bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2026–03–08
thirty-two papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Metabolic causal factor of immune cell function and fate in the tumor microenvironment.
  2. Gut Microbiota-Induced CTLA4 Expression on CD8+ T Cells Impairs Antitumor Immunity and Promotes Colorectal Cancer Progression.
  3. Mechanistic basis and therapeutic modulation of T cell fitness to enhance CAR-T cell efficacy in hematological malignancies.
  4. Glucocorticoid-induced leucine zipper is a primary checkpoint molecule that establishes a virus-specific CD8+ T-cell activation threshold.
  5. Dietary myo-inositol exerts pleiotropic effects on T cell activation, antioxidant defense and fatty acid metabolism to enhance anti-bacterial immunity in tilapia.
  6. Tissue-specific clonal selection and differentiation of CD4⁺ T cells during infection.
  7. T cell exhaustion in bi- and trispecific T cell engager therapy in hematologic malignancies: Mechanisms and implications.
  8. PCSK9-mediated degradation of cell-surface LDL receptors impairs human CD8+ T cell effector functions.
  9. SLAMF6 Restrains T-Cell Function and Limits Antitumor Immunity.
  10. Tumor-restraining fibroblasts emerge after chemotherapy specifically in responders.
  11. ITK-targeted immune remodeling enhanced the efficacy of anti-CD19 CAR-T cell therapy.
  12. Physical Fitness Dynamics Shape Immune Remodeling in Healthy Aging: A 3-Year Longitudinal Study.
  13. The scramblase anoctamin 9 controls the immune response in lymphocytes.
  14. Immune Microenvironment Dynamics and Therapeutic Targets in GIST Revealed by Multi-Omics and Functional Validation.
  15. Hepatic mitochondrial signaling as a systemic hub: inter-organ communication networks in aging and aging-related diseases.
  16. Erzhi pills: a potential aging-modulating agent targeting immunosenescence in mice.
  17. Fenofibrate targets PPARα-CPT1C axis to reverse aging by regulating lipid metabolism and mitochondrial function.
  18. Tumor-targeted IL2 promotes specific CD8+ T cells private clonal expansion enhancing lymphoma control.
  19. Citrate clearance is a major function of aconitase 2 in the canonical TCA cycle.
  20. The glycolytic metabolite phosphoenolpyruvate restricts cGAS-driven inflammation to promote healthy aging.
  21. Extracellular CD44 lactylation impairs CD8+ T cell function in KRAS-mutant colorectal cancer.
  22. Human VH-antibody-based CAR T cells targeting folate receptor-alpha show enhanced persistence and reduced T-cell exhaustion against ovarian cancer.
  23. Gas-sensing neurons prime mitochondrial fitness to offset metabolic stress.
  24. Regional delivery of hypoxia-responsive CAR T cells improves efficacy for solid tumors.
  25. T Cell Microenvironmental Impacts and Therapeutic Opportunities: Application to Human Testicular Germ Cell Tumors.
  26. Nanoassembly-mediated immunometabolic reprogramming of CD4+ T cells suppresses β-cell autoimmunity in type 1 diabetes.
  27. CD2 costimulation breaks the CD28 vs. 4-1BB tradeoff in CAR T cells.
  28. The natural flavonoid dihydromyricetin targets senescent cells via PRDX2 and alleviates age-related diseases.
  29. Mogamulizumab-induced drug eruption during multiagent chemotherapy: A possible CD8+ T cell-mediated mechanism.
  30. CDK8/CDK19 inhibition restores T-cell homeostasis in primary immune thrombocytopenia.
  31. Targeting metabolic reprogramming to enhance adoptive immunotherapy: emerging mechanisms and translational perspectives.
  32. ADAM9 supports regulatory T cell stability through TGF-β-SMAD signaling and is reduced in systemic lupus erythematosus.
  1. Bull Cancer. 2026 Mar 02. pii: S0007-4551(26)00105-0. [Epub ahead of print]
    Metabolic causal factor of immune cell function and fate in the tumor microenvironment.
    Fida Noor, Hafeez Noor.
      This study provides an in depth review of understanding the metabolic regulation of immune cells in cancer. Evidence has accumulated in the rapidly developing field of immune metabolism, in which immune cell function and fate are closely linked to their cellular metabolic programs, particularly within the tumor microenvironment. The TME is a metabolically disadvantaged niche characterized by hypoxia, nutrient deprivation, acidosis, and accumulation of immunosuppressive metabolites, all of which result from intense competition for essential resources such as glucose and amino acids. These metabolic constraints profoundly affect the activation, differentiation, and response capacity of the immune cells. This article systematically explores the metabolic reprogramming of immune cells in cancer, with a particular focus on T lymphocytes and myeloid cell populations. We have mapped the metabolic dynamics of T-cells from activation to dysfunction and depletion, elucidating myeloid lineage cells. Finally, we discuss emerging therapeutic strategies that target immune metabolism, including enhancing metabolic adaptation of effector cells, de-inhibiting metabolic checkpoints, reprogramming immunosuppressive cell populations, and combining metabolic interventions with existing immune checkpoint blockade therapies. A deeper understanding of metabolic competition and cooperation within the TME will provide conceptual and transformational evidence for developing more effective and durable cancer immunotherapy. Despite the promise of immunometabolic interventions, translating these strategies into safe and effective clinical therapies remains challenging.
    Keywords:  Cancer immunotherapy; Immune metabolism; Metabolic checkpoints; T-cell exhaustion; Tumor microenvironment; Tumor-associated macrophages
    DOI:  https://doi.org/10.1016/j.bulcan.2026.01.008
  2. Immunology. 2026 Mar 04.
    Gut Microbiota-Induced CTLA4 Expression on CD8+ T Cells Impairs Antitumor Immunity and Promotes Colorectal Cancer Progression.
    Meidie Cheng, Shuangcheng Zhi, Mengmeng Zheng, Sijin Zhang, Jun Hong.
      This study reveals a novel gut microbiota-CD8+ T cell axis driving immunosuppression in colorectal cancer. Analysis of 16S rRNA sequencing identified significant gut dysbiosis in CRC patients, with marked enrichment of Phocaeicola and Bacteroides. Single-cell transcriptomics uncovered substantial T cell depletion and elevated CTLA4+PD1+ immune cells within the tumour microenvironment. Critically, spatial transcriptomics demonstrated co-localization of CTLA4+CD8+ T cells with tumour cells, indicating direct immunosuppressive interactions. Functional validation confirmed CTLA4 overexpression impairs CD8+ T cell effector capacity, accelerating CRC cell proliferation and invasion. In vivo models demonstrated that faecal microbiota transplantation (FMT) promoted CTL activation, reduced Bacteroides abundance, decreased the formation of CD8+CTLA4+ T cells and ameliorated CRC symptoms. Additionally, CTLA4 knockdown inhibited tumour growth and metastasis. These findings establish a mechanistic pathway: gut dysbiosis induces chronic inflammation, triggering CTLA4 upregulation on CD8+ T cells to promote T cell exhaustion and tumour immune evasion. The study provides immunological evidence for targeting the microbiota-CTLA4 axis in CRC immunotherapy.
    Keywords:  CTLA4+CD8+ T cells; colorectal cancer; gut microbiota; immune suppression; tumour microenvironment
    DOI:  https://doi.org/10.1111/imm.70128
  3. Front Immunol. 2026 ;17 1762453
    Mechanistic basis and therapeutic modulation of T cell fitness to enhance CAR-T cell efficacy in hematological malignancies.
    Karama Makni-Maalej, Shaykhah Mujahhiz Alotaibi, Queenie Fernandes, Syed Osman Ahmed, Sarra Mestiri, Salim Bougarn, Waad Amir, Syed Farhatullah, Mohamed Kharfan-Dabaja, Maysaloun Merhi, Riad El Fakih, Mahmoud Aljurf, Said Dermime.
      T cell fitness has emerged as a critical determinant of the efficacy and persistence of Chimeric Antigen Receptor (CAR)-T cell therapy. Defined by the capacity of T cells to proliferate, resist exhaustion, persist in vivo, and exert sustained effector functions, T cell fitness reflects the integration of a dynamic network of intrinsic and extrinsic regulatory mechanisms. In this review, we present a comprehensive synthesis of the molecular and cellular foundations underlying T cell fitness, emphasizing the influence of differentiation trajectories, signaling pathways, metabolic reprogramming, and epigenetic modifications. We further discuss the impact of patient-specific conditions such as age as well as disease biology, prior therapeutic exposures, and timing and quality of T cell collection, on the phenotypic and functional efficacy of CAR-T cell products. Beyond delineating these determinants, we highlight emerging strategies aimed at enhancing T cell fitness. Importantly, we propose T cell fitness as an integrated, multi-layered systems property emerging from the interaction between differentiation state, signaling architecture, metabolic-mitochondrial competence, epigenetic stability, and host-specific inflammatory and treatment-related pressures. We introduce a mechanistic framework that links these layers across the CAR-T therapeutic timeline from leukapheresis to post-infusion tumor engagement and outline how this framework can be operationalized into measurable parameters to guide patient stratification, manufacturing decisions, and rational therapeutic interventions.
    Keywords:  CAR-T cell therapy; T cell fitness; T cell subsets; hematological malignancies; metabolic reprogramming
    DOI:  https://doi.org/10.3389/fimmu.2026.1762453
  4. J Immunol. 2026 Feb 09. pii: vkaf353. [Epub ahead of print]215(2):
    Glucocorticoid-induced leucine zipper is a primary checkpoint molecule that establishes a virus-specific CD8+ T-cell activation threshold.
    Taylah J Bennett, Charlene Lam, Jessie O'Hara, Vibha A V Udupa, Daniel Thiele, Jason K C Lee, Adele Barugahare, Jasmine Li, Nicole L La Gruta, Sarah A Jones, Brendan E Russ, Stephen J Turner.
      Naïve CD8+ T-cell activation needs to overcome a signaling threshold to initiate the resulting program of T cell proliferation and differentiation. While the strength of T-cell receptor (TCR) signaling and co-stimulation are known to dictate T-cell responsiveness, the role of other factors that determine strength of signal is not well studied. Glucocorticoid-induced leucine zipper (GILZ) is a regulatory protein that serves to dampen activation signals in several leukocyte populations. Here we demonstrate that GILZ is highly expressed in murine naïve CD8+ T cells and downregulated with activation. GILZ deficiency increased accumulation of antigen-specific CD8+ T-cell responses in a mouse model of influenza A virus infection, and this correlated with greater responsiveness to low-affinity ligands. GILZ-deficient CD8+ T cells were able to better engage optimal effector transcriptional programs at lower signaling thresholds, highlighting GILZ as a key checkpoint for naïve CD8+ T cell activation. Importantly, GILZ deficiency did not impact memory T cell formation or recall responses to influenza A virus infection. These data demonstrate that GILZ acts as an important naïve CD8+ T cell checkpoint by establishing a threshold for initial activation. Modulation of GILZ could be beneficial in improving CD8+ T cell responses against low-affinity ligands, particularly like those found in the context of tumor antigens.
    Keywords:  CD8+ T cell; T-cell memory; influenza virus; transcription factor
    DOI:  https://doi.org/10.1093/jimmun/vkaf353
  5. Fish Shellfish Immunol. 2026 Mar 03. pii: S1050-4648(26)00155-5. [Epub ahead of print] 111251
    Dietary myo-inositol exerts pleiotropic effects on T cell activation, antioxidant defense and fatty acid metabolism to enhance anti-bacterial immunity in tilapia.
    Zhichao Fang, Yuying Zheng, Minghui Zhang, Jiaying Xie, Chenxin Shen, Yating Zhu, Qiqi Jiang, Yishan Lu, Xiumei Wei, Jialong Yang.
      Bacterial diseases cause major economic losses in aquaculture, underscoring the need for feed additives that enhance fish immunity. Myo-inositol (MI), an essential nutrient for fish growth, possesses antioxidant and lipid-metabolism modulating properties. However, the role of MI in regulating T cell function remains unclear. In this study, Nile tilapia (Oreochromis niloticus) individuals were fed diets containing 850 or 1700 mg/kg MI to evaluate its effects on T cell immunity. The results demonstrated that dietary MI at 850 mg/kg significantly enhanced host anti-bacterial immunity in Nile tilapia by systematically improving T cell function. Specifically, during Edwardsiella piscicida infection, dietary MI increased the absolute number of T cells in Nile tilapia, and promoted their activation, proliferation, and cytokine production while reducing apoptosis. Mechanistically, MI elevated antioxidant enzymes expression to reduce intracellular reactive oxygen species (ROS) in T cells and drove fatty acid metabolic reprogramming. These coordinated enhancements collectively accelerated pathogen clearance and significantly improved host survival upon E. piscicida infection. Therefore, these findings reveal the pivotal role of dietary MI in promoting T cell mediated anti-bacterial immunity in Nile tilapia, and establish a foundation for using nutritional immunomodulation to improve health and disease resistance in farmed fish.
    Keywords:  Adaptive immunity; Feed additive; Myo-inositol; Nile tilapia; T cells
    DOI:  https://doi.org/10.1016/j.fsi.2026.111251
  6. Nat Immunol. 2026 Mar 05.
    Tissue-specific clonal selection and differentiation of CD4⁺ T cells during infection.
    Roham Parsa, Helder C Assis, Tiago B R de Castro, Gabriella Lima Dos Reis, Arpita Sushil, Harald Hartweger, Angelina M Bilate, Daniel Mucida.
      Pathogen-specific CD4⁺ T cells expand and contract during infection, generating memory clones that shape subsequent immune responses. How distinct tissue environments influence differentiation and clonal selection of polyclonal T cells remains unclear. Here we develop Tracking Recently Activated Cell Kinetics (TRACK) mice, a dual-recombinase fate-mapping system enabling the spatial and temporal labeling of recently activated CD4⁺ T cells. Using TRACK mice during influenza infection, we observed organ-specific transcriptional differentiation and clonal selection in lung, mediastinal lymph nodes (medLNs) and spleen. During the effector phase, spleen-derived CD4⁺ T cells adopted a stem-like migratory phenotype, whereas medLN-activated cells differentiated into T follicular helper cells. T cell receptor sequencing showed low clonal overlap between tissues during the effector response, consistent with distinct antigenic landscapes. During memory formation, overlap increased between lung- and medLN-derived cells, while splenic clones retained a distinct repertoire. These findings define tissue-dependent mechanisms that shape CD4⁺ T cell fate and clonal architecture.
    DOI:  https://doi.org/10.1038/s41590-026-02451-4
  7. Med. 2026 Feb 27. pii: S2666-6340(26)00034-6. [Epub ahead of print] 101031
    T cell exhaustion in bi- and trispecific T cell engager therapy in hematologic malignancies: Mechanisms and implications.
    Amelie Muth, Alessandra Holzem, Anne-Sophie Neumann, Veit L Buecklein, Marion Subklewe, Nora Philipp.
      T cell engagers (TCEs) have revolutionized the treatment of hematologic malignancies, with eight approved bispecific constructs and numerous bi- and trispecific TCEs currently in clinical trials. However, despite their clinical success, lack of response and high relapse rates remain major challenges. T cell exhaustion has emerged as an important mechanism of resistance to TCE therapy. Characterizing the T cell pool in patients prior to and during TCE therapy is warranted (1) to identify patients who will benefit most from TCE therapy and (2) to develop strategies to circumvent exhaustion during treatment to improve patient outcomes. We here review the current evidence of pre-existing and acquired T cell exhaustion during TCE therapy in patients with hematologic malignancies. We furthermore review state-of-the-art (pre)clinical strategies aimed at ameliorating exhaustion and reinvigorating T cell function.
    Keywords:  T cell exhaustion; T cell-based immunotherapy; bi- and trispecific T cell engagers; biomarkers; cereblon-modulating agents; checkpoint blockade; costimulation; epigenetic modulators; hematologic; malignancies; optimized administration schedules; tumor microenvironment; tyrosine kinase inhibitors
    DOI:  https://doi.org/10.1016/j.medj.2026.101031
  8. iScience. 2026 Mar 20. 29(3): 114859
    PCSK9-mediated degradation of cell-surface LDL receptors impairs human CD8+ T cell effector functions.
    Angela Markovska, Lara F Lommers, Alejandra Bodelón, Patrick Greve, Leonie C van Vark-van der Zee, Monique T Mulder, Jeanine E Roeters van Lennep, Noam Zelcer, Henk S Schipper, Marianne Boes.
      Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates circulating cholesterol levels by binding hepatic low-density lipoprotein (LDL) receptors (LDLRs) and directing them to lysosomal degradation. Beyond the liver, PCSK9 expression in multiple cancers, including colorectal, hepatocellular, and head and neck carcinomas, correlates with poor survival. We hypothesized that PCSK9 promotes LDLR degradation on CD8+ T cells, limiting cholesterol uptake and impairing antitumor immunity. Treatment of activated human CD8+ T cells from healthy donors with recombinant PCSK9 reduced surface LDLR and ICAM-1 expression, granzyme B secretion, and proliferation. The effects of PCSK9 treatment were reversed by PCSK9 inhibition or by culturing cells under lipoprotein-deprived conditions, confirming LDLR dependence. CD8+ T cells from patients with homozygous familial hypercholesterolemia, who harbor inactivating LDLR mutations, exhibited reduced proliferation and ICAM-1 expression upon activation. Together, these findings identify PCSK9 as a potential therapeutic target to enhance CD8+ T cell-mediated antitumor immunity.
    Keywords:  Cell biology; Immunology
    DOI:  https://doi.org/10.1016/j.isci.2026.114859
  9. Cancer Discov. 2026 Mar 02. OF1
    SLAMF6 Restrains T-Cell Function and Limits Antitumor Immunity.
      
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2026-028
  10. Cancer Cell. 2026 Mar 05. pii: S1535-6108(26)00107-8. [Epub ahead of print]
    Tumor-restraining fibroblasts emerge after chemotherapy specifically in responders.
    Krishnan K Mahadevan, Raghu Kalluri.
      In this issue of Cancer Cell, Ma et al. identify a neoadjuvant chemotherapy-induced population of PTGER3+ cancer-associated fibroblasts (CAFs) in patients with bladder cancer.1 These CAFs undergo lipid oxidation reprogramming and enhance CD8+ T cell function, facilitating tumor microenvironment remodeling and restraining tumor progression.
    DOI:  https://doi.org/10.1016/j.ccell.2026.02.009
  11. Cell Death Discov. 2026 Mar 06.
    ITK-targeted immune remodeling enhanced the efficacy of anti-CD19 CAR-T cell therapy.
    Zhenjun Li, Liangcheng Lv, Xiaoyu Yao, Zhiwei Feng, Yan Xie, Kecheng Li, Feifei Qi, Mei Yang, Jingwen Wang, Tao Pan, Xinghua Li, Haiyan Chen, Jing Wang, Yanping Ding, Jun Zhu, Yuqin Song, Xiaomin Wang, Ning Ding.
      Despite the promising efficacy of anti-CD19 CAR-T cells in treating B-cell lymphoma, T cell dysfunction and exhaustion remains a critical barrier to achieving durable responses. Based on the immunomodulatory effect in the clinical trial enrolled lymphoma patients, this study aims to explore the potential of the first in class highly selective ITK inhibitor soquelitinib in enhancing the persistence and antitumor functionality of CAR-T cells. We employed flow cytometric analysis to characterize T cell populations, RNA sequencing for gene expression profiling, and tumor bearing mice models to evaluate therapeutic efficacy. Our results demonstrated that the cytotoxic and anti-tumor activities of CAR-T cells were significantly increased post ITK inhibition treatment through elevation of cytotoxic and effector molecules, such as GZMB, TNF-α and IFN-γ. Meanwhile, soquelitinib promoted the expansion of CD8+ naïve and effector T cells while preventing exhaustion, as indicated by the downregulation of exhaustion markers such as TIM3, LAG3, and PD-1. Additionally, ITK inhibitor-treated CAR-T cells also exhibited increased cytotoxicity against malignant B cells and prolonged survival in tumor-bearing mice. Importantly, the modulation of transcription factors like TOX and TCF1 suggested a delay in T cell exhaustion and maintenance of effector functions. These findings provide a compelling rationale for the integration of clinical stage ITK inhibitor soquelitinib with CAR-T therapy, highlighting its potential to improve treatment outcomes in hematological malignancies and solid tumors.
    DOI:  https://doi.org/10.1038/s41420-026-03004-2
  12. Aging Cell. 2026 Mar;25(3): e70440
    Physical Fitness Dynamics Shape Immune Remodeling in Healthy Aging: A 3-Year Longitudinal Study.
    Christopher Weyh, Vincent Größer, Luciele Guerra Minuzzi, Torsten Frech, Kristina Gebhardt, Svenja Nolte, Theresa Dombrowski, Manuela Andrea Hoffmann, Natascha Sommer, Robert Ringseis, Klaus Eder, Samuel Sossalla, Pascal Bauer, Karsten Krüger.
      Aging is accompanied by functional decline and immune remodeling, yet the dynamics and early modifiability of these processes remain incompletely understood. Research suggests that lifestyle factors, particularly physical activity and fitness, influence immune aging. This study investigated longitudinal changes in physical performance and immune parameters in a well-characterized cohort of clinically healthy elderly. In this study, 49 clinically healthy elderly underwent repeated assessments of cardiorespiratory fitness, muscular strength, body composition, immune cell phenotypes, and serum cytokines at baseline, 1-year, and 3-year follow-up. We observed a shift toward an aged T cell profile, characterized by reductions in naïve and regulatory T cells (Tregs), alongside increases in differentiated and senescence-associated subsets. Treg subsets followed divergent trajectories, with resting Tregs (rTregs) declining and memory-like Tregs (mTregs) increasing. Serum levels of classical pro-inflammatory cytokines remained largely stable over the study period. Despite stable self-reported physical activity, participants showed declines in cardiorespiratory fitness and strength. Immune remodeling was primarily associated with declines in physical fitness, alongside an increase in highly differentiated CD4+ and senescent CD8+ T cell subsets, lower rTregs, higher mTregs, and increased CD4-CD8- lymphocyte frequencies, while habitual physical activity was independently related to effector T cell dynamics. Together, these findings indicate that subtle functional decline in clinically healthy older adults is paralleled by immune changes characteristic of early immunosenescence, occurring largely in the absence of overt systemic inflammation. These results highlight physical fitness as a potentially modifiable determinant of immune trajectories and immune resilience in healthy aging.
    Keywords:  T cells; healthy aging; immune aging; physical fitness
    DOI:  https://doi.org/10.1111/acel.70440
  13. Cell Mol Life Sci. 2026 Mar 04.
    The scramblase anoctamin 9 controls the immune response in lymphocytes.
    Rainer Schreiber, Jiraporn Ousingsawat, Karl Kunzelmann.
      
    Keywords:  ANO9; Anoctamin 9; Orai1; PMCA; T cells; T lymphocytes; TMEM16J; calcium signaling; immune response
    DOI:  https://doi.org/10.1007/s00018-026-06149-6
  14. J Cell Mol Med. 2026 Mar;30(5): e71069
    Immune Microenvironment Dynamics and Therapeutic Targets in GIST Revealed by Multi-Omics and Functional Validation.
    Xingyuan Li, Jun Xiang, Zewen Chang, Qingchao Tang.
      The tumour immune microenvironment (TIME) significantly influences the progression and treatment response of gastrointestinal stromal tumours (GIST), but the causal mechanisms and therapeutic targets remain incompletely understood. We integrated multi-omics analyses, including Mendelian randomization analysis of 731 immune cell phenotypes to assess their causal relationship with GIST, mediation analysis to identify plasma metabolite mediators, single-cell RNA sequencing (scRNA-seq) to characterise TIME heterogeneity and bulk RNA-seq to screen for differentially expressed genes. Using the GIST-882 cell and CD8+ T cell co-culture model, combined with functional assays such as proliferation, migration, invasion and protein uptake tracing, we validated the roles of candidate genes MYBL1 and AIF1L. Additionally, we evaluated their combined effects with PD-1 inhibitors. Mendelian randomization analysis identified 18 immune cell phenotypes with causal relationships to GIST (10 risk factors and 8 protective factors) and 4 mediating plasma metabolites. scRNA-seq revealed dynamic remodelling of the TIME. We identified genes that progressively increased or decreased from peritumoral tissues to primary tumours and metastatic tumours, and were positively correlated with PD-1 expression. The inhibitory effects of these genes on GIST malignant phenotypes were dependent on CD8+ T cells, and their proteins were taken up by T cells. Knockdown of MYBL1 or overexpression of AIF1L exhibited synergistic anti-tumour effects when combined with PD-1 blockade. Mendelian randomization analysis identified 18 immune cell phenotypes with causal relationships to GIST (10 risk factors and 8 protective factors) and 4 mediating plasma metabolites. scRNA-seq revealed dynamic remodelling of the TIME. We identified genes that progressively increased or decreased from peritumoral tissues to primary tumours and metastatic tumours, and were positively correlated with PD-1 expression. The inhibitory effects of these genes on GIST malignant phenotypes were dependent on CD8+ T cells, and their proteins were taken up by T cells. Knockdown of MYBL1 or overexpression of AIF1L exhibited synergistic anti-tumour effects when combined with PD-1 blockade. This study investigates changes in the immune microenvironment during GIST progression and identifies MYBL1 and AIF1L as key mediators regulating CD8+ T cell function and PD-1 response, providing new strategies for combined immunotherapy in GIST.
    Keywords:  gastrointestinal stromal tumour; immune cells; immune microenvironment; mendelian randomization; risk factors
    DOI:  https://doi.org/10.1111/jcmm.71069
  15. Front Cell Dev Biol. 2026 ;14 1745201
    Hepatic mitochondrial signaling as a systemic hub: inter-organ communication networks in aging and aging-related diseases.
    Yishuo Ji, Ying Wang, Xiaowei Yu, Yi Jin, Kai Zhao, Yue Hu, Zhenglin He.
      Aging and aging-related diseases are increasingly viewed as systemic disorders arising from disrupted inter-organ communication, yet the mechanisms linking local metabolic stress to organism-wide dysfunction remain unclear. The liver occupies a central position in this network, but how hepatic mitochondrial stress is translated into circulating signals that remodel distant tissues is incompletely understood. Here, we synthesize evidence identifying hepatic mitochondria as a systemic signaling hub that integrates metabolic and inflammatory stress and disseminates blood-borne cues during aging. We focus on three major classes of mitochondrial outputs: UPRmt-driven mitokines, including fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15); metabolites generated through mitochondrial metabolic reprogramming; and mitochondrial danger signals such as mitochondrial reactive oxygen species (mtROS) and oxidized mitochondrial DNA (mtDNA). These signals act through endocrine, metabolic, and immune pathways to reshape mitochondrial function, inflammation, and energy homeostasis across multiple organs. We further discuss how aging shifts hepatic mitochondrial signaling from adaptive to maladaptive states and emphasize that liver-centered regulation operates within bidirectional networks involving the gut, skeletal muscle, and immune system. Finally, we outline translational challenges and potential strategies for modulating hepatic mitochondrial outputs to restore systemic homeostasis in aging and aging-related diseases.
    Keywords:  UPRmt; aging; diseases; hepatic mitochondria; inter-organ communication; mitokines; mtDNA; mtROS
    DOI:  https://doi.org/10.3389/fcell.2026.1745201
  16. Biogerontology. 2026 Mar 02. pii: 67. [Epub ahead of print]27(2):
    Erzhi pills: a potential aging-modulating agent targeting immunosenescence in mice.
    Zhirui Fang, Wei Sun, Na Li, Tingting Shi, Xiuyun Ren, Rui Zhang, Yujing Zhang, Jing Chen, Qi Liu, Meng Wang, Lu Chen, Hong Wang.
      Erzhi Pills (EZP), a traditional Chinese herbal formula, has demonstrated potential aging-modulating properties, while its mechanisms in modulating immunosenescence remain incompletely understood. Two complementary aging murine models were employed to investigate the anti-immunosenescence efficacy of EZP, providing experimental validation for its translational application in delaying age-related immune decline. Morphological and physiological parameters were monitored and thymic/splenic organ coefficients were calculated. Histopathological evaluation of thymic involution was performed via hematoxylin-eosin (H&E) staining. Flow cytometry quantified splenic T cell subsets (naïve/memory CD4+ and CD8+ T cells). Reverse transcription quantitative PCR (RT-qPCR) analyzed mRNA expression of key immunosenescence markers (Lin28a, GDF-11, Sirt1, IL-2, IL-17), while enzyme-linked immunosorbent assay (ELISA) measured serum levels of pro-inflammatory cytokines (TNF-α, IFN-γ). Metabolomic profiling further elucidated EZP's bioactive pathways. EZP administration significantly attenuated age-related degeneration in both murine models by restoring thymic and splenic architecture, as evidenced by increased organ coefficients and reduced histopathological damage. EZP rebalanced T cell homeostasis through selective expansion of naïve T cells and contraction of memory T cell subsets, with a pronounced increase in CD8+ T cell populations. At the molecular level, EZP upregulated Lin28a, Sirt1, and IL-2 expression while modulating systemic cytokine profiles-reducing TNF-α and augmenting IFN-γ in the natural aging cohort. These findings suggest EZP mitigates chronic inflammatory aging and enhances immune responsiveness of effector T cells. EZP's anti-aging mechanism was mediated by fatty acid metabolism modulation. This study provides evidence supporting EZP's potential as a novel therapeutic strategy for immunosenescence and warrants further investigation into its clinical translation for geriatric populations.
    Keywords:  Erzhi Pills; Immune senescence; Immunometabolic regulation; T cells
    DOI:  https://doi.org/10.1007/s10522-026-10387-3
  17. Pharmacol Res. 2026 Feb 27. pii: S1043-6618(26)00069-1. [Epub ahead of print] 108154
    Fenofibrate targets PPARα-CPT1C axis to reverse aging by regulating lipid metabolism and mitochondrial function.
    Yanying Zhou, Yixin Chen, Linlin Zhu, Huilin Li, Yue Gao, Tu Xian, Pengfei Zhao, Shicheng Fan, Núria Casals, Min Huang, Huichang Bi.
      Aging poses a growing global health burden, creating an urgent need for effective interventions. This study reveals that fenofibrate, a clinically approved drug for hyperlipidemia, exerts significant anti-aging effects by targeting fundamental aging processes. We demonstrated that fenofibrate treatment delays systemic aging in D galactose-induced aging mice, 18-month-old mice and SAMP8 mice and reverses cellular senescence. Mechanistically, fenofibrate ameliorates age-related lipid accumulation, as evidenced by lipidomic profiling and histological analyses in both cellular and animal models. Notably, we identify carnitine palmitoyl transferase 1C (CPT1C) as a crucial mediator of fenofibrate's ability to restore mitochondrial function in senescent cells, as validated by comprehensive metabolic analyses. Fenofibrate is a specific peroxisome proliferator activated receptor α (PPARα) agonist. These effects are mediated through PPARα activation, upregulating downstream metabolic regulators CPT1C. Fenofibrate cannot reverse aging in Pparα-/- mice, establishing that its anti-aging effects are strictly PPARα-dependent. Our findings demonstrate that fenofibrate delays aging progression of mice and reverses cellular senescence in the PPARα-dependent way. Fenofibrate attenuates lipid accumulation and mitochondrial dysfunction in senescent cells and aged mice by activating the PPARα-CPT1C axis. This research provided the first evidence that pharmacological PPARα activation can directly modulate natural aging through coordinated improvement of lipid metabolism and mitochondrial function. The clinical relevance is underscored by the safety profile and widespread use of fenofibrate, suggesting its immediate potential as a repurposed anti-aging therapeutic. Furthermore, this work establishes PPARα as a master metabolic regulator of aging processes and reveals CPT1C as a novel therapeutic target for age-related metabolic dysfunction.
    Keywords:  Aging; Carnitine palmitoyl transferase 1C; Fenofibrate; Lipid accumulation; Mitochondrial metabolism; Peroxisome proliferator activated receptor α
    DOI:  https://doi.org/10.1016/j.phrs.2026.108154
  18. J Exp Clin Cancer Res. 2026 Mar 03.
    Tumor-targeted IL2 promotes specific CD8+ T cells private clonal expansion enhancing lymphoma control.
    T Virgilio, K Chahine, H Bansal, C Pizzichetti, L L Renner, A Capucetti, G Bilato, I Latino, D Morone, A Pulfer, P Ventura, F Mele, E Puca, D Mangani, C Junqueira, F Sallusto, D Neri, R De Luca, S F Gonzalez.
      
    Keywords:  CD8+ T cells; Diffuse large B cell lymphoma; IL2; Immunocytokine; Immunotherapy; Intravital microscopy
    DOI:  https://doi.org/10.1186/s13046-026-03678-7
  19. Cell. 2026 Feb 27. pii: S0092-8674(26)00115-7. [Epub ahead of print]
    Citrate clearance is a major function of aconitase 2 in the canonical TCA cycle.
    Abigail Xie, Julia S Brunner, Sangita Chakraborty, Angela M Montero, Anna E Bridgeman, Katrina I Paras, Ruobing Cui, Maider Fagoaga-Eugui, Monika Komza, Paige K Arnold, Benjamin T Jackson, Santiago Noriega Madrazo, Mohamed I Atmane, Sebastian E Carrasco, Lydia W S Finley.
      The tricarboxylic acid (TCA) cycle couples nutrient oxidation with the generation of reducing equivalents that power oxidative phosphorylation. Nevertheless, the requirement for components of the TCA cycle is context-specific, raising the question of which TCA cycle outputs support cell fitness. Here, we demonstrate that citrate clearance is an essential function of the TCA cycle. As citrate production increases, so do TCA cycle activity and dependence upon aconitase 2 (ACO2), the enzyme that initiates citrate catabolism in the TCA cycle. Disrupting citrate catabolism activates the integrated stress response and impairs cell fitness, and these effects are reversed by preventing citrate production or promoting mitochondrial citrate efflux. In vivo, ACO2 deficiency induces citrate accumulation and triggers tubular degeneration in the kidney, a tissue that physiologically takes up circulating citrate. Thus, intracellular citrate accumulation can be a metabolic liability, and citrate clearance is a major function of ACO2 in the TCA cycle.
    Keywords:  ACO2; TCA cycle; cell metabolism; citrate; integrated stress response
    DOI:  https://doi.org/10.1016/j.cell.2026.01.028
  20. Nat Aging. 2026 Mar 06.
    The glycolytic metabolite phosphoenolpyruvate restricts cGAS-driven inflammation to promote healthy aging.
    Zengqing Song, Huaibin Hu, Wanpeng Zhang, Xincheng Zheng, Liyun Liang, Bing Zhao, Guangping Song, Jianing Li, Sen Li, Yuqi Wen, Biyu Zhang, Wen Wang, Guozhen Deng, Cunjin Zhang, Hua Jiang, Supei Hu, Haiqing Tu, Min Wu, Huiyan Li.
      Aging involves multiple detrimental changes in the systemic milieu, leading to functional deterioration and age-related diseases. However, the potential self-protective adaptive alterations during aging remain underexplored. Here we show that phosphoenolpyruvate (PEP), a glycolytic metabolite, acts as a protective factor against age-related chronic inflammation. Longitudinal analyses in mice and humans reveal a biphasic PEP trajectory, characterized by initial accumulation followed by progressive decline. Blocking PEP accumulation exacerbates inflammation and accelerates aging phenotypes, whereas PEP administration before its decline promotes healthy aging in mice. In aged humans, high PEP levels strongly correlate with lower inflammation and healthier traits. Mechanistically, PEP acts as an endogenous inhibitor of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway by competitively binding to cGAS. Moreover, PEP alleviates neuroinflammation and improves cognitive function in an Alzheimer's disease mouse model. Thus, our findings define PEP accumulation as an evolutionarily conserved geroprotective mechanism, positioning PEP as a promising intervention for aging and associated diseases.
    DOI:  https://doi.org/10.1038/s43587-026-01087-1
  21. Nat Metab. 2026 Mar 04.
    Extracellular CD44 lactylation impairs CD8+ T cell function in KRAS-mutant colorectal cancer.
    Yun Yang, Yong Wu, Xin Guo, Wen-Juan Gan, Wen-Xin Wu, Wei-Yi Shi, Xiao-Shun He, Yi-Xuan Liu, Shan Wan, Zhi Jiang, Yue Liu, Xiu-Ming Li, Zu-Da Pan, Xue Zhang, You Xu, Xiao-Jiao Gao, Ling-Chuan Guo, Guideng Li, Hua Wu.
      
    DOI:  https://doi.org/10.1038/s42255-026-01482-3
  22. Biomed Pharmacother. 2026 Feb 27. pii: S0753-3322(26)00202-7. [Epub ahead of print]197 119169
    Human VH-antibody-based CAR T cells targeting folate receptor-alpha show enhanced persistence and reduced T-cell exhaustion against ovarian cancer.
    Nithidol Sakunrangsit, Kannika Khantasup, Natapol Pornputtipong, Koramit Suppipat, Nattiya Hirankarn, Supannikar Tawinwung.
       BACKGROUND: Folate receptor-alpha (FOLR1) is highly expressed in ovarian cancer and correlates with poor clinical outcomes, making it an attractive target for adoptive cell therapy. Single-domain antibodies (VH domains) have gained increasing interest as antigen-binding domains for CAR T-cell engineering.
    METHODS: We generated a second-generation FOLR1-specific CAR incorporating a fully human VH-only antibody and compared its in vitro functional activity with a MOv19-derived scFV CAR. CAR expression, memory phenotype, cytotoxicity, cytokine secretion, and exhaustion markers were evaluated following antigen stimulation. Antitumor efficacy was further assessed in 3D spheroids and repeated tumor-rechallenge assays.
    RESULTS: Both VH-based and scFV-based FOLR1 CAR T cells demonstrated potent and antigen-specific cytotoxicity against FOLR1-positive ovarian cancer cells. Intriguingly, FOLR1-VH CAR T cells showed lower activation and cytokine release upon initial stimulation, accompanied by reduced expression of exhaustion markers including PD-1 and LAG-3. FOLR1-VH CAR T cells preferentially preserved a central-memory phenotype and displayed superior persistence and tumor control during multiple rounds of antigen rechallenge. Both CAR formats achieved comparable cytotoxicity in 3D spheroid models.
    CONCLUSION: Human FOLR1-VH CAR T cells demonstrated potent antitumor activity with reduced exhaustion and enhanced persistence. These properties highlight the VH domain as a promising targeting module for next-generation CAR T-cell therapies in ovarian cancer.
    Keywords:  Chimeric antigen receptor; Folate receptor alpha; Ovarian cancer; V(H) domain antibody
    DOI:  https://doi.org/10.1016/j.biopha.2026.119169
  23. Proc Natl Acad Sci U S A. 2026 Mar 10. 123(10): e2525619123
    Gas-sensing neurons prime mitochondrial fitness to offset metabolic stress.
    Rebecca Cornell, Ava Handley, Roger Pocock.
      The mitochondrial unfolded protein response (UPRmt) is triggered by cells to alleviate proteotoxicity in response to metabolic stress. The ability to anticipate and prime cells against mitochondrial stress, by sensing potentially toxic changes in the external or internal environment, would provide a survival advantage. Yet, whether and how animals anticipate mitochondrial stress remains unclear. Here, we show that the Caenorhabditis elegans receptor guanylyl cyclase GCY-9 regulates neuropeptide signaling from carbon dioxide-sensing neurons to govern a noncanonical mitochondrial stress response in the intestine. This noncell autonomous stress response induces atypical mitochondrial chaperone transcription, confers mitochondrial stress resistance, and increases mitochondrial membrane potential and respiration. We show that starvation decreases GCY-9 expression and propose that the resultant cytoprotective program is launched to offset metabolic and proteotoxic risks. Thus, environmental sensing by peripheral neurons can preemptively enhance systemic mitochondrial function in response to metabolic uncertainty.
    Keywords:  Caenorhabditis elegans; gas-sensing; mitochondrial stress; neuropeptide
    DOI:  https://doi.org/10.1073/pnas.2525619123
  24. Nat Cancer. 2026 Mar 03.
    Regional delivery of hypoxia-responsive CAR T cells improves efficacy for solid tumors.
      
    DOI:  https://doi.org/10.1038/s43018-026-01129-y
  25. Andrology. 2026 Mar 03. e70200
    T Cell Microenvironmental Impacts and Therapeutic Opportunities: Application to Human Testicular Germ Cell Tumors.
    R Islam, M Figura, J Heyer, S Lieber, M Huber, K L Loveland, H C Schuppe, Daniela Fietz.
      Testicular germ cell tumors (TGCT) are the leading malignancy in adolescent and young adult males, yet the immunological and cellular mechanisms governing their tumor microenvironment (TME) remain poorly understood. Here, we present a comprehensive review of TGCT pathobiology with a focus on the immune landscape, particularly the role of tumor-infiltrating T lymphocytes. The mammalian testis represents an immune-privileged organ maintained by the coordinated actions of somatic cells (Sertoli and Leydig cells) and resident immune populations that collectively foster immune tolerance and suppress deleterious inflammatory responses. Immune privilege is disrupted in TGCT, resulting in significant alterations in the composition and function of immune cell subsets such as macrophages, mast cells, dendritic cells, and especially T cells. The phenotypic diversity and functional adaptability of CD4+ T cell subsets (Th1, Th2, Th9, Th17, Th22, Treg, and Tfh) along with CD8+ T cell subsets (Tc1, Tc2, Tc9, Tc17, and Tc22) are critically evaluated in terms of their roles in anti-tumor immune responses, modulating immune regulation, and enabling tumor immune evasion within the TME of TGCT. Despite the success of immunotherapies such as immune checkpoint inhibitors targeting PD-1/PD-L1 and CTLA4, and emerging CAR-T cell strategies in other malignancies, their efficacy in TGCT is limited due to the unique testicular immune milieu and limited understanding of T cell dynamics in TME. Recent advances in single-cell transcriptomics and clinical studies highlight the necessity for high-resolution characterization of T cell subpopulations and their intercellular interactions within the TGCT TME. Elucidating these mechanisms is critical for the rational development of novel immunotherapeutic strategies aimed at overcoming resistance, minimizing long-term treatment-related sequelae, and enhancing clinical outcomes for TGCT patients.
    Keywords:  T lymphocytes; immunotherapy; testicular germ cell tumor; testicular immune cells; tumor microenvironment
    DOI:  https://doi.org/10.1111/andr.70200
  26. J Control Release. 2026 Mar 02. pii: S0168-3659(26)00180-X. [Epub ahead of print] 114778
    Nanoassembly-mediated immunometabolic reprogramming of CD4+ T cells suppresses β-cell autoimmunity in type 1 diabetes.
    Xixi Nan, Shuotong Zhang, Xinyue Chu, Simiao Chen, Xinge Zhang, Zhongming Wu.
      The pathogenesis of type 1 diabetes mellitus (T1DM), known as autoimmune diabetes, is thought to be mediated by T cell-driven destruction of β cells, with the hyperactivation of CD4+ T cells playing a central role by triggering increased T helper (Th)1 and Th17 differentiation and impaired regulatory T (Treg) cell function. Herein, we constructed a nanoassembly (aNAJPH) capable of regulating immunometabolic reprogramming of activated CD4+ T cells, thereby suppressing β-cell autoimmunity in T1DM. The anti-CD154-F(ab')2 fragments on the surface of aNAJPH blocked the essential secondary costimulatory signal required for the pathogenic response, while the encapsulated L-type amino acid transporter 1 inhibitor suppressed the hyperactive metabolic pathways in activated CD4+ T cells. This synergistic mechanism achieved a specific reduction in the frequency of pathogenic CD4+ T cells and restoration of immune homeostasis by redirecting their differentiation away from pro-inflammatory Th1/Th17 lineages and toward protective Treg lineage. Through this effect, it ultimately reduced CD4+ T cell infiltration into pancreatic islets, preserved islet architecture, maintained blood glucose homeostasis, and lowered systemic inflammatory cytokine levels. This work presents a synergistic immunometabolic targeting strategy to restore immune homeostasis and suppress β-cell autoimmunity, offering a precision framework for treating a broader range of autoimmune diseases.
    Keywords:  CD4(+) T cell; Immunometabolic reprogramming; Precise targeting; Type 1 diabetes mellitus
    DOI:  https://doi.org/10.1016/j.jconrel.2026.114778
  27. Mol Ther Oncol. 2026 Mar 19. 34(1): 201149
    CD2 costimulation breaks the CD28 vs. 4-1BB tradeoff in CAR T cells.
    Avery D Posey.
      
    DOI:  https://doi.org/10.1016/j.omton.2026.201149
  28. Nat Commun. 2026 Mar 06.
    The natural flavonoid dihydromyricetin targets senescent cells via PRDX2 and alleviates age-related diseases.
    Qixia Xu, Gaoxiang Li, Hongwei Zhang, Zhirui Jiang, Xiuxia Gao, Zi Li, Larissa G P Langhi Prata, James L Kirkland, Guilong Zhang, Yu Sun.
      Aging is a primary risk factor for chronic diseases, with cellular senescence as an effective target to delay, prevent or alleviate age-related disorders. Here we report in vitro screening outputs from a natural medicinal agent library, wherein dihydromyricetin, a natural flavonoid, showed senotherapeutic potential. Dihydromyricetin protects senescent fibroblasts against further DNA damage and attenuates the senescence-associated secretory phenotype, acting as a senomorphic agent. Proteomics suggests that dihydromyricetin promotes nuclear translocation of peroxiredoxin 2 (PRDX2) to facilitate DNA repair in senescent cells. In prematurely aged mice, dihydromyricetin administration mitigates tissue aging and age-related physiological decline. In anticancer regimens, dihydromyricetin improves outcomes of chemotherapy. However, dihydromyricetin demonstrates senolytic activity against senescent microglial cells, whose basal PRDX2 expression remains low, by impairing mitochondrial function to promote apoptosis. In mice developing Alzheimer's disease, dihydromyricetin eliminates senescent microglial cells from amyloid β-protein plaques and alleviates neurodegenerative symptoms. Together, our study proposes dihydromyricetin as a natural senotherapeutic agent for mitigating age-related morbidities, including but not limited to cancers and Alzheimer's disease.
    DOI:  https://doi.org/10.1038/s41467-026-70302-9
  29. JAAD Case Rep. 2026 Mar;69 5
    Mogamulizumab-induced drug eruption during multiagent chemotherapy: A possible CD8+ T cell-mediated mechanism.
    Sakiho Inayoshi, Kazunari Sugita.
      
    DOI:  https://doi.org/10.1016/j.jdcr.2026.01.014
  30. Blood. 2026 Mar 02. pii: blood.2025031332. [Epub ahead of print]
    CDK8/CDK19 inhibition restores T-cell homeostasis in primary immune thrombocytopenia.
    Yan-Ming Wang, Hu Zhou, Shaoqiu Leng, Jun-Jie Ma, Huiyuan Yuan Li, Guosheng Li, Tao Sun, Yitong Xu, Shouqing Han, Yufeng Gu, Lin Dong, Zhenyu Yan, Lei Zhang, Jun Peng, Xin-Guang Liu.
      CD4+CD25+Foxp3+ regulatory T cells (Tregs) are pivotal negative regulators of the adaptive immune system. Abnormalities in the number and/or function of Tregs contribute to the pathogenesis of primary immune thrombocytopenia (ITP). Strategies aimed at modulating Tregs offer potential therapeutic opportunities for ITP management. In this study, we demonstrated that inhibition of cyclin-dependent kinase 8 (CDK8) and CDK19 activity by the small-molecule inhibitor AS2863619 (AS) robustly promoted the conversion of CD4+CD25- effector T cells (Teffs) into CD4+CD25+Foxp3+ Tregs, endowing the converted Tregs with lineage stability and potent suppressive capacity. Mechanistically, AS rapidly augmented STAT5 phosphorylation and subsequent Foxp3 induction. STAT5 blockade completely abrogated this effect, confirming that the Treg-promoting activity of AS was critically dependent on STAT5 signaling. In parallel, AS suppressed STAT3 phosphorylation under IL-6-driven conditions, thereby attenuating Th17 polarization. These mechanistic findings were supported by global transcriptomic analysis, which revealed a profound transcriptional shift by broadly suppressing gene programs of Teff differentiation and function while simultaneously upregulating a robust signature characteristic of stable Tregs. Crucially, unbiased upstream analysis of these changes pinpointed STAT5, STAT3, and FOXP3 as the core transcription factors mediating the drug's effect. Functional metabolic analysis further revealed that AS mediated metabolic reprogramming in T cells by suppressing glycolysis, thereby providing the necessary metabolic adaptations for Treg conversion. In a murine model of active ITP, CDK8/CDK19 inhibition elevated Treg frequencies and ameliorated thrombocytopenia in a STAT5-dependent manner. Collectively, our study highlighted the therapeutic potential of CDK8/CDK19 inhibition in restoring immune homeostasis and managing ITP.
    DOI:  https://doi.org/10.1182/blood.2025031332
  31. J Transl Med. 2026 Feb 28.
    Targeting metabolic reprogramming to enhance adoptive immunotherapy: emerging mechanisms and translational perspectives.
    Liu Yang, Chengyu Zhang, Zhongxiang Zhang, Songlin Yao, Jing Shen, Zhuo Zhang, Zhangang Xiao, Shurong Wang, Zhigui Wu.
      
    Keywords:  Adoptive cell therapy; Immune cell metabolism; Immune responses; Metabolic reprogramming; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s12967-026-07887-8
  32. Clin Immunol. 2026 Feb 27. pii: S1521-6616(26)00025-2. [Epub ahead of print]285 110687
    ADAM9 supports regulatory T cell stability through TGF-β-SMAD signaling and is reduced in systemic lupus erythematosus.
    Theodoros Vichos, Wei Li, Kohei Karino, Limor Rubin, Maria G Tsokos, Wenliang Pan, George C Tsokos.
       BACKGROUND: A Disintegrin and Metalloproteinase 9 (ADAM9) has been implicated in Th17 cell differentiation by activating TGF-β. Given the essential role of TGF-β in maintaining regulatory T (Treg) cell lineage, we hypothesized that ADAM9 supports Treg cell function.
    METHODS: We assessed the expression of ADAM9 on the surface membrane of human T cell subsets from patients with systemic lupus erythematosus (SLE) and matched healthy controls by flow cytometry. The effect of ADAM9 deletion on Treg cell function was evaluated using in vitro suppression assays, phospho-SMAD2/3 detection, and an in vivo adoptive-transfer colitis model.
    RESULTS: Treg cells exhibited the highest frequency of surface ADAM9+ cells among peripheral T cell subsets. Treg cells, but not other T cell subsets, from SLE patients displayed significantly reduced numbers of ADAM9+ cells compared with healthy controls. Although ADAM9-deficient murine Treg cells suppressed effector T cell proliferation in vitro at levels comparable to those of ADAM9-suficient cells, they demonstrated decreased SMAD2/3 phosphorylation and failed to effectively suppress the ability of CD45RBhi T cells to cause colitis when co-injected in immunodeficient Rag1-/- mice.
    CONCLUSION: ADAM9 promotes Treg cell stability and suppressive function in vivo by sustaining TGF-β-SMAD signaling. Reduced ADAM9 expression in SLE Treg cells signifies a potential mechanism contributing to Treg cell dysfunction.
    Keywords:  ADAM9; Autoimmunity; Colitis model; FoxP3; Regulatory T cells; SLE; TGF-β
    DOI:  https://doi.org/10.1016/j.clim.2026.110687
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