bims-imseme 2026-09-27 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2026–09–27
thirty-two papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Targeting ZMYND8 unleashes IL-2 signalling to override T cell exhaustion.
Thymic age and peripheral residence time determine antitumor competence of CD8+ T cells.
Dendritic cell PD-L2 restrains intratumoral CD8 + T cell immunity.
CD43 is a checkpoint against KLRG-1+CD49dhi effector CD8+ T cell formation.
IL-21 boosts T cell-therapy efficacy for solid tumors by enhancing mitochondrial Ca2+-mediated motility of effector CD8+ T cells.
Why Some People Live Past 100: The Role of the Immune System in Centenarians, Semi-Supercentenarians and Supercentenarians.
T cell exhaustion in parasitic infections.
Targeting Metabolic Pathways to Direct T-Cell Trafficking: Therapeutic Perspectives.
Author Correction: Exhausted CD8+ T cell fate is programmed by dynamic CTCF-mediated enhancer activation and invariant CTCF-imposed barriers.
Sirtuin signaling as therapeutic targets of immunosenescence.
Hepatocyte Growth Hormone Receptor Ablation Is Associated With Aging Phenotypes and Hepatic Mitochondrial Dysfunction.
The role of exercise in modulating NAD+ metabolic enzymes: mechanisms and health benefits.
High Frequencies of Senescent and Exhausted Natural Killer Cells and SARS-CoV-2-Specific Memory CD8+ T Cells Distinguish Critically Ill from Asymptomatic Unvaccinated COVID-19 Patients.
Lymph node extracellular matrix skews the immune function of human fibroblastic reticular cells.
Murine IL-2 outperforms human IL-2 in supporting the survival of naïve mouse CD8 T cells in vitro.
T-cell exhaustion and senescence in cancer: Regulatory circuits and therapeutic state engineering.
Author Correction: Mapping self-associating chromatin hubs identifies Id proteins as key determinants of exhausted CD8+ T cell fate.
PAG supports T cell immune synapse function by binding to actin.
IL-10's contextual role in cytotoxic antitumor immunity: evidence, controversies, and therapeutic translation.
Mechano-Chemical Coordination of Nanoparticle-Based Artificial Antigen-Presenting Cells Synergistically Tunes T Cell Activation and Expansion Phenotypes.
Sex-specific trajectories of nonlinear immune aging at single-cell level.
Slow-cooked naive T cells make better effectors.
Transient architecture of the embryonic pancreas determines endocrine mass.
Metabolic Reprogramming in Gastric Cancer Immunity Mechanisms and Therapeutic Implications.
Bioadaptive spatiotemporal nanomedicine promotes metabolic recovery after myocardial infarction through NAD+ and UCP2 regulation.
PD-L1+ neutrophils at the invasive margin drive contact-dependent CD8+ T cell exhaustion in hepatic alveolar echinococcosis.
The splicing axis of aging: mechanisms and therapeutic opportunities.
HLA-II Expression Marks Activated and Clonally Expanded CD8+ T Cells and Improves Tumor-Reactivity Prediction Across Human Cancers.
Novel lipid nanoparticle in a mRNA cancer vaccine drives tumor control via type I IFNs and effector CD8+ T cells.
Tumor-cell HMGB1 restrains CD8+ T-cell immunity during conventional fractionated radiotherapy.
Targeting BIRC6 rejuvenates hematopoietic stem cell aging and immunosenescence.
Restoring glucose metabolic homeostasis to attenuate ovarian aging: mechanisms and clinical prospects.

Nature. 2026 Sep 23.

Targeting ZMYND8 unleashes IL-2 signalling to override T cell exhaustion.

Yan Wang, Hao Shi, Nicole M Chapman, Anil Kc, Renqiang Sun, Hao Song, Xiaoxi Meng, Xiang Sun, Hongbo Chi.

CD8+ T cell exhaustion impedes control of chronic viral infection and cancer. This hypofunctional state is characterized by downregulation of the high-affinity IL-2 receptor (IL-2R) and STAT5 signalling, and differentiation from progenitor exhausted to terminally exhausted T cells rather than cytotoxic effector-like cells1-3. The epigenetic mechanisms and regulatory networks that mediate IL-2R-STAT5 signal attenuation and loss of effector-like cell differentiation remain unknown. Here, using in vivo single-cell CRISPR screens of epigenetic factors and IL-2 signalling regulators, we reveal that the chromatin reader ZMYND8 antagonizes IL-2R-STAT5 signals to restrain effector-like states while promoting terminal exhaustion. ZMYND8 expression was upregulated by chronic antigen stimulation, and targeting ZMYND8 in CD8+ T cells promoted both intermediate exhausted T cells and killer cell lectin-like receptor-expressing exhausted T cells. Accordingly, ZMYND8-deficient CD8+ T cells had markedly improved antiviral and antitumour effects, especially in combination with IL-2 therapy or immune checkpoint blockade. Mechanistically, ZMYND8 bound to the active enhancer regions of the Il2ra gene locus that were co-occupied by histone acetyltransferase p300 and suppressed p300 activity. Co-deletion of p300 reversed increased IL-2R expression and effector-like cell differentiation in ZMYND8-deficient cells, suggesting that ZMYND8 represses p300-mediated transcriptional activation to curtail IL-2R-STAT5 signalling. These findings establish an epigenetic rheostat imposing 'signal 1' (chronic antigen stimulation)-induced suppression of 'signal 3' (IL-2 signalling) to enforce T cell exhaustion, with ZMYND8 deletion unleashing effector-like over terminally exhausted states and enhancing immunotherapeutic efficacy.

DOI: https://doi.org/10.1038/s41586-026-11059-5
Proc Natl Acad Sci U S A. 2026 Sep 29. 123(39): e2612774123

Thymic age and peripheral residence time determine antitumor competence of CD8+ T cells.

Yuanqin Yang, Yunyi Wang, Amanda Wicki, Qianpeng Li, Chunrun Qu, Brian Debo, Berna Bou Tayeh, Tingyu Wen, Hui Huang, Amir Hosseini, Vinnycius Pereira Almeida, Carol S Leung, Georg A Holländer, Benoit Van den Eynde, Yang Shi.

  The developmental timing of T cell generation imprints durable functional programs, yet how this shapes antitumor immunity remains unclear. Here, we combine genetic fate mapping with functional assays to dissect how thymic age and peripheral residency regulate CD8+ T cell behavior within the same host. We find that, compared with adulthood-derived CD8+ T cells, the adolescent-derived counterparts consistently exhibit enhanced tumor infiltration, increased effector cytokine production, and superior proliferative fitness. Transcriptomic and phenotypic profiling identify a CXCR3+IL-18Rα+ subset preferentially enriched among adolescent-derived T cells that shares core virtual memory-like features and displays elevated cytotoxic potential. Mechanistically, thymic origin timing and time spent in the periphery independently regulate the abundance and activity of this subset, revealing a two-tier control comprising developmental bias and postthymic remodeling. Functionally, CXCR3+IL-18Rα+ CD8+ T cells mediate potent tumor killing and confer robust therapeutic benefit in adoptive transfer models. Together, these findings establish developmental imprinting as an important determinant of CD8+ T cell heterogeneity and identify CXCR3+IL-18Rα+ CD8+ T cells as key effectors for antitumor immunity.

Keywords:  CD8+ T cells; antitumor immunity; developmental timing; fate mapping; thymus

DOI:  https://doi.org/10.1073/pnas.2612774123
bioRxiv. 2026 Sep 16. pii: 2026.09.10.750646. [Epub ahead of print]

Dendritic cell PD-L2 restrains intratumoral CD8 + T cell immunity.

Jinwoo Nah, Amanda Sun, Anushka Yadav, Adina Scheinfeld, Tamjeed Azad, Samuel Rose, Burkhard Becher, James W Smithy, Michael A Postow, Charlotte E Ariyan, Yuri Pritykin, Chrysothemis C Brown.

Blockade of inhibitory PD-1 signaling on T cells is a cornerstone of cancer immunotherapy, with current strategies targeting PD-1 or its ligand PD-L1. However, PD-1 engages an alternative ligand, PD-L2, whose role in tumor immunity remains poorly defined. Here, we show that PD-L2 is upregulated on intratumoral CCR7⁺ conventional dendritic cells (cDCs) in both mouse and human melanoma. Using genetic mouse models enabling selective ablation of PD-L1 or PD-L2 in cDCs, we identify a division of labor between these ligands: PD-L1 controls the size of the progenitor CD8⁺ T cell pool in tumor-draining lymph nodes by modulating stem-like CD8⁺ T cells, whereas PD-L2 limits progenitor exhausted CD8 + T cell differentiation within the tumor microenvironment. Loss of PD-L2 in cDCs enhances cytotoxic CD8⁺ T cell responses and suppresses tumor growth, particularly in tumors enriched for CCR7⁺ cDC1s. Consistent with this, increased CCR7 + cDC abundance is associated with poor prognosis in human cancers. Spatial transcriptomic analyses reveal co-localization of CCR7⁺ cDC1s and Tpex within CCL19 hi niches, where cancer-associated fibroblasts serve as the predominant source of CCL19. Finally, intratumoral GM-CSF drives PD-L2 expression on CCR7⁺ cDCs, with Tpex and NK cells as major sources. Together, these findings establish cDC- associated PD-L1 and PD-L2 as spatially and functionally distinct checkpoints governing CD8⁺ T cell differentiation. Our results suggest that the abundance of CCR7⁺PD-L2⁺ cDC1s may guide the choice between anti-PD-1 and anti- PD-L1 therapies and support the development of PD-L2-directed blockade.

DOI: https://doi.org/10.64898/2026.09.10.750646
Transpl Immunol. 2026 Sep 24. pii: S0966-3274(26)00118-8. [Epub ahead of print] 102460

CD43 is a checkpoint against KLRG-1+CD49dhi effector CD8+ T cell formation.

Yukai Tang, Joel S Freibaum, Gregory S Cohen, Riley P Leathem, Scott M Krummey.

  Upon recognition of alloantigen, T cells rely on an array of costimulatory and coinhibitory receptors to shape their activation and function. The surface receptor CD43 has been reported to provide myriad functions on T cell related to adhesion, trafficking, and intracellular signaling. We investigated the role of CD43 on CD8+ T cells in vitro and in a fully allogeneic model of acute allograft rejection. Following polyclonal activation, CD43 did not impact the initial proliferation of CD8+ T cells, although CD43 deficient CD8+ T cells had mildly enhanced expression of IL-2Rα and PD-1 relative to CD43 wild-type CD8+ T cells (***p = 0.0008 and **p = 0.006, respectively). Following 7-9 days of in vitro culture, CD43 deficient CD8+ T cells had a stronger effector phenotype, displaying greater expression of Granzyme B, CD69, IL-2Rα, and PD-1. Following fully allogeneic skin grafting, alloantigen-specific CD43 deficient CD8+ T cells accumulated at greater numbers in the secondary lymphoid tissue and the allograft relative to CD43 wild-type CD8+ T cells (draining lymph nodes ***p = 0.007, spleen *p = 0.03). Hierarchical clustering and manual gating of revealed that CD43 deficient had an elevated frequency of effector populations with a CD62Llo, KLRG-1+, and CD49dhi phenotype, and that CD43 KO CD49dhi cells preferentially infiltrated the allograft tissue (***p = 0.0001). Together, these data provide evidence that CD43 acts as a checkpoint of alloantigen-specific CD8+ T cell differentiation after transplantation.

Keywords:  CD8(+) T cells; Costimulation; Graft rejection

DOI:  https://doi.org/10.1016/j.trim.2026.102460
Cancer Immunol Res. 2026 Sep 21.

IL-21 boosts T cell-therapy efficacy for solid tumors by enhancing mitochondrial Ca2+-mediated motility of effector CD8+ T cells.

Maureen Hoen Rauhut, Fahiima Abdullahi, Jay Walters, Hiten N Patel, Dominik Stich, Isabelle J Marié, Haitao Wen, David E Levy, Jeffrey G Jacot, Jordan Jacobelli, Felipe Valenca-Pereira, Mercedes Rincon.

Cell motility, characterized by random walk and exploratory search movement, enables effector CD8+ T cells to search for sparse antigen-specific cancer targets within a tumor. This is of special relevance for treatment of solid cancers with adoptive T-cell receptor (TCR) T-cell therapy, where administered effector CD8+ T cells recognize specific MHC-I-presented antigens. Cell motility requires cytoskeleton remodeling to facilitate shape changes and movement. Herein, we show that increased mitochondrial Ca2+ levels are essential to reduce cytoskeleton stiffness of effector CD8+ T cells, leading to acquisition of a polarized shape and high motility. IL-21, but not IL-7 or IL-15, was able to raise mitochondrial Ca2+ levels in effector CD8+ T cells and increase their motility without affecting survival and proliferation. This increase in mitochondrial Ca2+ levels triggered by IL-21 was driven by sustaining mitochondrial membrane potential through mitochondrial STAT3, independently of its transcriptional activity. Enhanced motility of effector CD8+ T cells led to a superior killing efficacy of antigen-specific melanoma cells in vitro. Furthermore, enhanced mitochondrial Ca2+-mediated motility of adoptive TCR-specific effector CD8+ T cells resulted in a superior antitumor efficacy of this treatment against solid tumors in vivo. Thus, enhancing effector CD8+ T-cell motility is a promising strategy to boost efficacy of adoptive T-cell therapies against solid tumors.

DOI: https://doi.org/10.1158/2326-6066.CIR-26-0401
Int J Mol Sci. 2026 Sep 21. pii: 8420. [Epub ahead of print]27(18):

Why Some People Live Past 100: The Role of the Immune System in Centenarians, Semi-Supercentenarians and Supercentenarians.

Calogero Caruso, Giulia Accardi, Anna Aiello, Anna Calabrò, Chiara Puleo, Rosa Zarcone, Giuseppina Candore.

  Centenarians, semi-supercentenarians and supercentenarians (i.e., oldest centenarians) display complex and heterogeneous immune remodelling. In this setting, immune attrition, memory, cytotoxic defence, inflammatory regulation and tissue surveillance remain sufficiently balanced to support survival with relatively preserved health. This review examines these processes within an integrated framework encompassing sex and gender differences, genetic background, the exposome and immunobiography. We consider how haematopoietic stem cell ageing, age-related myeloid bias, thymic involution, immune ageing and inflammaging contribute to immune-system remodelling across the life course. Findings from conventional phenotyping and single-cell transcriptomic studies in centenarians, semi-supercentenarians and supercentenarians indicate selective immune remodelling rather than preservation of a youthful immune system. These changes include NK-cell expansion, differentiated B-cell states, enrichment of effector-memory CD8+ T cells, marked expansion of clonally selected cytotoxic CD4+ T cells and increased GZMK+GZMB- CD8+ T cell populations. Exceptional longevity also appears to depend on limiting the detrimental consequences of chronic inflammation through delayed or better-controlled inflammaging, restrained NLRP3 inflammasome activation and preserved capacity to buffer oxidative stress. Thus, extreme survival appears to reflect successful accommodation of age-related immune change through sustained cytotoxic surveillance, immune memory, inflammatory control and favourable lifelong adaptation to antigenic exposures.

Keywords:  centenarians; immune ageing; immunosenescence; inflammaging; semi-supercentenarians; supercentenarians

DOI:  https://doi.org/10.3390/ijms27188420
Front Immunol. 2026 ;17 1910471

T cell exhaustion in parasitic infections.

Ge Gao, Hao Wang, Rafeezul Mohamed, Yinming Liang.

  T cell exhaustion is a state of progressive functional impairment that occurs upon persistent antigenic stimulation and is a key mechanism by which chronic parasitic infections evade host immunity. As research into T cell exhaustion continues to deepen, immunotherapies targeting exhausted T cells have emerged as a prominent area of interest, particularly in cancers and chronic viral infections. However, T cell exhaustion caused by parasitic infections exhibits significant differences from classic T cell exhaustion observed in chronic viral infections, and understanding how parasites with their complex life cycles and unique immune evasion strategies, drive or modulate T cell exhaustion will be essential for developing targeted therapeutic approaches for diverse diseases. Therefore, this review summarizes the current understanding of mechanisms and research progress regarding T cell exhaustion in the context of chronic infections, with a specific focus on parasitic infections and their different developmental changes, meanwhile raises several key questions which still remain unanswered, aiming to provide insights and references for immunotherapy development in related diseases.

Keywords:  T cell exhaustion; Th1/Th2 response; immunosuppressive microenvironment; inhibitory receptors; parasitic infection

DOI:  https://doi.org/10.3389/fimmu.2026.1910471
Biomedicines. 2026 Sep 17. pii: 2100. [Epub ahead of print]14(9):

Targeting Metabolic Pathways to Direct T-Cell Trafficking: Therapeutic Perspectives.

Xiayinan Song, Shengxuan Zhao, Weiheng Zhang, Yan Wang, Fengjie Zheng.

  Despite advances in immunomodulatory therapies, dysregulated T-cell trafficking persists as a pathological cornerstone in chronic inflammation, autoimmunity, and cancer. This spatially precise navigation-orchestrated by receptor-ligand cascades-ensures immune surveillance but drives disease when impaired. Targeting individual receptors faces limitations due to functional redundancy. Emerging research establishes metabolic reprogramming as a critical regulator of trafficking efficiency, where glucose, amino acid, lipid, and mitochondrial metabolism dynamically control all stages: from chemotaxis, selectin-mediated rolling, and integrin-dependent adhesion to transendothelial migration and interstitial migration. Critically, these pathways integrate energy supply, metabolite signaling, and epigenetic modulation to influence T-cell trafficking fates. Here, we dissect how reprogramming core metabolic networks calibrates trafficking cascades and highlight therapeutic strategies targeting key nodes to correct pathological migration in autoimmunity, cancer, and transplantation.

Keywords:  T cell; immunotherapy; metabolic reprogramming; trafficking

DOI:  https://doi.org/10.3390/biomedicines14092100
Nat Immunol. 2026 Sep 23.

Author Correction: Exhausted CD8+ T cell fate is programmed by dynamic CTCF-mediated enhancer activation and invariant CTCF-imposed barriers.

Wei Hu, Shaoqi Zhu, Qing Chen, Vladimir P Badovinac, Weiqun Peng, Hai-Hui Xue.

DOI: https://doi.org/10.1038/s41590-026-02694-1
Expert Opin Ther Targets. 2026 Sep 25. 1-23

Sirtuin signaling as therapeutic targets of immunosenescence.

Anna Calabrò, Giulia Accardi, Anna Aiello, Calogero Caruso, Damiano Galimberti, Chiara Puleo, Rosa Zarcone, Giuseppina Candore.

   INTRODUCTION: Aging is characterized by immunosenescence, encompassing, immune aging and inflammaging. Because immune competence is a critical determinant of lifespan and healthspan, targeting immunosenescence has become a major objective of geroscience. In this context, sirtuins have emerged as compelling therapeutic candidates.
AREAS COVERED: This review examines the role of sirtuin signaling in immunosenescence, focusing on its links with nicotinamide adenine dinucleotide (NAD)+ metabolism, oxidative stress, and inflammatory pathways. Pharmacological strategies aimed at enhancing sirtuin activity, including natural and synthetic activators as well as NAD+ precursors, are critically discussed.
EXPERT OPINION: Sirtuin signaling represents a biologically plausible strategy for targeting immunosenescence, as it integrates metabolic, mitochondrial, epigenetic, and inflammatory pathways involved in the age-related remodeling of innate and adaptive immunity. However, sirtuin modulation remains investigational rather than an established therapeutic approach. Although NAD+ precursors and sirtuin activators have yielded encouraging preclinical findings, robust evidence of clinically meaningful effects in humans is still lacking. Further progress will require validated biomarkers of immunosenescence, appropriately selected study populations, adequately powered randomized trials incorporating functional and clinically relevant immune endpoints, and long-term safety assessment. At present, mTOR-directed interventions appear closer to clinical translation, whereas NAD+- and sirtuin-based approaches remain promising complementary strategies requiring further investigation.

Keywords:  Immune aging; NAD+; immunosenescence; inflammaging; sirtuin-activating compounds (STACs); sirtuins

DOI:  https://doi.org/10.1080/14728222.2026.2737637
Aging Cell. 2026 Oct;25(10): e70741

Hepatocyte Growth Hormone Receptor Ablation Is Associated With Aging Phenotypes and Hepatic Mitochondrial Dysfunction.

Kangkang Yang, Yuli Jian, Fusheng Pang, Ming Ying, Qian Yang, Nian Liu, Shujing Wang, Yingjie Wu.

  Aging drives physiological decline and predisposes individuals to multiple age-related pathologies, constituting a major global health challenge. Growth hormone receptor (GHR), a critical regulator of growth, development, and metabolism, has emerged as a potential therapeutic target. However, its precise role in aging and age-related diseases remains incompletely defined. Here, we demonstrate that hepatocyte-specific GHR knockout mice display accelerated aging-related phenotypes, characterized by shortened lifespan, enhanced cellular senescence, reduced metabolic stress resilience, cognitive decline, impaired bone mineralization, and exacerbated inflammaging. Elevated circulating GH following hepatocyte-specific GHR ablation mediates adipose-liver crosstalk that promotes adipose lipolysis and CD36-dependent hepatic steatosis. Hepatocyte-specific GHR deficiency also promotes liver aging and aggravates age-related hepatic pathologies in both naturally aged and high-fat diet (HFD)-fed mice. Mechanistically, loss of hepatic GHR impairs STAT5b phosphorylation while upregulating PPARγ expression. Enhanced nuclear translocation of PPARγ activates transcription of Pdk4 and Cd36, leading to mitochondrial damage and ectopic lipid accumulation. Together, dysregulated lipid metabolism and mitochondrial dysfunction establish a self-amplifying vicious cycle that accelerates aging and its pathophysiology. Pharmacological inhibition of PDK4 in vivo effectively ameliorates the age-related pathologies induced by hepatocyte-specific GHR ablation. These findings identify hepatic GHR signaling as an important contributor to age-related hepatic pathology and a candidate node within the broader network of factors driving systemic aging phenotypes, highlighting hepatocyte GHR signaling as a promising therapeutic target for age-related liver disorders.

Keywords:  GH‐GHR; age‐related pathologies; aging; ectopic lipid accumulation; mitochondrial dysfunction

DOI:  https://doi.org/10.1111/acel.70741
Front Sports Act Living. 2026 ;8 1863337

The role of exercise in modulating NAD+ metabolic enzymes: mechanisms and health benefits.

Anas, Habiba Sundus, Sohrab Ahmed Khan, Syed Suhaib Ahmed, Punitha Muruganantham, Inamul Hasan Madar.

  Nicotinamide adenine dinucleotide (NAD+) is a critical coenzyme in cellular metabolism, acting as a substrate for NAD+-dependent enzymes such as sirtuins, poly(ADP-ribose) polymerases (PARPs), and CD38, which are involved in essential cellular processes including DNA repair, gene expression, and mitochondrial function. Exercise has been identified as a potent modulator of NAD+ metabolism and also influencing the expression and activity of enzymes involved in NAD+ biosynthesis and consumption. Our review focuses on the molecular mechanisms through which exercise regulates NAD+ metabolic enzymes, more in relation to aerobic and resistance exercise. Evidence indicates that exercise enhances the activity of key enzymes, such as nicotinamide phosphoribosyltransferase (NAMPT) and sirtuins, thereby improving mitochondrial efficiency, oxidative metabolism, and cellular homeostasis. Additionally, exercise has also been shown to mitigate the age-related decline in NAD+ levels, offering a potential strategy for addressing metabolic dysfunctions and age-associated diseases. Despite these findings, the exact molecular pathways underlying the exercise-induced modulation of NAD+ metabolism remain unclear and require further investigation.

Keywords:  NAD+ metabolism; exercise physiology; mitochondrial function; nicotinamide phosphoribosyltransferase (NAMPT); sirtuins

DOI:  https://doi.org/10.3389/fspor.2026.1863337
Viruses. 2026 Aug 28. pii: 940. [Epub ahead of print]18(9):

High Frequencies of Senescent and Exhausted Natural Killer Cells and SARS-CoV-2-Specific Memory CD8+ T Cells Distinguish Critically Ill from Asymptomatic Unvaccinated COVID-19 Patients.

Ruchi Srivastava, Swayam Prakash, Sweta Karan, Lbachir BenMohamed.

  COVID-19 disease severity in unvaccinated individuals spans a striking continuum from complete absence of symptoms to life-threatening critical illness, yet the immunological determinants driving this divergence remain poorly understood. While Natural Killer (NK) cells and CD4+/CD8+ T cells mount distinct responses against SARS-CoV-2, the phenotypic and functional signatures distinguishing protective immunity from pathogenic immune dysfunction have yet to be defined. In the present study, we present a comparative analysis of NK cell and SARS-CoV-2-specific T cell immunity in unvaccinated symptomatic (SYMP) versus asymptomatic (ASYMP) COVID-19 patients. Using multicolor flow cytometry, we interrogated key immune checkpoints, the senescence marker CD57, differentiation status (CD45RA/CCR7), exhaustion marker PD-1, and activation markers HLA-DR and CD38, across NK and T cell subsets from SYMP patients, ASYMP patients, and Healthy Donors (HD). SYMP COVID-19 patients harbor significantly elevated co-expression of exhaustion and senescence markers on both NK and T cells relative to ASYMP patients and HD controls. Within the T cell compartment, SYMP patients exhibit broad dysregulation across naïve, central memory, effector memory, and terminally differentiated effector memory subsets, with CD57 enriched most prominently on CD8+ TEM and CD8+ TEMRA populations. While cytokine profiles did not significantly differ between ASYMP and SYMP patients, both groups showed markedly elevated pro-inflammatory TNF-α, IFN-γ, IL-6, IL-8, and IL-17 compared to HD controls, underscoring systemic immune activation as a hallmark of SARS-CoV-2 infection regardless of clinical severity. Taken together, these findings suggest that NK and T cell exhaustion and senescence are correlates of severe COVID-19, highlighting potential targets for future mechanistic and therapeutic investigation.

Keywords:  CD8+ T cells; COVID-19; NK cells; SARS-CoV-2; senescence

DOI:  https://doi.org/10.3390/v18090940
iScience. 2026 Oct 16. 29(10): 117516

Lymph node extracellular matrix skews the immune function of human fibroblastic reticular cells.

Daphne Panocha, Janna E G Roet, Michael de Kok, Tanja Konijn, Henk P Roest, Luc J W van der Laan, Charlotte M de Winde, Reina E Mebius.

  Lymph node (LN) fibroblastic reticular cells (FRCs) are key immunomodulators that regulate adaptive immune responses and provide structural support via extracellular matrix (ECM) production. However, how ECM composition shapes FRC-immune cell interactions remains unclear. Here, we show that ECM composition, specifically collagen type I, laminin α4, or laminin α5, critically determines the immunological status of human FRCs. Bulk RNA sequencing shows that FRCs grown on collagen closely resemble those in native human LN ECM, whereas laminin α4 and α5 differentially skew FRC transcriptomes toward homeostatic/tolerogenic or pro-inflammatory profiles, respectively. These ECM-imprinted FRC states subsequently shape distinct CD4+ T cell fates in autologous co-culture assays: laminin α4-FRCs maintain tissue-resident T cells, whereas laminin α5-FRCs selectively enhance effector T cell proliferation. Together, these findings identify ECM as an active instructive signal that, through FRCs, orchestrates immune cell behavior and offers a tunable axis for therapeutic immune modulation.

Keywords:  T cell; adaptive immunity; extracellular matrix; fibroblastic reticular cell; laminin; lymph node

DOI:  https://doi.org/10.1016/j.isci.2026.117516
Life Sci Alliance. 2026 Dec;pii: e202603711. [Epub ahead of print]9(12):

Murine IL-2 outperforms human IL-2 in supporting the survival of naïve mouse CD8 T cells in vitro.

Yangle Yu, Tete I Obot, Madaleine M Niznikiewicz, Craig M Podszus, Julio S Dos-Santos, Elena L Pobezinskaya, Priyadharshini Devarajan, Leonid A Pobezinsky, Brian S Sheridan.

Much of the immunology community relies on human IL-2 to support murine CD8 T-cell expansion in vitro. Although human and murine IL-2 share high similarity in amino acid sequence and exhibit similar biological activity, the potential cross-species implications of this practice remain largely unexamined, representing a significant yet overlooked variable in many in vitro studies that serve as the foundation of T-cell biology. Here, we compared the effects of human and murine IL-2 on CD8 T cells in vitro to uncover potential differences in T-cell biology. Murine IL-2 more effectively supported the survival of mouse naïve CD8 T cells in vitro and induced a distinct phenotype of IL-2 receptor expression on activated mouse CD8 T cells. In addition, murine IL-2 promoted enhanced antigen-independent expansion of memory-like CD8 T cells from naïve animals. Collectively, these findings should encourage laboratories to reevaluate their human IL-2 dosing strategies or consider transitioning to murine IL-2 for in vitro studies using murine CD8 T cells.

DOI: https://doi.org/10.26508/lsa.202603711
Cancer Lett. 2026 Sep 19. pii: S0304-3835(26)00605-1. [Epub ahead of print]660 218841

T-cell exhaustion and senescence in cancer: Regulatory circuits and therapeutic state engineering.

Jiashu Han, Xiaohong Lyu, Mengwei Wu, Chen Lin, Yidong Zhou, Weibin Wang.

  In cancer, T-cell state strongly influences antitumor immunity and response to immunotherapy. High-parameter cytometry, single-cell transcriptomics, and multiomic profiling now resolve lineage identity, differentiation history, clonality, metabolic fitness, and tissue adaptation in parallel. These studies place naïve, activated, effector, memory, exhausted, and senescent T cells along continuous, context-dependent trajectories rather than within rigid subset boundaries. Their transitions are shaped by interacting transcriptional, epigenetic, signaling, and metabolic programs that integrate antigen strength, co-stimulation, and cytokines with cues from the tumor microenvironment. Within that microenvironment, suppressive myeloid, erythroid, and stromal populations, extracellular matrix (ECM) remodeling and spatial exclusion, nutrient competition, and tissue-specific conditioning impose a chronic stress that, together with sustained immune-checkpoint signaling, drives exhaustion and senescence and underlies immune evasion. This mechanistic view shifts the therapeutic question from how broadly to activate T cells to which states should be generated, preserved, or rescued. We organize dysfunctional T-cell states along five complementary dimensions: reversibility, antigen dependence, proliferative history, epigenetic fixation, and metabolic collapse. We then map precision cytokines, spatially restricted co-stimulation, metabolic interventions, epigenetic modulation, immune-checkpoint blockade, and genome engineering onto the state transitions they are intended to influence. This framework separates clinically established approaches from exploratory strategies and provides a testable basis for state-informed biomarker development and therapeutic design.

Keywords:  Cancer immunotherapy; Extracellular matrix; Immune checkpoint; Immune evasion; T-cell exhaustion; T-cell senescence; T-cell state engineering; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.canlet.2026.218841
Nat Immunol. 2026 Sep 23.

Author Correction: Mapping self-associating chromatin hubs identifies Id proteins as key determinants of exhausted CD8+ T cell fate.

Wei Hu, Qing Chen, Shaoqi Zhu, Shengen Shawn Hu, Haibo Yu, Vanita Patel, Ying Wang, Vladimir P Badovinac, Yi Zhang, Chongzhi Zang, Weiqun Peng, Hai-Hui Xue.

DOI: https://doi.org/10.1038/s41590-026-02695-0
Sci Signal. 2026 Sep 22. 19(956): eaef0327

PAG supports T cell immune synapse function by binding to actin.

Emily K Moore, Shoiab Bukhari, Justin Zhong, Carly Tymm, Matthieu Paiola, Shalom Lerrer, Marianne Strazza, Michael J Shannon, Xinping Xie, Emily M Mace, Robert Winchester, Adam Mor.

Immunotherapies affect T cell function by modifying the immune synapse, which forms at the interface between T cells and their targets. Phosphoprotein associated with glycosphingolipid-rich microdomains 1 (PAG) is a T cell adaptor protein within the immune synapse that mediates signaling by the inhibitory co-receptor PD-1. Because PAG undergoes palmitoylation, which positions it within plasma membrane lipid rafts, and contains a carboxyl-terminal PDZ-binding motif that connects to the actin cytoskeleton, PAG is a potential target for modulating immune function. Here, we investigated how PAG functioned with actin to regulate T cell immune synapse organization and function. We found that the dynamics of PAG and actin were closely synchronized during immune synapse maturation. Mutation of the PDZ-binding motif of PAG disrupted the PAG-actin interaction, impairing immune synapse formation, stability, and function. To assess the function of the PDZ-binding motif of PAG in vivo, we used mouse models of type IV hypersensitivity and highly immunogenic cancer. In both cases, mice with T cells expressing mutant PAG lacking this motif showed reduced immune responses, particularly in terms of cytotoxicity. These results highlight the importance of the PAG-actin connection for optimal formation and function of the T cell immune synapse. Our research indicates that targeting PAG may be a promising approach to improving immunotherapy in those patients who do not respond or experience immune-related adverse events.

DOI: https://doi.org/10.1126/scisignal.aef0327
Front Immunol. 2026 ;17 1898790

IL-10's contextual role in cytotoxic antitumor immunity: evidence, controversies, and therapeutic translation.

Minchuan Zhang, Qi-Jing Li, Kong Peng Lam, Shengli Xu.

  Interleukin-10 (IL-10) is classically defined as a potent anti-inflammatory cytokine that protects tissues by constraining myeloid activation and limiting inflammatory cytokine production. Yet, accumulating evidence indicates that, in defined contexts, IL-10 can also promote antitumor immunity by enhancing the fitness and cytotoxic programs of CD8+ T cells and natural killer (NK) cells. Conversely, in other tumor contexts, IL-10 may reinforce immunosuppressive myeloid and regulatory programs, and the factors that determine these divergent outcomes remain incompletely understood. Although these effects converge on a common JAK1/TYK2-STAT3 signaling hub, the downstream biological outcomes are combinatorially shaped by the identity, activation, and chromatin state of the responding cell, co-engaged pathways, including STAT1, mTORC1, and NF-κB/AP, receptor abundance, feedback regulation, and the surrounding microenvironment. Recent studies suggest IL-10 can sustain cytotoxic lymphocyte function under tumor microenvironmental stress through effector programming, restraint of terminal exhaustion, mitochondrial metabolic reprogramming, and remodeling of the tumor microenvironment (TME). However, several of these mechanisms remain supported primarily by limited preclinical models and correlative human data. These advances have promoted the development of pharmacokinetically optimized IL-10 variants, tumor-targeted immunocytokines, surrogate bispecific IL-10 receptor agonists, and IL-10-armored adoptive cell therapies. Although several approaches have shown immune activation and preliminary antitumor activity in early-phase studies, pegilodecakin-the only IL-10-based agent to complete a randomized phase III oncology trial-did not improve survival in gemcitabine-refractory pancreatic cancer, underscoring the gap between pharmacodynamic activity and established clinical benefit. In this review, we synthesize mechanistic and translational advances with conflicting and cautionary evidence, discuss safety considerations associated with IL-10-based agents and IL-10-armored cell therapies, and propose a context-dependent framework for their further development based on tumor and microenvironmental features, spatiotemporal control, rational combination strategies, and candidate biomarkers.

Keywords:  CAR-T cell; CD8+ T cells; IL-10 receptor blockade; T-cell exhaustion; cancer immunotherapy; interleukin-10; metabolic reprogramming; natural killer cells

DOI:  https://doi.org/10.3389/fimmu.2026.1898790
Small. 2026 Sep 22. e75859

Mechano-Chemical Coordination of Nanoparticle-Based Artificial Antigen-Presenting Cells Synergistically Tunes T Cell Activation and Expansion Phenotypes.

Zichao Guo, Fei Hou, Yali Zhang, Zilin Ye, Yang Li, Supun Ranaweera, Yue Hui, Chun-Xia Zhao.

  Particle-based artificial antigen-presenting cells (aAPCs) are widely used for ex vivo T cell activation, but rigid, high-avidity stimulation can promote differentiation and exhaustion, reducing therapeutic efficacy. Because T cells sense mechanical forces through the T cell receptor, we engineered nanocapsule aAPCs with three stiffness regimes, spanning MPa to GPa Young's moduli, and two αCD3/αCD28 ligand densities to define how mechanical and biochemical cues shape primary human T cell responses. Across six formulations benchmarked against Dynabeads, stiffness and ligand density acted as orthogonal but synergistic design parameters. Expansion increased with both variables, and the stiff, high-density nanocapsules matched or exceeded Dynabead-mediated expansion by day 8. However, unlike Dynabeads, enhanced expansion did not coincide with strong exhaustion or terminal differentiation. Nanocapsules maintained CD8+ PD-1+ frequencies near baseline, mitigated Dynabead-associated CD4+ bias, and promoted CD8 enrichment, with CD8/CD4 ratios reaching approximately 2.7. They also produced transient, tunable CD25 upregulation, reduced granzyme B expression, and preserved TCF-1+ stem-like populations depending on signal strength. These results establish mechano-chemically tunable nanocapsule aAPCs as a versatile platform for generating expanded, CD8-enriched T cell products with reduced exhaustion-associated phenotypes for adoptive cell therapy manufacturing and provide a rational framework for programmable T cell product design ex vivo applications.

Keywords:  T cell activation; aAPCs; antibody density; immunotherapy; mechanotransduction; silica nanocapsules; stiffness

DOI:  https://doi.org/10.1002/smll.75859
Nat Commun. 2026 Aug 21. pii: 10008. [Epub ahead of print]17(1):

Sex-specific trajectories of nonlinear immune aging at single-cell level.

Harry Park, Nina Le Bert, Antonio Bertoletti, Nicholas Tolwinski, Jan Gruber, Jacques Behmoaras.

Despite the female predominance in age- and immune-associated diseases, the pathways underlying sex differences in healthy immune aging remain incompletely understood. Here, we analyze a multi-ethnic single-cell transcriptome of healthy human immune aging (35% Asian), comprising 3.8 million peripheral blood mononuclear cells (PBMCs) from 1,828 individuals aged 19-97 years. Prominent peaks of differential gene expression around 40 (mainly CD4 T cells) and after 60 (mainly CD8 T cells) years of age were accompanied by an age-dependent decline in RNA/protein homeostasis and inflammatory PBMC polarization with sex-dependent kinetics. While females displayed sustained CD8 T cell activation and late-life aging signatures in CD4 T, NK, and B cells, males exhibited early-life fluctuations in CD4 T cell immunometabolism associated with hypomethylation of SSH3 at chromosome 11q13. Deep learning-based biological age clocks stratified for sex outperformed sex-combined models, learning from transcriptional immune trajectories. We thus unravel a nonlinear PBMC aging whereby targeting sex-specific pathways might allow precision geromedicine.

DOI: https://doi.org/10.1038/s41467-026-76737-4
J Exp Med. 2026 Oct 05. pii: e20261490. [Epub ahead of print]223(10):

Slow-cooked naive T cells make better effectors.

Hee Yeun Won, Jung-Hyun Park.

While the TCR diversity of naive T cells is well established, the extent of their functional heterogeneity remains largely uncharted. In this issue of JEM, Sajiki et al. (https://doi.org/10.1084/jem.20252076) demonstrate that long-lived naive CD8 T cells accrue tonic TCR signaling during homeostasis, driving their differentiation into functionally superior effectors.

DOI: https://doi.org/10.1084/jem.20261490
Res Sq. 2026 Sep 14. pii: rs.3.rs-10935206. [Epub ahead of print]

Transient architecture of the embryonic pancreas determines endocrine mass.

Neha H Ahuja, Christopher Chaney, Tyler Bierschenk, Tuli Pramanik, Austin Mills, Peter M Luo, Mitzy A Cowdin, Jinlong Lin, Jun Tsunezumi, Kevin M Dean, Denise K Marciano, Thomas J Carroll, Ondine Cleaver.

  During organogenesis, epithelial tissues undergo extensive three-dimensional remodeling while simultaneously generating specialized cell types, yet whether transient architectural states actively instruct lineage allocation remains unclear. During pancreas development, de novo lumen formation transforms a stratified epithelium into a transient lumenal plexus from which endocrine, acinar and ductal lineages emerge. Here we identify the mechanosensitive Hippo pathway regulator Merlin as a critical link between epithelial architecture and cell fate. Loss of Merlin impairs de novo lumen formation, preventing epithelial destratification and establishment of the pancreatic plexus. Disruption of this architecture alters lineage allocation, impairing acinar differentiation and ultimately reducing adult endocrine cell mass and glucose homeostasis. Mosaic deletion reveals that these lineage defects arise non-cell autonomously, demonstrating that epithelial architecture itself instructs cell fate decisions. Mechanistically, Merlin coordinates polarized membrane trafficking to nascent lumens and restrains PI3K signaling; PI3K activation phenocopies Merlin loss, whereas PI3K inhibition partially rescues epithelial morphogenesis. Together, these findings establish the pancreatic plexus as an instructive developmental niche and reveal how transient tissue architecture can shape the cellular composition and function of mature organs.

Keywords:  Crumbs3; Ezrin; Hippo; Merlin; Nf2; PI3K; Pancreas; Rab11; Rab5; Yap1; cell fate; endocrine mass; epithelial architecture; epithelium; lumen; lumenogenesis; morphogenesis; organogenesis; plexus; vesicle trafficking

DOI:  https://doi.org/10.21203/rs.3.rs-10935206/v1
Oncol Res. 2026 ;34(10): 10

Metabolic Reprogramming in Gastric Cancer Immunity Mechanisms and Therapeutic Implications.

Xiangyang Wang, Ying Wu, Yutong Fu, Ejakpovi Emmanuel Oghenefejiro, Zakari Shaibu, Cunxi Li, Qi Zhou, Liang Yin.

  Gastric cancer (GC) remains a leading cause of global cancer mortality, with progression and therapy resistance heavily influenced by the dynamic tumor microenvironment (TME). Despite advances in surgical techniques, chemotherapy, targeted therapy, and immunotherapy, overall survival for advanced disease remains poor, underscoring the need for a deeper understanding of resistance mechanisms. A hallmark of the TME is metabolic reprogramming, which sustains tumor growth and actively shapes an immunosuppressive landscape. This review aims to detail the coordinated metabolic adaptations of GC cells, cancer-associated fibroblasts (CAFs), and immune cells within the TME, focusing on nutrient competition, immunosuppressive metabolite accumulation, and dysregulated lipid metabolism. We analyze how glucose depletion, lactate accumulation, and amino acid deprivation establish a hostile metabolic niche that impairs cytotoxic T lymphocyte (CTL) function while paradoxically supporting regulatory T cells (Tregs), M2-like tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs). We examine four major immunosuppressive metabolic pathways, lactate, adenosine, tryptophan-kynurenine, and arginine and demonstrate their convergence on immune checkpoint upregulation, forming an integrated metabolic-immune checkpoint axis. These pathways establish a self-reinforcing immunosuppressive circuit that drives T cell exhaustion and limits immune checkpoint blockade efficacy. We highlight emerging therapeutic strategies targeting this crosstalk, including inhibitors of glycolysis, glutaminolysis, indoleamine 2,3-dioxygenase 1 (IDO1), and adenosine signaling, often combined with immunotherapy. The metabolic supply-demand mismatch explains why certain interventions can revive effector cells while potentially harming other cell types. Finally, we discuss challenges and future directions, emphasizing the need for spatially resolved metabolic profiling, biomarker-driven patient stratification, and personalized therapies to overcome metabolic immunosuppression and improve clinical outcomes in GC.

Keywords:  Gastric cancer (GC); immunometabolism; immunotherapy; metabolic reprogramming; tumor microenvironment (TME)

DOI:  https://doi.org/10.32604/or.2026.087144
Nat Cardiovasc Res. 2026 Sep 22.

Bioadaptive spatiotemporal nanomedicine promotes metabolic recovery after myocardial infarction through NAD+ and UCP2 regulation.

Jue Wang, Yingci Xia, Wenxuan Zheng, Wenqin Yuan, Yunying Huang, Yuntao Zhang, Qiong Huang, Kelong Ai.

Myocardial infarction causes persistent mitochondrial and metabolic dysfunction that drives adverse cardiac remodeling. Here we develop NAD+-genipin nanomedicine for metabolic balance (NGB), a physiologically adaptive nanomedicine with staged intracellular release. In a mouse myocardial infarction model, NGB preferentially accumulates in ischemic myocardium, rapidly replenishes nicotinamide adenine dinucleotide (NAD+) and subsequently provides mitochondria-associated sustained NAD+-genipin exposure. This phase-linked delivery limits early mitochondrial stress, apoptosis and inflammation and later restores coordination between oxidative phosphorylation, glycolysis and fatty-acid utilization. Mechanistically, NGB supports sirtuin-1-associated oxidative metabolism and suppresses sustained upregulation of the mitochondrial uncoupling protein 2 (UCP2). In hypoxic cardiomyocytes, UCP2 knockdown plus NAD+ supplementation partially reproduces the NGB metabolic phenotype, whereas UCP2 overexpression and sirtuin 1 inhibition reverse distinct components of NGB-mediated respiratory and glycolytic recovery. NGB thereby reduces fibrosis and ventricular remodeling and preserves cardiac function, supporting temporally coordinated metabolic intervention after myocardial infarction.

DOI: https://doi.org/10.1038/s44161-026-00874-8
Front Immunol. 2026 ;17 1917606

PD-L1+ neutrophils at the invasive margin drive contact-dependent CD8+ T cell exhaustion in hepatic alveolar echinococcosis.

Dalin Shi, Chengwei Tie, Mingquan Pang, Xiaolei Xu, Zhixin Wang, Haijiu Wang, Haining Fan.

   Introduction: Hepatic alveolar echinococcosis (HAE), a lethal chronic helminth infection caused by Echinococcus multilocularis, is characterized by pronounced local immune evasion and progressive CD8+ T cell exhaustion at the parasite?host invasive margin. However, the spatial cellular network and core regulatory subsets driving this localizedimmunosuppression remainpoorly understood.
Methods: We performed high-resolution spatial immune profiling of the lesion invasive margin (collagenous layer tissue, CLT) and paired distal normal liver tissues (DLT) from 12 HAE patients by integrating imaging mass cytometry, single-cell RNA sequencing, and multiplex immunofluorescence. The underlying molecular mechanism was validated via in vitro co-culture assays with or without Transwell physical separation, and the therapeutic potential was further confirmed in a delayed?treatment HAE mouse model using neutrophil depletion(anti-Ly6G) or PD-L1 blockade (anti-PD-L1).
Results: Spatial multi-omics identified a specific subset of APC-like PD-L1 neutrophils exclusively enriched at the HAE invasive margin, which showed striking spatial co-localization and frequent membrane-to-membrane contacts with PD-1 CD8 T cells. In vitro, activated CD8 Tcells potently induced PD-L1 upregulation on neutrophils; reciprocally, PD-L1 neutrophils significantly suppressed T cell effector function (downregulating GZMB, IFN-γ, and TNF-α) and upregulated exhaustion-associated transcription factors TOX and NR4A1 via a contact-dependent PD-L1/PD-1 pathway, effects largely abolished by Transwell separation. In the HAE mouse model, both neutrophil depletion and PD-L1 blockade significantly reduced parasite burden, alleviated liver inflammation and fibrosis, and restored CD8 T cell cytotoxicity; notably, neutrophil depletion achieved superior therapeutic efficacy compared with PD-L1 monotherapy.
Conclusion: Collectively, our findings demonstrate that PD-L1-expressing neutrophils at the HAE invasivefront contribute importantly to localized CD8 T cell exhaustion via direct cell-cell contact, anddisrupting this crosstalk represents a promising targeted strategy to restore host protective immunity against parasitic infection.

Keywords:  CD8+ T cell exhaustion; PD-L1+ neutrophils; PD-L1/PD-1 axis; hepatic alveolar echinococcosis; spatial immune niche

DOI:  https://doi.org/10.3389/fimmu.2026.1917606
Trends Mol Med. 2026 Sep 21. pii: S1471-4914(26)00217-0. [Epub ahead of print]

The splicing axis of aging: mechanisms and therapeutic opportunities.

Sada Raza, Ankita Kumari, Maciej Cieśla.

  Aging is characterized by progressive loss of molecular fidelity that compromises stem-cell function and tissue homeostasis. Aging transcriptomes show widespread disruption of RNA processing, including increased intron retention, cryptic splice-site usage, and altered RNA quality control. These changes arise from somatic mutations as well as accumulated transcriptional, metabolic, and proteostatic stress. Importantly, similar splicing abnormalities are observed in age-associated diseases such as clonal hematopoiesis and neurodegeneration, overlapping with physiological aging states. Here, we synthesize mechanistic, stem-cell, and longevity studies to define declining RNA-processing fidelity as a unifying contributor to aging across systems. We propose the 'splicing axis of aging' as a framework linking RNA-processing dysfunction to tissue decline and outline emerging therapeutic strategies to restore spliceosome integrity and RNA homeostasis.

Keywords:  clonal hematopoiesis; gene expression; neurodegeneration; spliceosome; splicing; tissue aging

DOI:  https://doi.org/10.1016/j.molmed.2026.09.001
Int J Mol Sci. 2026 Sep 19. pii: 8338. [Epub ahead of print]27(18):

HLA-II Expression Marks Activated and Clonally Expanded CD8+ T Cells and Improves Tumor-Reactivity Prediction Across Human Cancers.

Xue Mi, Jinghua Zhu, Zhu Dai, Ruyue Yang, Dongmei Tian, Guochun Cao, Zhongdang Xiao.

  Tumor-infiltrating CD8+ T cells are transcriptionally heterogeneous, and robust features linking their clonal dynamics to experimentally defined tumor reactivity remain incompletely characterized. We integrated single-cell RNA sequencing (scRNA-seq) and paired T-cell receptor sequencing (scTCR-seq) data from 31 single-cell immune datasets to characterize CD8+ T-cell states associated with clonal expansion and tumor reactivity. Across cancers, HLA-II-expressing CD8+ T cells were enriched in activated, cytotoxic, proliferative, exhausted, and terminally differentiated states and were preferentially associated with expanded TCR clonotypes. Pseudotime analysis indicated that HLA-II expression occurs along late differentiation states. HLA-DR blockade reduced CD25 upregulation in activated mixed PBMC and purified CD8+ T-cell cultures and attenuated CellTrace CFSE dilution in purified CD8+ T cells. An HLA-II-associated CD8+ T-cell signature showed cancer-type-dependent survival associations, including longer overall survival in several cohorts. To evaluate its contribution to tumor-reactivity prediction, an expansion-pretrained DNN was adapted using experimentally annotated tumor-reactive and non-tumor-reactive clonotypes from six pancreatic ductal adenocarcinoma samples and evaluated in 2225 functionally annotated CD8+ T cells from three held-out samples. Adding six HLA-II genes improved ROC-AUC across three feature panels from 0.540 to 0.781, 0.626 to 0.732, and 0.838 to 0.878, respectively, and improved PR-AUC from 0.570 to 0.739, 0.640 to 0.718, and 0.799 to 0.869. These findings identify HLA-II expression as a feature of activated and clonally expanded CD8+ T-cell states and support the complementary value of HLA-II-associated transcriptional features for prioritizing candidate tumor-reactive TCRs.

Keywords:  HLA-II+ CD8+ T cell; TCR-epitope; biomedical engineering; deep learning; single-cell

DOI:  https://doi.org/10.3390/ijms27188338
Mol Ther Nucleic Acids. 2026 Dec 08. 37(4): 103076

Novel lipid nanoparticle in a mRNA cancer vaccine drives tumor control via type I IFNs and effector CD8+ T cells.

Matthew J Gold, Douglas G Millar, Jun Liu, Haritha Menon, Yury Karpov, Kirstin Olsen, Liliam Teixeira Oliveira, Charlotte Dubé, Charles W Tran, Alisha R Elford, Jordan A Schwartz, Rajesh Krishnan Gopalakrishna Panicker, Eric G Marcusson, Pamela S Ohashi, Natalia Martin Orozco.

  mRNA based vaccines utilizing lipid-based delivery systems have been used for cancer therapy with some success targeting tumor-associated antigens (TAAs) or neoantigens. However, in many patients, T cell exhaustion or tumor suppression impedes the induction of a protective anti-tumor T cell response, which suggests that additional activation signals are required to reduce antagonistic tumor effects and reinvigorate the T cells. Here we sought to evaluate novel ionizable lipids for lipid nanoparticle (LNP)-formulations containing a tumor antigen mRNA as a therapeutic treatment for solid tumors and identify key immunogenic features of successful ionizable lipid candidates. Focusing on the induction of a tissue-destructive immune response became the ideal in vivo screening to compare two novel ionizable lipids, INTENT-1 and INTENT-2. Both LNPs carrying the same mRNA- encoded antigen induced similar CD8+ T cell responses, but only INTENT-2.1 LNPs could cause tissue destruction. Mechanism-of-action studies revealed that INTENT-2.1, but not INTENT-1.1 LNP, induced type I interferons independently of the mRNA to enhance anti-tissue CD8+ T cell responses. These results demonstrate the efficacy of INTENT-2.1 LNP for cancer vaccines, shed light on its mechanism of action, and support its use in clinical trials to treat solid tumors.

Keywords:  MT: clinical applications; cancer immunotherapy; cellular immunity; mRNA/LNP; therapeutic cancer vaccine; type I IFN

DOI:  https://doi.org/10.1016/j.omtn.2026.103076
Cancer Lett. 2026 Sep 19. pii: S0304-3835(26)00607-5. [Epub ahead of print]660 218843

Tumor-cell HMGB1 restrains CD8+ T-cell immunity during conventional fractionated radiotherapy.

Chen Chen, Jiahong Shi, Peihai Cao, Juan Bai, Yutiantian Lei, Mengdi Huang, Mingjun Si, Ruiying Wang, Tingting Lv, Rui Jia, Qiuyu Mu, Dingge Jiang, Yuzhu Hou, Shan Huang.

  Conventional fractionated radiotherapy (CFRT) remains a mainstay for many solid tumors, yet it often fails to elicit durable anti-tumor immunity. How CFRT engages tumor-cell programs to shape the immune microenvironment and determine therapeutic outcome remains unclear. Here we show in preclinical mouse models that CFRT is associated with increased tumor-cell HMGB1 relative to stereotactic body radiotherapy (SBRT), and that loss of tumor-cell HMGB1 eliminates the efficacy gap between the regimens. HMGB1 deficiency markedly restrains tumor progression under CFRT in immunocompetent, but not immunodeficient, hosts, accompanied by increased intratumoral CD8+ T cells and effector function. In esophageal squamous cell carcinoma (ESCC) specimens from patients receiving CFRT plus platinum-based chemotherapy, tumor-cell HMGB1 increases after treatment, and elevated pretreatment HMGB1 is associated with poor treatment response, reduced post-treatment CD8+ T-cell infiltration, and adverse outcomes. Mechanistically, HMGB1 restrains CFRT-induced CD8+ T-cell immunity through two convergent arms: CCL2-CCR2-dependent accumulation of suppressive monocytes and FUT8-linked regulation of PD-L1 fucosylation in tumor cells. TCF4 is linked to HMGB1-dependent induction of CCL2 and FUT8. Blocking CCL2 or inhibiting PD-L1 fucosylation restores CD8+ T-cell effector function and enhances CFRT efficacy, alone or in combination with anti-PD-1 therapy. Together, these findings identify a tumor-cell HMGB1 program that underpins CFRT-associated immune suppression and nominate actionable targets to improve CFRT-immunotherapy combinations.

Keywords:  CD8(+) T cells; ESCC; HMGB1; Immunosuppression; Radiotherapy

DOI:  https://doi.org/10.1016/j.canlet.2026.218843
Signal Transduct Target Ther. 2026 Sep 23. pii: 404. [Epub ahead of print]11(1):

Targeting BIRC6 rejuvenates hematopoietic stem cell aging and immunosenescence.

Weinian Liao, Fangze Shao, Shaoyan Wang, Yetong Wang, Xinliang Chen, Yue Zhang, Zhang Zhang, Xiaodong Zai, Yilong Yang, Ying Yin, Youliang Wang, Jun Zhang, Junping Wang, Junjie Xu.

Immunosenescence represents a central hallmark of organismal aging, characterized by a progressive decline in immune function, which compromises host defense and accelerates systemic aging. Hematopoietic stem cell (HSC) aging is a key contributor to this process, characterized by aberrant expansion, myeloid-biased differentiation, and impaired self-renewal, culminating in hematopoietic-immune imbalance. Although the expansion and survival advantages of aged HSCs have been well-demonstrated, the underlying mechanisms remain elusive. Here, we reveal that regulatory T cells (Tregs) within the bone marrow (BM) microenvironment actively safeguard the survival of aged HSCs via a previously uncharacterized signaling pathway. We identify a novel aged HSC subpopulation characterized by high expression of Baculoviral IAP Repeat Containing 6 (BIRC6), an apoptosis inhibitor. This BIRC6-high subpopulation is markedly expanded in aged mice and recapitulates the hallmarks of HSC aging. Mechanistically, cAMP derived from BM Tregs activates the PKA-CREB pathway in HSCs, activating Birc6 transcription, which reduces apoptotic priming in aged HSCs, thereby promoting hematopoietic-immune imbalance. Strikingly, targeted BIRC6 inhibition in HSCs using antibody-conjugated lipid nanoparticle-encapsulated antisense oligonucleotides (LNP-ASOs) significantly reverses hematopoietic-immune aging phenotypes and ameliorates age-associated immune dysfunction in middle-aged mice. LNP-ASO treatment dramatically rebalances immune cell production, reduces immunosenescence markers, and enhances vaccine responses in middle-aged mice. More importantly, this strategy was also effective in HSCs from middle-aged human donors, highlighting its potential for clinical translation. These findings elucidate a key microenvironmental pathway (Treg-cAMP-PKA-CREB-BIRC6) driving HSC aging and offer a novel strategy to ameliorate the aged hematopoietic system and combat age-related immune decline.

DOI: https://doi.org/10.1038/s41392-026-02787-1
J Ovarian Res. 2026 Aug 29. pii: 293. [Epub ahead of print]19(1):

Restoring glucose metabolic homeostasis to attenuate ovarian aging: mechanisms and clinical prospects.

Genping Zeng, Mengyuan Chu, Jiaqi Yang, Yunfei Han, Qianyi Zhou, Han Zhang, Ying Yan.

  Ovarian aging has emerged as a major challenge to female reproductive health worldwide, primarily characterized by a decline in oocyte quality and/or quantity, diminished granulosa cell function, and impairment of the surrounding microenvironment. Within this microenvironment, glucose metabolism participates in the synergistic regulation of ovarian homeostasis through specific metabolic networks and metabolite-driven signaling. Metabolic disruption can impair intercellular communication mechanisms, induce oxidative stress and mitochondrial dysfunction, and ultimately drive ovarian aging. Ovarian granulosa cells surround the oocyte and facilitate bidirectional communication via gap junctions or molecular signaling. These cells continuously supply energy substrates to support oocyte growth and maturation, while the oocyte, in turn, promotes granulosa cell proliferation and differentiation. Impairment of glycolysis in granulosa cells leads to energy deficits and triggers apoptosis. Concurrently, metabolic reprogramming in the oocyte links glucose metabolic homeostasis with mechanisms governing developmental competence. Glucose-derived metabolites drive various post-translational modifications (PTMs), including glycosylation, acetylation, phosphorylation, and succinylation, that contribute to ovarian function and intersect with pathological processes such as oxidative stress, chronic inflammation, and autophagy. Therefore, therapeutic strategies targeting glucose metabolism, such as modulating metabolic pathways, metabolite signaling, and associated PTMs, offer promising avenues for treating ovarian aging. However, the glucose metabolic network within the ovarian microenvironment is highly complex, and targeting a single node is often insufficient to restore metabolic homeostasis. A comprehensive approach that integrates multiple strategies to simultaneously intervene at different regulatory levels is needed. This review summarizes recent advances in understanding the ovarian glucose metabolic network, metabolite-driven post-translational modifications, and the interplay among various pathological mechanisms. We further explore potential regulators that could restore glucose metabolic balance and propose that future efforts should focus on developing precision strategies, guided by artificial intelligence and multi-omics data to modulate the metabolic reprogramming of both the microenvironment and functional cells, ultimately translating these insights into clinical interventions for ovarian aging.

Keywords:  Glucose Metabolism; Metabolic Homeostasis; Metabolic Reprogramming; Ovarian Aging; Post-translational Modifications; Therapeutic Target

DOI:  https://doi.org/10.1186/s13048-026-02244-1