells, mainly in skin melanoma and endometrial cancer. In addition, we reveal the existence of widespread CNVs and hypomethylation affecting both Treg signatures in most cancer types. Last, we identified a few correlations between the expression of CCR8 and TNFRSF9 and sensitivity to several drugs, including COL-3, Chlorambucil and GSK1070916, in pan-cancer. Overall, these findings highlight new evidence that both Treg signatures are crucial regulators of cancer progression, providing potential clinical outcomes for cancer therapy.

Chimeric antigen receptor T cells recognizing CD19 (19CAR-T) cell therapy has achieved robust clinical efficacy when treating some hematological malignancies, but which patient subgroups benefit mostly remains elusive. Here we summarized the data of 541 patients from 30 clinical trials who underwent 19 CAR-T therapy and analyzed the different clinical responses between young (<44 years), middle-aged (45-59 years) and elderly (>60 years) patients and found that the young patients showed a higher level of complete response (CR) rate. Therefore, we then summarize the advances of studies focusing on the effects of age on anti-tumor efficacy of CAR-T therapy and analyze the reasons for the low CR rate after CAR-T cell therapy in elderly patients with tumors, aiming to provide hints for oncologists to select the most suitable candidate for this cancer immunotherapy.

Osteoporosis is the most common skeletal disease worldwide, characterized by low bone mineral density, resulting in weaker bones, and an increased risk of fragility fractures. The maintenance of bone mass relies on the precise balance between bone synthesis and resorption. The close relationship between the immune and skeletal systems, called "osteoimmunology", was coined to identify these overlapping "scientific worlds", and its function resides in the evaluation of the mutual effects of the skeletal and immune systems at the molecular and cellular levels, in both physiological and pathological states. Lipids play an essential role in skeletal metabolism and bone health. Indeed, bone marrow and its skeletal components demand a dramatic amount of daily energy to control hematopoietic turnover, acquire and maintain bone mass, and actively being involved in whole-body metabolism. Statins, the main therapeutic agents in lowering plasma cholesterol levels, are able to promote osteoblastogenesis and inhibit osteoclastogenesis. This review is meant to provide an updated overview of the pathophysiology of bone remodelling cycle, focusing on the interplay between bone, immune system and lipids. Novel therapeutic strategies for the management of osteoporosis are also discussed.

Regulatory T (Treg) cells are critical for maintaining peripheral tolerance and preventing autoimmunity. Treg cell depletion or dysfunction results in fatal multiorgan inflammation linked to unrestrained effector T cell expansion. Here, we combine in vivo gene targeting and fate-mapping with high-dimensional cytometry to identify Treg cells' steady-state function and suppressive mechanisms that prevent autoimmune inflammation and dissect the T helper (TH) cell-derived cytokines and responding cells executing tissue damage upon global loss of peripheral tolerance. We unveil that type 1 cytokines, granulocyte-macrophage colony-stimulating factor (GM-CSF) and interferon (IFN)γ, but not interleukin (IL)-17A, direct the ensuing immunopathology and mortality. GM-CSF orchestrates tissue invasion by monocytes and granulocytes and enhances their reactive oxygen species production and phagocytic capability. IL-2 modulation by Treg cells is crucial in restraining pathogenic GM-CSF-producing TH cells. Our study highlights the critical role of Treg cells and IL-2 signaling in controlling GM-CSF-producing TH cells and type 1 responses to curb phagocyte-mediated tissue destruction.

Chronic social stress (CSS) is a significant public health challenge that negatively impacts behavior and immune function through brain-spleen interactions. Oxytocin (OT), a neuropeptide critical for social behavior and immune regulation, is upregulated during CSS, though its underlying mechanisms remain unclear. This study investigates the role of OT in splenic immune modulation using a murine model of CSS. Behavioral evaluations, serum oxytocin quantification, and splenic immunophenotypic analysis were performed. Splenic denervation confirmed OT's neuromodulatory role, whereas OTR antagonism revealed its endocrine function. CSS-induced OT elevation was associated with immunosuppression, characterized by increased Foxp3⁺ regulatory T cells and reduced CD4⁺ T and CD19⁺ B cells. OT also modulated macrophage polarization, inhibiting M1-like (pro-inflammatory) and enhancing M2-like (anti-inflammatory) phenotypes. Denervation or pharmacological blockade of OT signaling partly reversed CSS-induced splenic immunosuppression but adversely affected survival in CSS-exposed mice. Additionally, denervation or OTR antagonism reduced the mice's response to social defeat, as shown by decreased social avoidance behavior. These findings suggest that OT-mediated immunosuppression likely represents a compensatory mechanism in response to chronic social stress. Targeting the OT-immune axis could offer innovative therapeutic approaches for stress-associated disorders by restoring immune homeostasis while maintaining behavioral integrity.

Heart transplantation remains the gold-standard treatment for end-stage heart failure, yet long-term graft survival is hindered by chronic rejection and the morbidity and mortality caused by lifelong immunosuppression. While advances in medical and device-based therapies have reduced the overall need for transplantation, patients who ultimately require a transplant often present with more advanced disease and comorbidities. Recent advances in tolerance-inducing strategies offer promising avenues to improve allograft acceptance, while minimizing immunosuppressive toxicity. This review explores novel approaches aiming to achieve long-term immunological tolerance, including co-stimulation blockade, mixed chimerism, regulatory T-cell (Treg) therapies, thymic transplantation, and double-organ transplantation. These strategies seek to promote donor-specific unresponsiveness and mitigate chronic rejection. Additionally, expanding the donor pool remains a critical challenge in addressing organ shortages. Innovations such as ABO-incompatible heart transplantation are revolutionizing the field by increasing donor availability and accessibility. In this article, we discuss the mechanistic basis, clinical advancements, and challenges of these approaches, highlighting their potential to transform the future of heart transplantation with emphasis on clinical translation.

Regulatory T cells (Tregs) can persist as memory cells (mTregs) in both infectious and non-infectious settings. However, their functional behavior, phenotypic stability, and suppressive properties upon antigen re-exposure remain poorly understood. Emerging evidence suggests that mTregs exhibit enhanced proliferation and suppressive capacity upon re-encountering the same antigen, a feature that may be critical in recurrent infections such as malaria. In malaria, Tregs are known to modulate immune responses and influence acute disease outcomes, suggesting that mTreg recall may play a significant role in long-term immunity. This review explores the biology of Treg memory, with a focus on malaria, and examines the immunological implications of maintaining a suppressive mTreg population in malaria immunity.

Microsatellites are essential genomic components increasingly linked to transcriptional regulation. FoxP3, a transcription factor critical for regulatory T cell (Treg) development, recognizes TTTG repeat microsatellites by forming multimers along DNA. However, FoxP3 also binds a broader range of TnG repeats (n = 2-5), often at the edges of accessible chromatin regions. This raises questions about how FoxP3 adapts to sequence variability and the potential role of nucleosomes. Using cryoelectron microscopy and single-molecule analyses, we show that murine FoxP3 assembles into various distinct supramolecular structures, depending on DNA sequence. This structural plasticity enables FoxP3 to bridge 2-4 DNA duplexes, forming ultrastable structures that coordinate multiple genomic loci. Nucleosomes further facilitate FoxP3 assembly by inducing local DNA bending, creating a nucleus that recruits distal DNA elements through multiway bridging. Our findings thus reveal FoxP3's unusual ability to shapeshift to accommodate evolutionarily dynamic microsatellites and its potential to reinforce chromatin boundaries and three-dimensional genomic architecture.

Regulatory T cells (Tregs) play a crucial role in moderating immune responses offering promising therapeutic options for autoimmune diseases and allograft rejection. Genetically engineering Tregs with chimeric antigen receptors (CARs) enhances their targeting specificity and efficacy. With non-viral transfection methods suffering from low efficiency and reduced cell viability, viral transduction is currently the only viable approach for GMP-compliant CAR-Treg production. However, viral transduction raises concerns over immunogenicity, insertional mutagenesis risk, and high costs, which limit clinical scalability. This study introduces a scalable nanoneedle electroporation (nN-EP) platform for GMP-compatible transfection of HLA-A2-specific CAR plasmids into primary human Tregs. The nN-EP system achieves 43% transfection efficiency, outperforming viral transduction at multiplicity of infection 1 by twofold. Importantly, nN-EP preserves Treg viability, phenotype and proliferative capacity. HLA-A2-specific CAR-Tregs generated using nN-EP show specific activation and superior suppressive function compared to polyclonal or virally transduced Tregs in the presence of HLA-A2 expressing antigen presenting cells. These findings underscore the potential of nN-EP as a GMP-suitable method for CAR-Treg production, enabling broader clinical application in immune therapies.

AZD8701 uses next-generation antisense oligonucleotide (ASO) technology to selectively reduce human forkhead box P3 (FOXP3) expression in regulatory T cells, reversing their immunosuppressive function. FOXP3 ASO alone or with PD-(L)1 inhibition attenuated tumor growth in mice. We report a phase I study of AZD8701 alone or combined with durvalumab in patients with advanced solid tumors.

Eligible patients had solid tumors and received prior standard-of-care treatment, including anti-PD-(L)1 therapy. Patient cohorts were treated with AZD8701 intravenously weekly at escalating doses, either alone (60-960 mg) or combined (240-720 mg) with durvalumab 1,500 mg intravenous every 4 weeks. The primary objective was safety and tolerability, with the aim of determining the MTD.

Forty-five patients received AZD8701 monotherapy, and 18 received AZD8701 with durvalumab. One dose-limiting toxicity (increased alanine aminotransferase) occurred with AZD8701 960 mg. The most common adverse events related to AZD8701 monotherapy were fatigue (22.2%), asthenia, pyrexia, and increased alanine aminotransferase (20% each); the safety profile was similar when combined with durvalumab. With AZD8701 monotherapy, 24.4% and 15.6% of the patients had stable disease for ≥16 and ≥24 weeks, respectively; one patient treated with AZD8701 720 mg and durvalumab had a partial response. FOXP3 mRNA changes were heterogeneous (8/13 patients showed a reduction), with no clear dose relationship. ASO accumulated in the tumor epithelium and stroma.

This study demonstrates the clinical feasibility of ASO therapy, with generally manageable adverse events, FOXP3 knockdown, and ASO delivery to the tumor.

Regulatory T (Treg) cells are known to impede antitumor immunity, yet the regulatory mechanisms and functional roles of these cells remain poorly understood. In this study, through the characterization of multiple cancer models, we identified a substantial presence of peripherally induced Treg cells in the tumor microenvironment (TME). Depletion of these cells triggered antitumor responses and provided potent therapeutic effects by increasing functional CD8+ T cells. Fate-mapping and transfer experiments revealed that IFN-γ-expressing T helper (Th) 1 cells differentiated into Treg cells in response to TGF-β signaling in tumors. Pseudotime trajectory analysis further revealed the terminal differentiation of Th1-like Treg cells from Th1 cells in the TME. Tumor-resident Treg cells highly expressed T-bet, which was essential for their functions in the TME. Additionally, CD39 was highly expressed by T-bet+ Treg cells in both mouse and human tumors, and was necessary for Treg cell-mediated suppression of CD8+ T cell responses. Our study elucidated the developmental pathway of intratumoral Treg cells and highlighted novel strategies for targeting them in cancer patients.

FOXP3-expressing regulatory T (Treg) cells play a pivotal role in maintaining immune homeostasis and tolerance, with their activation being crucial for preventing various inflammatory responses. However, the mechanisms governing the epigenetic program in Treg cells during their dynamic activation remain unclear. In this study, we demonstrate that CXXC-finger protein 1 (CXXC1) interacts with the transcription factor FOXP3 and facilitates the regulation of target genes by modulating H3K4me3 deposition. Cxxc1 deletion in Treg cells leads to severe inflammatory disease and spontaneous T cell activation, with impaired immunosuppressive function. As a transcriptional regulator, CXXC1 promotes the expression of key Treg functional markers under steady-state conditions, which are essential for the maintenance of Treg cell homeostasis and their suppressive functions. Epigenetically, CXXC1 binds to the genomic regulatory regions of Treg program genes in mouse Treg cells, overlapping with FOXP3-binding sites. Given its critical role in Treg cell homeostasis, CXXC1 presents itself as a promising therapeutic target for autoimmune diseases.

Human and fly FoxP homologs are well-known for their roles in the development of cognitive abilities. These findings have led to the hypothesis that the ancestral function of FoxP was in the development of cognitive neural circuits. However, complex brains in human and fly evolved independently, and the similar cognitive function of FoxP in human and fly may thus be interpreted as a result of convergent evolution. In addition, the 4 gnathostome FoxP paralogs also possess diverse developmental functions unrelated to neurodevelopment, which might have been overlooked in comparative studies of invertebrate FoxP homologs. To resolve these uncertainties, we set out to improve the phylogenetic reconstruction of vertebrate FoxP homologs and broaden the taxonomic sampling of gene expression profiling to include an invertebrate chordate, ambulacrarian deuterostomes, and a spiralian protostome. Using phylogenetic analysis combined with synteny mapping, we elaborated the hypothesis that the 4 FoxP paralogs arose through the 2R-WGD events shared by all gnathostome species. Based on this evolutionary scenario, we examined the FoxP expression pattern in amphioxus development and concluded that FoxP already had complex developmental functions across all germ layers in the chordate ancestor. Moreover, in sea urchin, hemichordate, and catenulid flatworm, FoxP was expressed in the gut prominently, in addition to the anterior neurogenic ectoderm. This surprising similarity shared among these distantly related species implies that FoxP may have a significant function in gut development in addition to the neural development function in the last common ancestor of bilaterians.

CD4 T cells orchestrate the immune response, facilitating cytotoxic and humoral responses while preventing the destruction of one's own tissues by more autoreactive T cells. However, unlike complete CD4 T cell deficiency, the apparent deficiency caused by mutations in the CD4 gene that prevent its expression does not result in severe combined immunodeficiency in humans. The absence of the CD4 molecule limits the number of clones selected in the thymus on the basis of major histocompatibility complex type II, but does not prevent the acquisition of the T helper lymphocyte program, allowing them to retain most of their effector capacity. This observation raises new questions about the function of CD4 T cells and, in particular, the intrinsic role of the CD4 molecule.

Inflammatory bowel disease (IBD) involves a range of immune-mediated disorders marked by systemic and local intestinal inflammation. We synthesized a novel compound DJ-X-025 and uncovered its anti-inflammatory properties using lipopolysaccharide (LPS)-induced RAW 264.7 macrophages in vitro and a dextran sodium sulfate (DSS)-induced model of colitis.

We evaluated the alteration in cell morphology, cytoskeletal proteins, and inflammatory markers of DJ-X-025 treated LPS-stimulated RAW 264.7 macrophages. We administered DJ-X-025 by oral gavage in DSS-induced colitis, examined colon histology, and alterations of immune cells by flow cytometry, and performed molecular studies using RT-qPCR and western blot analysis. DJ-X-025 treatment markedly altered the morphology of LPS-treated RAW 264.7 macrophages from elongated to round shapes, modulated actin and tubulin, and reduced the level of inflammatory markers like TNF-α, IL-1β, IL-6, and iNOS. Further, we observed that DJ-X-025 steered to improve colon length, muscularis mucosa thickness, and colon inflammatory score compared to the DSS group alone. DJ-X-025 effectively inverted the increased population of activated T cells, Th17, and macrophages in lamina propria by DSS treatment, leading to a substantial reduction in the inflammatory response in the colon. Strikingly, DJ-X-025 treatment enhanced the expression of occludin and diminished the expression of NF-κB and phosphorylation of STAT3 in the colon of DSS-treated mice compared to DSS-alone. Additionally, DJ-X-025 induced the expression of Foxp3 in the colon and, reduced systemic inflammatory cytokine/chemokine levels further supporting its immunomodulatory effects. These results suggest that DJ-X-025 is linked to the induction of occludin expression and decreased expression of p-STAT3/NF-κB and Th17 response in the colon, which together suppresses systemic and colon inflammatory cytokines for effective amelioration of experimental colitis.

These findings suggest that DJ-X-025 might be a promising therapeutic agent for the treatment of IBD.

Fatty acid metabolism (FAM) plays a critical role in tumor progression and therapeutic resistance by enhancing lipid biosynthesis, storage, and catabolism. Dysregulated FAM is a hallmark of prostate cancer (PCa), enabling cancer cells to adapt to extracellular signals and metabolic changes, with the tumor microenvironment (TME) playing a key role. However, the prognostic significance of FAM in PCa remains unexplored.

We analyzed 309 FAM-related genes to develop a prognostic model using least absolute shrinkage and selection operator (LASSO) regression based on The Cancer Genome Atlas (TCGA) database. This model stratified PCa patients into high- and low-risk groups and was validated using the Gene Expression Omnibus (GEO) database. We constructed a nomogram incorporating risk score, clinical variables (T and N stage, Gleason score, age), and assessed its performance with calibration curves. The associations between risk score, tumor mutation burden (TMB), immune checkpoint inhibitors (ICIs), and TME features were also examined. Finally, a hub gene was identified via protein-protein interaction (PPI) networks and validated.

The risk score was an independent prognostic factor for PCa. High-risk patients showed worse survival outcomes but were more responsive to immunotherapy, chemotherapy, and targeted therapies. A core gene with high expression correlated with poor prognosis, unfavorable clinicopathological features, and immune cell infiltration.

These findings reveal the prognostic importance of FAM in PCa, providing novel insights into prognosis and potential therapeutic targets for PCa management.

Hashimoto's thyroiditis (HT) is the most common autoimmune thyroid disease (AITD), which is distinguished by high thyroid peroxidase antibody (TPOAb) or thyroglobulin antibody (TgAb). The differentiation of CD4+T cell subsets in patients with HT is imbalanced, with Treg cells decreased and Th17 cells abnormally activated. Fatty acid oxidation supports the differentiation of Th17 cells and induces inflammation, but the specific mechanism is still unknown. This study aimed to explore the role of fatty acid oxidation and its pathway in the pathogenesis of autoimmune thyroiditis and the immune mechanism.

In in vitro experiments, a total of 60 HT patients and 20 healthy controls were selected and their CD4+T cells were sorted by magnetic beads. All 80 samples were divided into 4 groups on average: HC group (Healthy control group), HT group (Hashimoto thyroiditis CD4+T cell inactive group), TCC group(Hashimoto thyroiditis CD4+T cell activation), TCC + ETO group(Hashimoto thyroiditis CD4+T cell activation + Etomoxir group). In in vivo experiments, the mice were randomly divided into 3 groups: Con group(Control group), mTg group (CBA/J mice were injected with mTg for modeling, that is EAT mice group), and mTg + ETO group (Etomoxir intervention in EAT mice group). Fatty acid oxidation substrates of CD4+T cells in human peripheral blood were detected by targeted metabolomics. The expressions of key fatty acid oxidation proteins mTOR, ACC1 and CPT1A were detected by Western blotting. The proportion of CD4+T cell subtype differentiation in human and mouse models was detected by flow cytometry. The severity of EAT was detected by HE staining.

Compared with healthy controls, the level of CPT1A in CD4+T cells of HT patients was increased, and the intracellular fatty acid content was significantly decreased, indicating that the level of fatty acid oxidation was enhanced in HT patients. After adding Etomoxir, the level of fatty acid oxidation was significantly inhibited, and the imbalance of CD4+T cell subpopulation differentiation in HT patients was reversed. In EAT mice, the mTOR/ACC1/CPT1A pathway was significantly activated, and its expression level was decreased after adding Etomoxir. At the same time, Etomoxir could reverse the reprogramming of abnormal metabolism in EAT mice cells, reduce the spleen index, and improve lymphocyte infiltration in the thyroid.

The mTOR/ACC1/CPT1A fatty acid oxidation pathway of CD4+T cells in Hashimoto's thyroiditis was increased, and treatment with Etomoxir could inhibit the activation of this pathway, and reverse the reprogramming of abnormal metabolism in CD4+T cells, thereby reducing Hashimoto's thyroiditis.

The hypothalamus in the central nervous system (CNS) has important functions in controlling systemic metabolism. A calorie-rich diet triggers CNS immune activation, impairing metabolic control and promoting obesity and Type 2 Diabetes (T2D), but the mechanisms driving hypothalamic immune activation remain unclear. Here we identify regulatory T cells (Tregs) as key modulators of hypothalamic immune responses. In mice, calorie-rich environments activate hypothalamic CD4+ T cells, infiltrating macrophages and microglia while reducing hypothalamic Tregs. mRNA profiling of hypothalamic CD4+ T cells reveals a Th1-like activation state, with increased Tbx21, Cxcr3 and Cd226 but decreased Ccr7 and S1pr1. Importantly, results from Treg loss-of function and gain-of-function experiments show that Tregs limit hypothalamic immune activation and reverse metabolic impairments induced by hyper-caloric feeding. Our findings thus help refine the current model of Treg-centered immune-metabolic crosstalk in the brain and may contribute to the development of precision immune modulation for obesity and diabetes.