bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2025–09–14
seventeen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Targeting IL-6 receptor mediated metabolic pathways to control Th17 cell differentiation and inflammatory responses.
  2. Oxidative-stress-induced telomere instability drives T cell dysfunction in cancer.
  3. Beneficial effect of resveratrol on T cell oxidative metabolism and anti-tumor function is conditioned by prior in vivo T cell history.
  4. Autoimmune disease risk gene ANKRD55 promotes TH17 effector function through metabolic modulation.
  5. The Immune System and Cellular Senescence: A Complex Interplay in Aging and Disease.
  6. CD160+CD8+ T cells for improved immunotherapy.
  7. TOX-induced lnc-SUMF2-8 compromises antitumor function and anti-PD-1 response of CD8+ T cells via lysosome-dependent degradation of TCF-1.
  8. Aberrant Nutrient Metabolism in T Cells: Pathogenesis Insight and Therapeutic Target for Autoimmune Diseases.
  9. mTOR activity and metabolic reprogramming of CD8+ T cells is impaired under hypoxia and within the multiple myeloma bone marrow.
  10. Metabolic control of innate-like T cells.
  11. Metabolites as regulators of autoimmune diseases.
  12. CD160 dictates anti-PD-1 immunotherapy resistance by regulating CD8+ T cell exhaustion in colorectal cancer.
  13. Dendritic cells: understanding ontogeny, subsets, functions, and their clinical applications.
  14. SIRT2 and NAD+ Boosting Broadly Suppress Aging-Associated Inflammation.
  15. TIM-3 ameliorates host responses to Salmonella infection by controlling iron driven CD4+ T cell differentiation and interleukin-10 formation.
  16. Platelet Factor 4 (PF4) Regulates Hematopoietic Stem Cell Aging.
  17. Integrating Metabolic Modulation and Nanomedicine for Cancer Immunotherapy.
  1. Front Immunol. 2025 ;16 1568514
    Targeting IL-6 receptor mediated metabolic pathways to control Th17 cell differentiation and inflammatory responses.
    Yazan Alwarawrah, Amanda G Nichols, Isha Patel, Andréa B Ball, Nancie J MacIver.
      Interleukin-6 (IL-6) is a multifunctional cytokine that plays important roles in inflammation. Several studies have shown that IL-6 regulates various aspects of T cell function, including the differentiation of CD4+ T cells into the pro-inflammatory Th17 subset. Given the tight link between T cell metabolism and function, and the role of IL-6 in regulating cellular metabolism across tissues, we investigated the role of IL-6 signaling in Th17 cell metabolism. Using T cell specific IL-6 receptor (IL-6R) conditional knockout mice and littermate controls, we found that IL-6R signaling regulates the proportions of CD4+ and CD8+ T cells and drives CD4+ T cell differentiation into Th17 cells. We also found that IL-6R signaling is required for Th17 cell glycolytic metabolism. In T cell-specific IL-6R knockout mice, Th17 cells had reduced glucose uptake and glycolysis, as well as decreased expression of key glycolytic enzymes, while showing increased basal oxygen consumption. However, we also found that IL-6R signaling enhanced oxidative capacity and mitochondrial coupling efficiency in Th17 T cells. Importantly, inhibition of lactate dehydrogenase using FX11 selectively impaired Th17 cell differentiation with minimal effects on Treg cells. These findings suggest that targeting metabolic pathways regulated by IL-6R signaling can selectively inhibit inflammatory Th17 responses, offering a potential strategy for controlling IL-6 mediated inflammation.
    Keywords:  T cells; Th17; cellular metabolism; glycolysis; immunometabolism; inflammation; interleukin-6 (IL-6)
    DOI:  https://doi.org/10.3389/fimmu.2025.1568514
  2. Immunity. 2025 Sep 03. pii: S1074-7613(25)00371-1. [Epub ahead of print]
    Oxidative-stress-induced telomere instability drives T cell dysfunction in cancer.
    Dayana B Rivadeneira, Sanjana Thosar, Kevin Quann, William G Gunn, Victoria G Dean, Bingxian Xie, Angelina Parise, Andrew C McGovern, Kellie Spahr, Konstantinos Lontos, Ryan P Barnes, Marcel P Bruchez, Patricia L Opresko, Greg M Delgoffe.
      The tumor microenvironment (TME) imposes immunologic and metabolic stresses sufficient to deviate immune cell differentiation into dysfunctional states. Oxidative stress originating in the mitochondria can induce DNA damage, most notably telomeres. Here, we show that dysfunctional T cells in cancer did not harbor short telomeres indicative of replicative senescence but rather harbored damaged telomeres, which we hypothesized arose from oxidative stress. Chemo-optogenetic induction of highly localized mitochondrial or telomeric reactive oxygen species (ROS) using a photosensitizer caused the accumulation of DNA damage at telomeres, driving telomere fragility. Telomeric damage was sufficient to drive a dysfunctional state in T cells, showing a diminished capability for cytokine production. Localizing the ROS scavenger GPX1 directly to telomeres reduced telomere fragility in tumors and improved the function of therapeutic T cells. Protecting telomeres through expression of a telomere-targeted antioxidant may preserve T cell function in the TME and drive superior responses to cell therapies.
    Keywords:  DNA damage; ROS; T cell dysfunction; adoptive cell therapy; mitochondria; telomere; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.immuni.2025.08.008
  3. Mol Ther Methods Clin Dev. 2025 Sep 11. 33(3): 101553
    Beneficial effect of resveratrol on T cell oxidative metabolism and anti-tumor function is conditioned by prior in vivo T cell history.
    Patricia Mercier-Letondal, Chrystel Marton, Bernard Royer, Paul Peixoto, Barbara Dehecq, Olivier Adotévi, Jeanne Galaine, Yann Godet.
      Despite the clinical success of redirected T cells in the setting of cancer adoptive cell immunotherapy, patients may exhibit resistance to treatment, resulting in uncontrolled disease and relapses. This phenomenon partly relies on impaired ex vivo-produced T cell metabolic fitness, including a decreased respiratory reserve, as well as a greater sensitivity to tumor-mediated metabolic stress. To improve the respiratory capacity of cultured T cells, we sought to target the nicotinamide adenine dinucleotide/sirtuine-1/reactive oxygen species (ROS) axis through supplementation of culture medium with resveratrol. Resveratrol-treated T cells display broader respiratory capacities, along with sustained ROS control ability. Strikingly, we reveal that the effect of resveratrol on T cells is restricted to cytomegalovirus (CMV)-exposed donors, a virus known to promote immune aging. Herein, CMV prior infection is associated with the influence of terminally differentiated T cells on the fate of companion T cell subsets. Moreover, beyond resveratrol's effect on redirected T cell metabolic features, it provides a functional anti-tumor advantage to these CMV-seropositive donor-derived T cells, in a third-generation CD123-specific chimeric antigen receptor-T cell in vitro model. This highlights the necessity to consider patient's intrinsic attributes, especially immune aging-related ones, when assessing new T cell production processes to improve clinical efficacy, pushing the limits of personalized medicine.
    Keywords:  T cell differentiation profile; T cell fitness; T cell metabolism; adoptive immunotherapy; cytomegalovirus; immune aging; nicotinamide adenine dinucleotide; redirected T cells; resveratrol
    DOI:  https://doi.org/10.1016/j.omtm.2025.101553
  4. J Exp Med. 2025 Nov 03. pii: e20250185. [Epub ahead of print]222(11):
    Autoimmune disease risk gene ANKRD55 promotes TH17 effector function through metabolic modulation.
    Jinjin Xu, Lingjia Kong, Elizabeth A Creasey, Sneha Rath, Lei Deng, Julian Avila-Pacheco, Chenhao Li, Blayne A Oliver, Tyler T Dao, Angela R Shih, Mark J Daly, Alex K Shalek, Clary B Clish, Daniel B Graham, Jacques Deguine, Ramnik J Xavier.
      Genome-wide association studies (GWAS) have linked the locus encoding ankyrin repeat domain 55 (ANKRD55) with numerous autoimmune diseases; however, its biological function and role in inflammation are unclear. Here, we demonstrate that Ankrd55-deficient mice are protected from T cell-mediated colitis but are more susceptible to Citrobacter rodentium infection. Mechanistically, Ankrd55 deletion impairs CD4+ T cell proliferation and reduces effector cytokine production in T helper 17 (TH17) cells in a cell-intrinsic manner. ANKRD55 is associated with mitochondria, and its loss is associated with impaired mitochondrial respiration and activation of the LKB1 pathway. Consistently, IL-17 production can be rescued by the deletion of LKB1 in Ankrd55-deficient T cells. Altogether, our study implicates the protein ANKRD55 as a functional modulator of T cell metabolism that directly impacts TH17 responses, highlighting it as a potential target across multiple autoimmune diseases.
    DOI:  https://doi.org/10.1084/jem.20250185
  5. Immunology. 2025 Sep 12.
    The Immune System and Cellular Senescence: A Complex Interplay in Aging and Disease.
    Marc Ayoub, Chris Abou Jaoude, Mohamad Ayoub, Aline Hamade, Mohamad Rima.
      Immunosenescence is the process of immune dysfunction and gradual deterioration of the immune system associated with aging, while cellular senescence is the stable cell cycle arrest that can occur in non-immune or immune cells in response to stress or damage. Immunosenescence significantly impacts both the innate and adaptive immune responses and is characterised by physical changes in lymphoid organs, as well as dysfunctions in cellular and molecular mechanisms. Key features of immunosenescence include T-cell dysfunction, thymic involution, B cell aging, an imbalance in the ratio of naïve to memory cells, chronic inflammation known as inflammaging and metabolic dysregulation. This decline in immune cell diversity and functionality contributes to various age-related diseases. Therefore, restoring a more 'juvenile' immune function in aging populations, through interventions targeting immunosenescence, holds promise for alleviating many age-related diseases and promoting healthier aging. In this review, we provide a comprehensive understanding of the interplay between the immune system and senescent cells in both healthy and disease contexts. We then dissect the immune dysfunction that occurs with aging, known as immunosenescence, and explore its impact on the health of elderly individuals. Finally, we discuss recent advances in targeting immune system aging to promote healthier longevity, with a special focus on Programmed Death-Ligand 1 (PD-L1), an emerging and promising target for therapeutic intervention.
    Keywords:  aging; chronic diseases; immune system; immunosenescence; inflammation; longevity
    DOI:  https://doi.org/10.1111/imm.70036
  6. Nat Cell Biol. 2025 Sep;27(9): 1389-1390
    CD160+CD8+ T cells for improved immunotherapy.
    Yi-Hao Wang, Stanislav Dergun, Ping-Chih Ho.
      
    DOI:  https://doi.org/10.1038/s41556-025-01756-0
  7. Mol Ther. 2025 Sep 10. pii: S1525-0016(25)00734-8. [Epub ahead of print]
    TOX-induced lnc-SUMF2-8 compromises antitumor function and anti-PD-1 response of CD8+ T cells via lysosome-dependent degradation of TCF-1.
    Pan Jiang, Dongming Chen, Jialin Chen, Junbin Wu, Yumin Zhong, Sijing Huang, Xiaoxin Mu, Xiaojie Lu, Xiaochen Wang.
      The reduction of TCF-1 during CD8+ T cell exhaustion leads to attenuated antitumor activity and diminished responsiveness to immune checkpoint inhibitors. However, how TCF-1 is downregulated remains unclear. Here, we showed that during CD8+ T cell exhaustion, lnc-SUMF2-8, induced by transcription factor TOX, can bind to cytosolic TCF-1, and direct it to the lysosome for degradation. The reduction of TCF-1 promotes Texprog differentiation into Texint/eff and further drives functional Tex cells into a fully dysfunctional Texterm state. We demonstrated that TCF-1 reduction during T cell exhaustion is initiated by lnc-SUMF2-8-dependent lysosomal degradation of TCF-1 protein, followed by transcriptional suppression of TCF7 mRNA. Deletion of lnc-SUMF2-8 blocks lysosomal TCF-1 degradation, which maintains stable TCF-1 levels in Tex cells, thereby expands the anti-PD-1-responsive Texprog cells, and enhances the persistence of functional CD8+ T cells. Our findings suggest targeting lnc-SUMF2-8 could enhance the anti-tumor CD8+ T-cells function and synergistically improve the efficacy of anti-PD-1 treatment and CAR-T cell therapies.
    DOI:  https://doi.org/10.1016/j.ymthe.2025.09.006
  8. Eur J Immunol. 2025 Sep;55(9): e70059
    Aberrant Nutrient Metabolism in T Cells: Pathogenesis Insight and Therapeutic Target for Autoimmune Diseases.
    Shumei Cao, Jiao Jiang, Haoyuan Yin, Xiaoyu Su, Qilin Li, Junhui Wu, Wenrui Li, Lai Wang, Qianjin Lu.
      Abnormal T-cell activation and differentiation are pivotal in the pathogenesis of autoimmune disorders. Traditionally, T cell activation is orchestrated by three canonical signals: antigen recognition through the T-cell receptor (TCR) and major histocompatibility complex (MHC) interaction, co-stimulatory signals, and cytokine signaling. Recent studies have highlighted nutrients as a key fourth signal in modulating T cell immunity. T cell metabolism is integral to regulating cell proliferation, survival, and differentiation. Dysregulation of nutrient metabolism, including glucose, amino acids, and lipids, has been considered a crucial determinant of T cell activation, differentiation, and function, and may lead to the disease progression of autoimmune disorders, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and multiple sclerosis (MS). This review aims to elucidate the impact of T cell metabolic reprogramming on autoimmune disease development and explore potential therapeutic approaches targeting nutrient metabolism for treating autoimmune disorders.
    Keywords:  T cell; autoimmune disease; multiple sclerosis; nutrient metabolism; rheumatoid arthritis; systemic lupus erythematosus
    DOI:  https://doi.org/10.1002/eji.70059
  9. Blood Adv. 2025 Sep 12. pii: bloodadvances.2025016439. [Epub ahead of print]
    mTOR activity and metabolic reprogramming of CD8+ T cells is impaired under hypoxia and within the multiple myeloma bone marrow.
    Taylor Fulton-Ward, Nancy Gudgeon, Isaac Thirlwell, Emma Louise Bishop, Bryan Marzullo, Hannah Victoria Giles, Graham McIlroy, Paul Ferguson, Bhuvan Kishore, Kate Rogers, Nuri Nuri Alfasi, Timothy Wong, Satnam Aytain, Daniel A Tennant, Guy Pratt, Sarah Dimeloe.
      Novel therapies for multiple myeloma aim to engage anti-tumour functions of T cells. However, evidence indicates these functions are limited within the bone marrow environment. This is relatively hypoxic in health and studies indicate widespread hypoxia in multiple myeloma. In this study, CD8+ T cell responses to stimulation were assessed under hypoxia, which identified that activation, proliferation and interferon-gamma (IFN-γ) secretion were profoundly suppressed, whilst cytotoxicity and tumour necrosis factor-alpha (TNF-α) expression were unaffected. These changes occurred alongside decreased mTOR activity and expression of c-Myc, which drives T cell metabolic reprogramming upon stimulation. Consistently, hypoxic CD8+ T cells demonstrated decreased activation-induced glycolysis and mitochondrial glutamine oxidation. Mechanistically, this was linked to elevated BNIP3 expression under hypoxia and reciprocally decreased abundance of its interaction partner, Rheb, an important mTOR activator. Assessment of BCMAxCD3 bispecific antibody activity confirmed impaired capacity to elicit CD8+ T cell activation, IFN-γ expression, proliferation and altered memory differentiation under hypoxia, although initial target cell killing was unaffected. Finally, assessment of bone marrow CD8+ T cells from multiple myeloma patients identified decreased proliferation, c-Myc and Rheb expression compared to peripheral blood cells, alongside elevated BNIP3, confirming mechanistic features of hypoxic exposure in this environment. Taken together, the findings indicate potential for bone marrow hypoxia to influence efficacy of T cell-directed therapies for multiple myeloma.
    DOI:  https://doi.org/10.1182/bloodadvances.2025016439
  10. Nat Rev Immunol. 2025 Sep 08.
    Metabolic control of innate-like T cells.
    Thomas Riffelmacher, Mitchell Kronenberg.
      Immunometabolism, the intersection of cellular metabolism and immune function, has revolutionized our understanding of T cell biology. Changes in cellular metabolism help guide the development of thymocytes and the transition of T cells from naive to effector, memory and tissue-resident states. Innate-like T cells are a unique group of T cells with special characteristics. They respond rapidly, reside mainly in tissues and express T cell receptors with limited diversity that recognize non-peptide antigens. This group includes invariant natural killer T (iNKT) cells, mucosal-associated invariant T (MAIT) cells and some populations of γδ T cells. Different subsets of innate-like T cells rely on specific metabolic pathways that influence their differentiation and function and distinguish them from conventional CD4+ and CD8+ T cells. Although there are differences between innate-like T cell types, they share metabolic and functional features. In this Review, we highlight recent research in this emerging field. Understanding how metabolic programmes differ between innate-like T cells and other T cells may open opportunities for tailoring innate-like T cell responses and adoptive T cell therapies for use in cancer, metabolic and autoimmune diseases.
    DOI:  https://doi.org/10.1038/s41577-025-01219-5
  11. Front Immunol. 2025 ;16 1637436
    Metabolites as regulators of autoimmune diseases.
    Maria Tada, Michihito Kono.
      Immune cell metabolism is essential for regulating immune responses, including activation, differentiation, and function. Through glycolysis and oxidative phosphorylation (OXPHOS), metabolism supplies energy and key intermediates for cell growth and proliferation. Importantly, some metabolites generated during these processes act as signaling molecules that influence immune activity. Autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) involve multiple immune cell types, and recent research in immunometabolism has revealed that disrupted metabolic pathways in these cells contribute to disease progression. Effector T cells, for instance, undergo metabolic reprogramming, particularly increased glycolysis, to meet the demands of proliferation and function during autoimmune responses. Targeting metabolic enzymes has shown therapeutic potential. In addition, metabolites themselves, termed immunometabolites, can directly modulate immune responses. These include both intracellularly generated and secreted molecules. Itaconate is a key immunometabolite and is derived from the TCA cycle by aconitate decarboxylase 1 (ACOD1) in activated macrophages. It inhibits the NLRP3 inflammasome and pro-inflammatory cytokines, such as IL-1β and IL-6. Beyond macrophages, itaconate alters metabolism and epigenetics in T cells by reducing 2-hydroxyglutarate and the S-adenosyl-L-methionine (SAM)/S-adenosyl-L-homocysteine (SAH) ratio, thereby suppressing Th17 differentiation and enhancing Foxp3 expression in Tregs. Itaconate ameliorates disease in experimental autoimmune encephalomyelitis, RA, SLE, and others. It also exhibits antimicrobial effects by blocking bacterial isocitrate lyase and viral replication. Despite increasing interest, reviews focusing specifically on immunometabolites remain limited. This review highlights emerging insights into metabolites involved in glycolysis, the TCA cycle, glutaminolysis, one-carbon metabolism, and lipid metabolism that influence autoimmune pathophysiology.
    Keywords:  cellular metabolism; glutaminolysis; glycolysis; itaconate; metabolite
    DOI:  https://doi.org/10.3389/fimmu.2025.1637436
  12. Nat Cell Biol. 2025 Sep;27(9): 1555-1571
    CD160 dictates anti-PD-1 immunotherapy resistance by regulating CD8+ T cell exhaustion in colorectal cancer.
    Tongsen Zheng, Chujie Ding, Shihui Lai, Yang Gao, Cheng Lyu, Caiqi Liu, Jiaqi Shi, Xiaobo Li, Mingwei Li, Hongxue Meng, Mingqi Li, Yingjian Liang, Sheng Tai, Liang Cheng, Yan Zhang, Li Li, Peng Han, Bin Sun, Te Liu, Feng Geng, Dapeng Hao, Xue Zhang.
      The colon exhibits higher propensity for tumour development than ileum. However, the role of immune microenvironment differences in driving this disparity remains unclear. Here, by comparing paired ileum and colon samples from patients with colorectal cancer (CRC) and healthy donors, we identified ileum-enriched CD160+CD8+ T cells with previously unrecognized characteristics, including resistance to terminal exhaustion and strong clonal expansion. The transfer of CD160+CD8+ T cells significantly inhibits tumour growth in microsatellite instability-high and inflammation-induced CRC models. Cd160 knockout accelerates tumour growth, which is mitigated by transferring CD160+CD8+ T cells. Notably, in microsatellite instability-high and anti-PD-1-resistant CRC models, CD160+CD8+ T cells improve anti-PD-1 efficacy and overcome its resistance by increasing tumour-infiltrating progenitor-exhausted T cells, nearly eradicating tumours. Mechanistically, we uncover a CD160-PI3K (p85α) interaction that promotes FcεR1γ and 4-1BB expression via the AKT-NF-κB pathway, thereby enhancing CD8+ T cell cytotoxicity. Our study reveals CD160 as a crucial regulator of CD8+ T cell function and proposes an innovative immunotherapy strategy of transferring CD160+CD8+ T cells to overcome anti-PD-1 resistance.
    DOI:  https://doi.org/10.1038/s41556-025-01753-3
  13. Mol Biomed. 2025 Sep 08. 6(1): 62
    Dendritic cells: understanding ontogeny, subsets, functions, and their clinical applications.
    Wenhao Li, Chenyu Yu, Xujian Zhang, Yunshen Gu, Xiaobo He, Rongrong Xu, Jia Xu, Ganjun Yu, Yanfeng Wu.
      Dendritic cells (DCs) play a central role in coordinating immune responses by linking innate and adaptive immunity through their exceptional antigen-presenting capabilities. Recent studies reveal that metabolic reprogramming-especially pathways involving acetyl-coenzyme A (acetyl-CoA)-critically influences DC function in both physiological and pathological contexts. This review consolidates current knowledge on how environmental factors, tumor-derived signals, and intrinsic metabolic pathways collectively regulate DC development, subset differentiation, and functional adaptability. Acetyl-CoA emerges as a dual-function metabolite, serving not only as an energy carrier but also as an epigenetic regulator that controls DC fate via lipid biosynthesis, mitochondrial metabolism, and chromatin modification. In the tumor microenvironment (TME), DCs may experience immune suppression polarization and insufficient T cell activation due to disrupted acetyl-CoA related metabolic pathways. While existing DC-based therapies remain constrained by TME-induced metabolic limitations, emerging approaches that restore acetyl-CoA related metabolic pathways balance show enhanced antitumor efficacy. The review further examines distinct metabolic adaptations among DC subsets and their relevance to autoimmune diseases, infectious immunity, and transplant outcomes. By integrating current research on targeting DC metabolic targets, we outline strategies for developing immunotherapies that target DC metabolic flexibility. Remaining hurdles include tailoring interventions to specific subsets, refining metabolic manipulation techniques, and addressing TME heterogeneity through combination therapies. These findings position acetyl-CoA as a key therapeutic target for recalibrating immunometabolism circuits, with significant implications for DC-focused cancer treatment.
    Keywords:  Acetyl-CoA; Cancer therapy; Dendritic cells; Immunotherapy; Metabolic reprogramming; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s43556-025-00300-8
  14. Aging Cell. 2025 Sep;24(9): e70162
    SIRT2 and NAD+ Boosting Broadly Suppress Aging-Associated Inflammation.
    Marine Barthez, Zehan Song, Yufan Feng, Yifei Wang, Chih-Ling Wang, Danica Chen.
      Aging leads to chronic inflammation that is linked to aging-associated conditions and diseases. Multiple immune pathways become activated during aging, posing a challenge to effectively reduce aging-associated inflammation. SIRT2, an NAD+-dependent deacetylase, suppresses several immune pathways that become activated during aging and may represent an attractive target to broadly dampen aging-associated inflammation. Here, we show that SIRT2 deficiency leads to increased inflammation governed by multiple immune pathways and tissue function decline at an old age, while NAD+ boosting with 78c suppresses aging-associated inflammation and improves tissue function. These findings highlight SIRT2 as a master regulator of aging-associated inflammation and support NAD+ boosting as an effective strategy to counteract aging-associated inflammation and tissue function decline.
    DOI:  https://doi.org/10.1111/acel.70162
  15. EBioMedicine. 2025 Sep 11. pii: S2352-3964(25)00354-8. [Epub ahead of print]120 105910
    TIM-3 ameliorates host responses to Salmonella infection by controlling iron driven CD4+ T cell differentiation and interleukin-10 formation.
    Christa Pfeifhofer-Obermair, Natascha Brigo, Chiara Volani, Piotr Tymoszuk, Egon Demetz, Sabine Engl, Günter Weiss.
       BACKGROUND: Iron loading increases infection risk in being a nutrient for invading siderophilic bacteria and by modulating immune functions including the expression of the immune checkpoint regulator T-cell immunoglobulin-and-mucin-containing-domain-3 (TIM-3). TIM-3 affects specific immune cell functions including T-helper cell differentiation but also T cell dysfunction, and immune exhaustion. Given the prevalence of iron overload specifically in patients at higher risk for infection such as those suffering from hemo-oncological diseases, we investigated TIM-3's role in immune control of bacterial sepsis.
    METHODS: A sepsis model was employed in wildtype and Tim3-/- mice with transgenic expression of a functional natural resistance associated macrophage protein 1 (NRAMP1). This creates a chronic inflammation model with enhanced resistance to infections with Gram negative Salmonella typhimurium, enabling to study T cell immune responses over time.
    FINDINGS: Dietary iron supplementation reduced mouse survival, which was further exaggerated by TIM-3 deletion. This indicates that TIM-3 dependent immune regulation was essential for effective host defence against Salmonella. TIM-3 deletion increased the production of immune-deactivating interleukin (IL) -10 as a result of impaired interleukin-12 receptor (IL-12R)-dependent CD4+ cytotoxic T cell signalling and development which subsequently reduced the production of anti-microbial interferon gamma (IFNγ). Anti-IL-10 treatment in iron-loaded Tim3-/- mice improved Salmonella control and restored CD4+ T cell mediated IFNγ production.
    INTERPRETATION: Our study uncovers TIM-3 as a crucial regulator of T cell driven immune control of bacterial infection and identifies the underlying treatable pathways, which is of major importance to better combat infection related mortality in subjects with iron overload syndromes.
    FUNDING: Christian-Doppler-Society, FWF (I-3321, W-1253).
    Keywords:  CD4 T cells; IFNgamma; IL-10; Intracellular bacteria; Iron; TIM-3
    DOI:  https://doi.org/10.1016/j.ebiom.2025.105910
  16. Blood. 2025 Sep 08. pii: blood.2024027432. [Epub ahead of print]
    Platelet Factor 4 (PF4) Regulates Hematopoietic Stem Cell Aging.
    Sen Zhang, Charles E Ayemoba, Anna M Di Staulo, Kenneth Joves, Chandani M Patel, Eva Hin Wa Leung, Maura Lima Pereira Bueno, Xiaoping Du, Mortimer Poncz, Sang-Ging Ong, Claus Nerlov, Maria Maryanovich, Constantinos Chronis, Sandra Pinho.
      Hematopoietic stem cells (HSCs) responsible for blood cell production and their bone marrow regulatory niches undergo age-related changes, impacting immune responses and predisposing individuals to hematologic malignancies. Here, we show that the age-related alterations of the megakaryocytic niche and associated downregulation of Platelet Factor 4 (PF4) are pivotal mechanisms driving HSC aging. PF4-deficient mice display several phenotypes reminiscent of accelerated HSC aging, including lymphopenia, increased myeloid output, and DNA damage, mimicking physiologically aged HSCs. Remarkably, recombinant PF4 administration restored old HSCs to youthful functional phenotypes characterized by improved cell polarity, reduced DNA damage, enhanced in vivo reconstitution capacity, and balanced lineage output. Mechanistically, we identified LDLR and CXCR3 as the HSC receptors transmitting the PF4 signal, with double knockout mice showing exacerbated HSC aging phenotypes similar to PF4-deficient mice. Furthermore, human HSCs across various age groups also respond to the youthful PF4 signaling, highlighting its potential for rejuvenating aged hematopoietic systems. These findings pave the way for targeted therapies aimed at reversing age-related HSC decline with potential implications in the prevention or improvement of the course of age-related hematopoietic diseases.
    DOI:  https://doi.org/10.1182/blood.2024027432
  17. Adv Sci (Weinh). 2025 Sep 12. e10004
    Integrating Metabolic Modulation and Nanomedicine for Cancer Immunotherapy.
    Xiaosu Zhou, Ruibing Deng, Zunde Liao, Xiaoyu Huang, Junting Huang, Hanlou Yang, Kam W Leong, Yiling Zhong.
      Cancer cells undergo significant metabolic reprogramming to support rapid growth, survival under stress, and resistance to therapies. As our understanding of tumor metabolism and the tumor microenvironment (TME) deepens, there is growing interest in exploiting metabolic vulnerabilities as therapeutic strategies. This review explores key alterations in metabolic pathways, including glucose, amino acid, lipid, nucleotide metabolism, and mitochondrial function, and highlights their impact on tumor progression, the TME, and immune cell function. In addition, the review discusses emerging strategies aimed at targeting these metabolic pathways with a focus on nanomaterial-based therapies. This includes the use of nanoparticles and drug delivery systems designed to modulate immunometabolism within cancer. These innovative approaches aim to reprogram the TME, enhance immune responses, and improve the targeted delivery of therapeutic agents to tumor sites, offering new ways to overcome conventional therapeutic resistance. Finally, the review also addresses the foreseeable challenges and potential future developments in this field, outlining the opportunities and obstacles that must be addressed for the clinical translation of these strategies in cancer therapy.
    Keywords:  immunometabolism; immunotherapy; metabolic reprogramming; nanomedicine; tumor microenvironment
    DOI:  https://doi.org/10.1002/advs.202510004
This page is being maintained by Thomas Krichel. It was last updated on 2025‒09‒14 at 6:03.