bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2026–06–14
forty-two papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Cysteine's metabolic fork: Sulfur partitioning shapes T cell function.
  2. CD7 drives CD8 T cell exhaustion during chronic viral infection.
  3. Targeting TMED4 enhances CD8+ T cell function and CAR T cell efficacy in solid tumors through the IRE1α-autophagy axis.
  4. Limited adaptability of virtual memory CD8 T cells to chronic viral infection.
  5. Quercetin targets BCAT1 to potentiate CD8+ T cell immunity by rewiring branched-chain amino acid metabolism against colorectal cancer metastasis.
  6. m6A-Mediated Glycolysis by IL-37 Drives T Cell Metabolic Reprogramming to Regulate Colitis.
  7. Materials-Guided Gene-Ionizable Lipid Nanoparticles to Reverse Iron-Associated Immune Resistance in Renal Cancer.
  8. Exhaustion in name only: CD8+ T cells drive lupus nephritis.
  9. Metabolic Regulation of Immune Responses: Molecular Mechanisms, Diseases, and Therapeutic Targets.
  10. Sleeve Gastrectomy Is Associated with Improved Systemic Redox Homeostasis in T2DM Through Ghrelin-GHSR Attenuation, POMC Neuronal Modulation, and CD4+ T Cell Metabolic Reprogramming.
  11. Manufacturing strategies for prolonged CAR-T cell persistence.
  12. Mitochondrial remodeling by lithium drives CD4+ naïve T cell fate and immune homeostasis in bipolar disorder.
  13. Critical illness expands a transcriptionally distinct hypometabolic CD8 + T effector program associated with respiratory failure and mortality.
  14. Immunosenescence and cancer predisposition in pediatric transplant recipients: An emerging paradigm.
  15. Longitudinal spatial neutrophil profiling during ACT in murine melanoma reveals distinct lymph node infiltration patterns.
  16. Ferro-Aging: A Novel Paradigm Linking Iron Overload, Lipid Peroxidation and Cellular Senescence.
  17. CD8 T-cell activation occurs 24 hours post-AAV administration and is driven by muscle promoter specificity.
  18. Systematic review assesses link between physical activity and epigenetic age.
  19. Preserved CD4 + T cell helper function and coordinated antiviral immunity in people with HBV/HIV co-infection on long-term therapy.
  20. Distinct T cell lineages marked by expression of cd4 paralogues in medaka.
  21. An overview of current research on exercise interventions in aging and aging-related disease.
  22. Peptide-MHC-targeted engineered virus-like particles enable selective priming and gene editing of tumor-specific T cells.
  23. Jump-starting the T cell response in established tumors.
  24. Topical resiquimod elicits systemic protection and improves anti-PD1 therapy in melanoma via priming of CD8+ T cells.
  25. Local delivery of GPC3-CAR T cells in a thermosensitive hydrogel enhances antitumor efficacy in hepatocellular carcinoma.
  26. HBV-driven expansion of CXCR6+-exhausted T cells and CXCL16+ macrophage interaction: Implications for immunotherapy in HCC.
  27. In vitro generation of RORγt+ regulatory T cells reveals enhanced immunosuppressive function and OXPHOS-dependent metabolism.
  28. Mitochondrial transfer between tumor and immune cells: a nexus of metabolic adaptation and immune dysfunction.
  29. Placental nicotinamide adenine dinucleotide modulates the timing of labor.
  30. Depletion of NAT10 in T cells attenuates metabolic dysfunction-associated steatohepatitis in mice.
  31. Tumor-resident T cells and dendritic cells form an in situ archetype during immunotherapy response in melanoma.
  32. Deviation from physiologically appropriate oxygen levels alters proliferation, cytokine production and proximal antigen receptor signalling in CD4+ memory T cells.
  33. Mitochondrial Metabolic Reprogramming in Colorectal Cancer-Associated Fibroblasts: An Up-to-Date Review.
  34. DNA hypomethylating agents preserve T cell stemness and potentiate the efficacy of CD3-bispecific antibodies.
  35. Time-restricted feeding rejuvenates cerebrovascular function and preserves cognition during aging.
  36. Unraveling the intricate link: gut microbiota and recurrent spontaneous abortion.
  37. HIRA-mediated H3.3 deposition preserves hepatocyte cell identity during liver aging.
  38. Intracellular CD3 and surface CD8β distinguish activated human T cells from natural killer cells after αCD3/αCD28 stimulation.
  39. Neutrophil immunometabolism in ACLF and sepsis: mechanisms, dysfunction, and therapeutic opportunities.
  40. Single-cell characterization of the CD8+ T cell landscape and repertoire in HIV-1 Infection following antiretroviral therapy.
  41. Dysregulated transcription in core- and pol-specific CD8 T cells can be targeted by HDAC inhibition to improve T-cell function in chronic hepatitis B.
  42. mRNA-LNP vaccine providing antigen and co-stimulation in the tumor microenvironment enhances CAR T cell function (CART-Vac).
  1. Cell. 2026 Jun 11. pii: S0092-8674(26)00570-2. [Epub ahead of print]189(12): 3506-3508
    Cysteine's metabolic fork: Sulfur partitioning shapes T cell function.
    Melanie Grusdat, Dirk Brenner.
      T cells live or die by their metabolism, yet one nutrient can serve very different ends. In this issue of Cell, Kelly et al. show that cysteine's sulfur is partitioned between glutathione and iron-sulfur cluster synthesis. This routing drives CD8+ T cell proliferation, effector function, and anti-tumor immunity.
    DOI:  https://doi.org/10.1016/j.cell.2026.05.011
  2. J Immunol. 2026 06 07. pii: vkag091. [Epub ahead of print]215(6):
    CD7 drives CD8 T cell exhaustion during chronic viral infection.
    Kayla Reisch, Amanda Scherer, Rebecca Bartell, Fernando Santana, Peng Shao, Noah S Butler, Ryan Zander.
      Viral or tumor persistence is often associated with CD8 T cell "exhaustion," a differentiation process characterized by co-inhibitory receptor upregulation and loss of effector function. Recent data show that "exhausted" T cells are a heterogenous population that includes a progenitor subset that transitions through an intermediate state before bifurcating into either terminally exhausted cells or cytolytic effector cells crucial for viral or tumor control. However, the mechanisms underlying this bifurcation process remains unclear. In this study, we show that the Ig superfamily member CD7 is selectively upregulated on terminally exhausted T cells responding to chronic viral infection and cancer. Genetic deletion of CD7 in virus-specific CD8 T cells resulted in an expansion of effector T cells and reduced exhausted T cell formation, decreased inhibitory receptor expression, and augmented IFN-γ secretion following chronic lymphocytic choriomeningitis virus (LCMV) infection in mice. Deletion of CD7 in antigen-specific CD8 T cells conferred enhanced control over viral replication during chronic LCMV infection and suppressed tumor outgrowth in a preclinical lung cancer model. Conversely, retroviral overexpression of CD7 was sufficient to drive T cell exhaustion and upregulate expression of immune checkpoint inhibitory receptors and the transcription factor Tox. Mechanistically, our data indicate that CD7 may function to amplify TCR signaling strength and the induction of TCR-sensitive transcription factors such as Nur77 and Tox that program T cell exhaustion. These data highlight CD7 as a potential therapeutic target that can be manipulated to improve effector CD8 T cell-mediated control over chronic infection and/or malignancy.
    Keywords:  CD7; CD8 T cell differentiation; T cell exhaustion
    DOI:  https://doi.org/10.1093/jimmun/vkag091
  3. Sci Adv. 2026 Jun 12. 12(24): eaee0517
    Targeting TMED4 enhances CD8+ T cell function and CAR T cell efficacy in solid tumors through the IRE1α-autophagy axis.
    Huizi Wang, Licai Shi, Ke Jiang, Shuyao Wu, Zhenyan Jiang, Yuexiao Tao, Jia Li, Xin Li, Jiamin Liu, Jun Ni, Emily Jiatong Wu, Sophia Jiaxin Wu, Guang Chen, Ming Qin, Lin Xu, Chu-Hu Lai, Alexandra Aicher, Youqiong Ye, Christopher Heeschen, Yu J Cao, Xuefeng Wu.
      Endoplasmic reticulum stress (ERS) and autophagy regulate tumor-infiltrating T cell function and exhaustion, but the underlying mechanisms remain unclear. Here, we identified the ERS-related transmembrane protein TMED4 (transmembrane emp24 domain-containing 4) as a critical regulator of CD8+ T cell antitumor immunity. Tmed4 deletion in T cells enhanced antitumor responses by promoting CD8+ T proliferation, infiltration, and killing capacity, while reducing terminal exhaustion. Mechanistically, Tmed4 deficiency hyperactivated the inositol-requiring enzyme 1α (IRE1α)-X-box binding protein 1 (XBP1) axis and induced autophagy flux in an IRE1α-dependent manner. Genetic deletion of Ern1 (IRE1α) or Becn1 (Beclin1) impaired the antitumor effects of Tmed4 deficiency, underscoring the role of ERS and autophagy in CD8+ T cell function. Moreover, Tmed4-deficient chimeric antigen receptor T cells (CAR T cells) displayed improved antitumor immunity. Pharmacological inhibition of Tmed4 using antisense oligonucleotide also enhanced CD8+ T cell-mediated tumor control. In summary, our study reveals that TMED4 governs CD8+ T cell effector function and limits terminal exhaustion through IRE1α-driven autophagy, establishing TMED4 as a promising immunotherapeutic target for improving CAR T cell efficacy.
    DOI:  https://doi.org/10.1126/sciadv.aee0517
  4. Front Immunol. 2026 ;17 1804320
    Limited adaptability of virtual memory CD8 T cells to chronic viral infection.
    Yamato Sajiki, Yi-Chung Huang, Charles M Perkins, Satomi Ando, Koichi Araki.
      Antigen-inexperienced CD8 T cells include naïve and virtual memory (VM) subsets. VM CD8 T cells exhibit a memory-like phenotype despite lacking prior exposure to their specific antigen. While they can efficiently respond to and control acute infections where pathogens are cleared, their response during chronic infection remains poorly characterized. Using a chronic lymphocytic choriomeningitis virus infection model, we found that VM CD8 T cells exhibit a diminished response to persistent antigen stimulation compared to naïve CD8 T cells. Mechanistically, VM CD8 T cells show impaired engagement of the T cell exhaustion program due to lower TOX expression, resulting in a marked reduction of TCF1+ stem-like CD8 T cells which are critical for sustaining antigen-specific responses during chronic infection. Instead, VM CD8 T cells preferentially differentiate into KLRG1+PD-1- cells, a population rarely observed in naïve-derived progeny. Moreover, VM-derived CD8 T cells exhibit limited expansion following PD-1 blockade, consistent with their reduced TCF1+ stem-like compartment. In summary, VM CD8 T cells fail to properly engage the exhaustion program during chronic viral infection, leading to a fundamental limitation in their adaptability to persistent antigen-stimulation.
    Keywords:  CD8 T cells; chronic infection; immunotherapy; t cell exhaustion; virtual memory
    DOI:  https://doi.org/10.3389/fimmu.2026.1804320
  5. Phytomedicine. 2026 Jun 05. pii: S0944-7113(26)00614-8. [Epub ahead of print]158 158382
    Quercetin targets BCAT1 to potentiate CD8+ T cell immunity by rewiring branched-chain amino acid metabolism against colorectal cancer metastasis.
    Chuyi Wang, Yunxing Xu, Pengcheng Ding, Yunhai Ding, Liangfeng Zheng, Tianyi Li, Shouliang Cheng, Chen Zhang, Feiyue Ji, Xiaojiang Liu, Kai Chen, Guiyuan Gu, Xiaomin Lu.
      Colorectal cancer (CRC) metastasis is a major cause of cancer‑related death, highlighting the need for therapies that target immune‑metabolic pathways. Here, we show that quercetin inhibits CRC progression via dual actions: directly suppressing tumor cell growth and migration, while systemically reinvigorating CD8+ T cell mediated immunity. In vitro, quercetin potently inhibited CRC cell proliferation, migration, and survival. In an experimental lung metastasis mouse model, quercetin enhanced the effector function of CD8+ T cells, as evidenced by increased production of Granzyme B, Perforin, and IFN-γ in metastases, blood, and tumor-draining lymph nodes. Metabolomic profiling uncovered a pronounced remodeling of branched-chain amino acid (BCAA) metabolism following quercetin intervention. Screening via the HERB database identified BCAA transaminase 1 (BCAT1) as a candidate target, confirmed by molecular docking and surface plasmon resonance (SPR). Importantly, the combination of oral leucine and quercetin produced a synergistic effect, significantly boosting CD8+ T cell cytotoxicity and dramatically reducing the lung metastatic burden. Taken together, these data identify BCAT1 as a direct target of quercetin and elucidate a resultant immunometabolic circuit that bolsters CD8+ T cell function, providing a rationale for targeting this pathway in advanced CRC.
    Keywords:  BCAT1; Branched-chain amino acid; Colorectal cancer metastasis; Quercetin
    DOI:  https://doi.org/10.1016/j.phymed.2026.158382
  6. Adv Sci (Weinh). 2026 Jun 09. e20472
    m6A-Mediated Glycolysis by IL-37 Drives T Cell Metabolic Reprogramming to Regulate Colitis.
    Xiaoyan Wang, Jiadong Yu, Guolin Li, Ya Li, Fanlian Zeng, Jing Hu, Yifan Zhou, Chengcheng Yue, Qixiang Zhao, Chen Zhang, Hong Zhou, Fulei Zhao, Yawen Hu, Pei Zhou, Linna Gu, Yuting Feng, Mingxiang He, Shishi Huang, Xiaochi Sun, Xinmeng Wang, Jie Tang, Xinyu Zeng, Wenling Wu, Nongyu Huang, Xinai Cui, Kaijun Cui, Jiong Li.
      N6-methyladenosine (m6A) modification and T-cell metabolic reprogramming are increasingly recognized as critical drivers of inflammatory bowel disease (IBD). However, how the anti-inflammatory cytokine interleukin-37 intersects with m6A-mediated metabolic regulation remains unclear. Here, we show that IL-37 alleviates colitis by reducing global m6A levels and reshaping CD4+ T-cell metabolism. Mechanistically, IL-37 signals through its receptor SIGIRR to inhibit IRAK4 and JNK phosphorylation, suppress NF-κB p65 activation, and downregulate METTL14, thereby decreasing m6A deposition. The IL-37/METTL14 axis notably reduces m6A enrichment at the A2445 site in the 3'UTR of SLC2A1, destabilizing its mRNA and suppressing glycolysis. In vitro T-cell polarization and adoptive transfer of METTL14-overexpressing CD4+ T cells confirmed that this metabolic shift restrains Th1/Th17 differentiation while promoting Th2 expansion. Together, these findings reveal the IL-37/SIGIRR-METTL14-m6A axis as a novel regulator of T-cell metabolism and highlight SLC2A1 as a potential therapeutic target in IBD.
    Keywords:  IL‐37; T cell metabolism; colitis; glycolysis; m6A methylation
    DOI:  https://doi.org/10.1002/advs.202520472
  7. Adv Sci (Weinh). 2026 Jun 09. e00078
    Materials-Guided Gene-Ionizable Lipid Nanoparticles to Reverse Iron-Associated Immune Resistance in Renal Cancer.
    Xin Jin, Yulong Hong, Chengliang Yin, Wanyang Guo, Yaxuan Wang, Ruijiang Zeng, Ruilin Liu, Zexian Ding, Xinlin Liu, Shangqing Ren, Qiyang Liang, Yaohui Wang, Xu Zhang, João Conde, Yuan Li, Xin Ma, Liangyou Gu.
      Iron overload is a common metabolic disturbance in cancer and contributes to poor outcomes in renal cell carcinoma (RCC), yet its effects on the tumour immune microenvironment remain unclear. Here we identify a previously unrecognized immunosuppressive axis in which iron overload downregulates the palmitoyltransferase ZDHHC12 in CD8+ T cells, leading to impaired palmitoylation of the mitochondrial protein FDX1. This stabilizes FDX1 and drives cuproptosis, a recently described copper-dependent cell death pathway, thereby compromising T cell effector function and diminishing responses to immune checkpoint blockade. To restore T cell activity, we engineered lipid nanoparticles (ZDHHC12-LNPs) for the delivery of Zdhhc12. These nanoparticles exhibited optimal physicochemical properties, efficiently restored FDX1 palmitoylation, rescued CD8+ T cell function, and synergized with PD-1 blockade in preclinical RCC models without inducing systemic toxicity. Our findings uncover the iron-ZDHHC12-FDX1 axis as a metabolic checkpoint of T cell immunity and demonstrate a nanotechnology-based strategy to overcome iron-driven immunosuppression, offering translational potential for patients with iron-overloaded RCC.
    Keywords:  CD8+ T cells; FDX1 palmitoylation; Iron overload; lipid nanoparticles; renal cell carcinoma
    DOI:  https://doi.org/10.1002/advs.202600078
  8. Immunity. 2026 Jun 09. pii: S1074-7613(26)00219-0. [Epub ahead of print]59(6): 1484-1486
    Exhaustion in name only: CD8+ T cells drive lupus nephritis.
    Guillem Montamat-Garcia, Claudia Mauri.
      Systemic lupus erythematosus is characterized by autoantibodies against nuclear antigens. In this issue of Immunity, Al Souz et al. report that kidney damage in lupus nephritis is sustained by stem-like CD8+ T cells that migrate from lymphoid tissues and then, driven by CD4+ T cells and IL-15 and IL-21, differentiate into cytotoxic effectors within tissue and retain pathogenic function despite exhaustion markers.
    DOI:  https://doi.org/10.1016/j.immuni.2026.05.008
  9. MedComm (2020). 2026 Jun;7(6): e70801
    Metabolic Regulation of Immune Responses: Molecular Mechanisms, Diseases, and Therapeutic Targets.
    Chunwei Li, Ziqiang Liu, Dezheng Kong, Zhengze Li, Yiming Yan, Yanyu Dong, Lili Zhu, JiaNing Cao, Zhirui Fan, Gautam Sethi, Lifeng Li.
      Cancer-associated metabolic reprogramming profoundly reshapes the tumor microenvironment (TME), emerging as a central driver of immune evasion and therapeutic resistance. Increasing evidence indicates that metabolic enzymes function not only as bioenergetic regulators but also as active modulators of immune signaling, immune cell fate, and immune checkpoint expression. To elucidate these complex immunometabolic networks, this review utilizes fructose-1,6-bisphosphatase 1 (FBP1)-a key gluconeogenic enzyme-as a paradigmatic metabolic gatekeeper to illustrate how metabolic dysregulation drives tumor progression. By examining both the canonical metabolic effects and noncanonical signaling mechanisms of such enzymes, we synthesize recent advances demonstrating how metabolic rewiring promotes glycolytic reprogramming, immune suppression, and resistance to immunotherapy. Specifically, we explore broad mechanisms of immune evasion, including STAT3-PD-L1 regulation, modulation of innate immune surveillance, T cell exhaustion, and remodeling of stromal and fibrotic tumor niches. Furthermore, we discuss emerging therapeutic strategies targeting these immunometabolic pathways, encompassing small-molecule modulators, vitamin- and gene-based interventions, nanotechnology-enabled delivery systems, and metabolism-informed combination immunotherapy. Finally, we highlight key challenges, including metabolic heterogeneity and context-dependent enzyme function, emphasizing the need for biomarker-guided precision strategies to translate fundamental immunometabolic insights into durable and safe cancer therapies.
    Keywords:  FBP1; cancer immunotherapy; immunometabolism; tumor microenvironment
    DOI:  https://doi.org/10.1002/mco2.70801
  10. Antioxid Redox Signal. 2026 Jun 08. 15230864261455465
    Sleeve Gastrectomy Is Associated with Improved Systemic Redox Homeostasis in T2DM Through Ghrelin-GHSR Attenuation, POMC Neuronal Modulation, and CD4+ T Cell Metabolic Reprogramming.
    Xin Li, Ren-Yi Zhang, Wei-Hui Liu.
       OBJECTIVE: Sleeve gastrectomy (SG) improves obesity-associated type 2 diabetes mellitus (T2DM) beyond mere weight loss. We investigated whether SG enhances systemic metabolic homeostasis by suppressing the Ghrelin-growth hormone secretagogue receptor (GHSR) axis, remodeling hypothalamic pro-opiomelanocortin (POMC) neuronal activity, and reprogramming CD4+ T cell immunometabolism.
    METHODS: Using a diet-induced T2DM mouse model undergoing SG or Sham surgery, we integrated bulk/single-cell RNA sequencing and metabolomics to evaluate systemic neuro-immune-metabolic alterations. Functional assays validated Ghrelin's effects on CD4+ T cell metabolism and differentiation, alongside assessments of hepatic/pancreatic function and hypothalamic neuronal activity.
    RESULTS: SG globally remodeled peripheral immunity, expanding Tregs while reducing pro-inflammatory Th17 cells. scRNA-seq and metabolomic profiling revealed that CD4+ T cells shifted metabolically from glycolysis toward oxidative phosphorylation, matching increased tricarboxylic acid cycle intermediates. Functionally, Ghrelin-GHSR signaling promoted CD4+ T cell glycolysis, mitochondrial damage, and Th17 skewing; GHSR antagonism successfully reversed these detrimental effects. Systemically, SG reduced hyperglycemia and hepatic lipidosis, restored islet α/β-cell balance, activated anorexigenic POMC neurons, and suppressed AgRP neurons.
    CONCLUSION: SG alleviates T2DM through coordinated suppression of the Ghrelin-GHSR axis, bridging central appetite regulation with peripheral immunometabolic reprogramming. By shifting CD4+ T cells toward oxidative metabolism and restoring the Treg/Th17 balance, SG drives systemic metabolic recovery, providing critical molecular insights into the neuro-immune mechanisms of metabolic surgery. Antioxid. Redox Signal. 00, 000-000.
    Keywords:  CD4+ T cells; Ghrelin–GHSR signaling axis; POMC neurons; immune homeostasis; multiomics integration; sleeve gastrectomy
    DOI:  https://doi.org/10.1177/15230864261455465
  11. Cytotherapy. 2026 Mar 11. pii: S1465-3249(26)00739-5. [Epub ahead of print]28(8): 102778
    Manufacturing strategies for prolonged CAR-T cell persistence.
    Noriko Shimasaki.
      Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of hematologic malignancies, achieving durable remission in patients who are refractory to conventional therapies. However, the limited persistence of infused CAR-T cells, due to T-cell exhaustion and the loss of CAR-T cells, remains a major obstacle to sustained therapeutic efficacy. Recent studies have demonstrated that CAR-T cell products enriched for less-differentiated memory T cell subsets exhibit superior long-term persistence, greater cytotoxicity, and improved clinical outcomes compared with conventional CAR-T cell products. To enrich for less-differentiated memory T cells, various strategies have been explored throughout the manufacturing process. These strategies include selecting cell sources enriched for less-differentiated memory T cells and delaying their differentiation into terminally differentiated states by regulating signaling pathways, remodeling epigenetics, and modulating metabolism. This review provides an overview of current and emerging manufacturing strategies for CAR-T cells, focusing on enhancing their prolonged persistence. Further investigations are warranted to determine the optimal composition of differentiated and less-differentiated T cells in CAR-T cell products under the respective clinical conditions. This could facilitate the personalized manufacturing of CAR-T cell products with the ideal cell composition, thereby maximizing the efficacy of CAR-T cell therapy.
    Keywords:  CAR-T cells; differentiation; exhaustion; manufacturing; memory T cells; persistence
    DOI:  https://doi.org/10.1016/j.jcyt.2026.102778
  12. Brain Behav Immun. 2026 Jun 09. pii: S0889-1591(26)00611-2. [Epub ahead of print] 106863
    Mitochondrial remodeling by lithium drives CD4+ naïve T cell fate and immune homeostasis in bipolar disorder.
    Zhenni Chen, Yingrui Lin, Bingqi Wang, Min Wang.
       BACKGROUND: Immune signaling and mitochondrial redox biology have been implicated in bipolar disorder (BD), but the relationship between the clinical efficacy of lithium (Li) and immune dysfunction remains unclear.
    METHODS: We performed transcriptomic profiling of peripheral blood mononuclear cells (PBMCs) from BD patients during the manic phase before and after Li treatment, and conducted Li intervention experiments in a mouse model exhibiting BD manic-like behaviors (BD-manic). At the cellular level, we assessed mitochondrial metabolic and bioenergetic parameters in CD4⁺ naïve T cells, along with the distribution of T cell subsets. We further measured peripheral cytokines and central nervous system inflammatory markers to characterize peripheral and central inflammatory changes.
    RESULTS: Transcriptomic analysis of PBMCs from BD patients before and after Li treatment revealed significant alterations in metabolic pathways. In BD-manic mice, CD4⁺ naïve T cells exhibited metabolic alterations characterized by reduced mitochondrial membrane potential, decreased ATP production, impaired glucose uptake, increased ROS accumulation, and mitochondrial fragmentation compared with Control. These abnormalities were accompanied by increased total Drp1 expression, enhanced Drp1 Ser616 phosphorylation, and reduced Mfn2/Opa1 expression. Relative to BD-manic mice, Li treatment improved behavioral abnormalities, partially restored mitochondrial structure and bioenergetic function, and was associated with T cell subsets distribution. Li also reduced peripheral pro-inflammatory cytokines and attenuated hippocampal IL-6 expression, accompanied by amelioration of neuronal and microglial abnormalities.
    CONCLUSION: These findings indicate that Li treatment is accompanied by mitochondrial remodeling in CD4⁺ naïve T cells together with peripheral immune and central inflammatory changes in BD.
    Keywords:  Bipolar disorder; CD4⁺ naïve T; Immune Homeostasis; Lithium; Mitochondria
    DOI:  https://doi.org/10.1016/j.bbi.2026.106863
  13. bioRxiv. 2026 Jun 02. pii: 2026.05.28.728555. [Epub ahead of print]
    Critical illness expands a transcriptionally distinct hypometabolic CD8 + T effector program associated with respiratory failure and mortality.
    Casey M Nichols, Erin L Mwizerwa, Chooi Ying Sim, Sarah N Obeidalla, Jacqueline-Yvonne Cephus, Caroline E Roe, Jonathon M Irish, Dawn C Newcomb, V Eric Kerchberger, Julie A Bastarache, Jeffrey C Rathmell, Lorraine B Ware, Matthew T Stier.
      Immune dysfunction is a major driver of morbidity and mortality in critical illness syndromes including sepsis. Specifically, CD8 + T cell dysfunction has been linked to organ failure and death. To characterize the immune substructure of circulating CD8 + T cells in critical illness at high dimension, we used single-cell RNA sequencing of peripheral blood CD8 + T cells from 38 critically ill patients and 9 healthy controls. We annotated seven CD8 + T cell clusters, which included a CD8 + effector subset, termed T effector state 2 (T Eff-2 ), that was only present in critically ill patients and associated with more severe respiratory failure and higher mortality. T Eff-2 showed effector activation and inflammatory stress conditioning yet had markedly reduced metabolic transcripts without canonical features of exhaustion. Trajectory analyses positioned T Eff-2 as a terminal CD8 + T effector cell fate driven in part by DDIT4 and DUSP1 , which negatively regulate mTOR and MAPK signaling, respectively. Interestingly, this transcriptional program was indistinguishable by classical protein cytometry methods. These results, including the mortality association, were validated in a larger (n=91) independent external cohort of critically ill patients with sepsis. In summary, T Eff-2 represents a latent transcriptional program that delineates a clinically high-risk CD8 + T cell state in critical illness.
    DOI:  https://doi.org/10.64898/2026.05.28.728555
  14. World J Transplant. 2026 Jun 18. 16(2): 117357
    Immunosenescence and cancer predisposition in pediatric transplant recipients: An emerging paradigm.
    Aya Mohamed Adel Arafat, Soliman M A Soliman, Habiba Elfandy, Moamen O Othman, Walaa Elsayed, Mai M Lotfy, Noura A A Ebrahim.
      Pediatric solid organ and hematopoietic stem cell transplant recipients paradoxically experience accelerated immune aging despite chronological youth, establishing a paradigm with profound implications for cancer risk and long-term outcomes. This comprehensive review synthesizes current evidence demonstrating how transplantation-related factors, anti-thymocyte globulin-mediated T cell depletion, cytomegalovirus reactivation, chronic immunosuppression, and thymic dysfunction, induce premature immunosenescent phenotypes. These processes converge to generate T cell populations exhibiting CD28 loss, killer cell lectin-like receptor G1 positivity, telomere attrition, and functional exhaustion characteristic of elderly individuals. Concurrently, inflammaging pathways and senescence-associated secretory phenotypes establish pro-tumorigenic microenvironments. Consequently, pediatric recipients demonstrate 4- to 20-fold elevated cancer incidence, with standardized incidence ratios for post-transplant lymphoproliferative disease exceeding 200 in some cohorts. Beyond hematological malignancies, significant increases in solid tumors suggest fundamental immunosurveillance failure. Emerging biomarkers including flow cytometric senescence panels, telomere length measurement, and epigenetic clocks enable personalized risk stratification. Therapeutic horizons encompass senolytic agents, checkpoint inhibitor modulation, thymic regeneration strategies, and metabolic interventions targeting aging pathways. This paradigm shift necessitates reconceptualizing pediatric transplantation through the aging lens, integrating precision medicine approaches that balance graft survival, immune competence preservation, and cancer prevention in this vulnerable population.
    Keywords:  Cancer predisposition; Cytomegalovirus; Immunosenescence; Inflammaging; Pediatric transplantation; Post-transplant lymphoproliferative disease; Senescence-associated secretory phenotype; T cell exhaustion; Telomere dysfunction; Thymic involution
    DOI:  https://doi.org/10.5500/wjt.v16.i2.117357
  15. NPJ Syst Biol Appl. 2026 Jun 11. pii: 84. [Epub ahead of print]12(1):
    Longitudinal spatial neutrophil profiling during ACT in murine melanoma reveals distinct lymph node infiltration patterns.
    Gemma van der Voort, Maike Effern, Michelle C R Yong, Lukas Kiwitz, Roberta Turiello, Sonia Leonardelli, Susanna Ng, Dillon Corvino, Tobias Bald, Nicole Glodde, Kevin Thurley, Jan Hasenauer, Michael Hölzel.
      Reactive neutrophil infiltration can restrain CD8+ T cell expansion in lymph nodes during adoptive T cell therapy (ACT), yet its spatiotemporal regulation remains incompletely understood. Levaraging flow cytometry and multiplex immunofluorescence data, we performed a time-resolved quantitative assessment of immune cell dynamics in tumor-draining lymph node (tdLN) and non-tumor-draining lymph node (non-tdLN) in a melanoma mouse model receiving ACT. Transferred tumor-reactive CD8+ T cells accumulated and expanded early after treatment initiation, showing the highest frequency of a favorable central memory 13 CD8+ T cell phenotype in the tdLN. Enhancing innate immune signaling in melanomas increased neutrophil influx into lymph nodes, particularly the non-tdLN; however, within the tdLN, neutrophils were enriched in the T cell zone, which also contained the largest absolute reservoir of transferred CD8+ T cells. Together, these findings indicate that tdLN and non-tdLN differ in early neutrophil dynamics and compartmentalization during ACT, influenced by the strength of innate immune signaling in the tumor.
    DOI:  https://doi.org/10.1038/s41540-026-00765-5
  16. Free Radic Biol Med. 2026 Jun 05. pii: S0891-5849(26)00858-0. [Epub ahead of print]
    Ferro-Aging: A Novel Paradigm Linking Iron Overload, Lipid Peroxidation and Cellular Senescence.
    Shang Gao, Lijie Qi, Wenjun Bai, Jie Zhang, Zhao Yao Xu, Zhaoqi Zhao, Nianhu Li, Wei Liu.
      Iron is a double-edged sword in aging, and age-related iron accumulation acts as a critical amplifier, rather than a sole driver, of ageing; disrupted iron homeostasis with progressive iron accumulation drives oxidative stress, mitochondrial damage and inflammaging. Ferroptosis and cellular senescence, two critical aging-related processes, share upstream drivers like oxidative stress and lipid peroxidation. This study proposed the novel ferro-aging paradigm, a cascade pathway where age-related iron overload initiates iron-catalyzed reactive oxygen species production and lipid peroxidation, ultimately inducing cellular senescence and ferroptosis to to exacerbate, rather than independently cause, tissue dysfunction and age-related diseases. Iron accumulation in senescent cells stems from dysregulated iron uptake, storage, efflux, impaired ferritinophagy, and critical mitochondrial dysfunction. Senescent cells acquire ferroptosis resistance, leading to persistent tissue accumulation and chronic inflammation. Ferroptosis and senescence interact dynamically and form a positive feedback loop, with lipid peroxidation as the core executor. Ferro-aging participates in multiple age-related diseases of the nervous, cardiovascular, metabolic and skeletal systems. Targeting iron homeostasis, lipid peroxidation, senescent cells, and mitochondrial function provides promising anti-aging interventions. This review clarifies the connotation and mechanism of ferro-aging, and reveals its potential as a unified target for delaying aging and treating age-related diseases.
    Keywords:  Cellular senescence; Ferro-aging; Ferroptosis; Iron overload
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.06.012
  17. JCI Insight. 2026 Jun 09. pii: e202541. [Epub ahead of print]
    CD8 T-cell activation occurs 24 hours post-AAV administration and is driven by muscle promoter specificity.
    Lindsay Jeanpierre, Coralie Pecquet, Hanadi Saliba, Pauline Finard, Stéphane Terry, Gianni Tavella, Inès Guesmia, Sylvie Boutin, Bérangère Bertin, Sofia Benkhelifa-Ziyyat, Giuseppe Ronzitti, David-Alexandre Gross.
      Immune responses against transgene products can compromise AAV-mediated gene transfer. Although several factors influencing this immunogenicity have been described, the early in vivo events driving CD8+ T cell activation remain poorly defined. Here, we examined antigen presentation kinetics following intramuscular AAV administration in mice. Strikingly, viral genomes were detected in draining lymph nodes as early as one hour post-injection, and transgene-derived peptides were presented to CD8+ T cells from day 1, resulting in progressive activation and first cell divisions detected at day 4. Removal of the injection site demonstrated that AAV particles reaching draining lymph nodes within the first hour were sufficient to induce cytotoxic transgene-specific CD8+ T cells. Finally, AAV vectors incorporating different muscle-specific promoters and regulatory sequences were evaluated. Although muscle-specific, all promoters exhibited variable transgene expression in dendritic cells in vitro, correlating with early T-cell activation in vivo; notably, those associated with higher early antigen presentation induced robust T cell response, whereas reduced presentation correlated with absence of CD8+ T cells. These findings reveal an unexpectedly early onset of transgene-derived epitope presentation, modulated by promoter specificity, which critically shapes CD8+ T cell response. This provides a rationale for evaluating and mitigating AAV immunogenicity in gene therapy design.
    Keywords:  Gene therapy; Immunology; Muscle biology
    DOI:  https://doi.org/10.1172/jci.insight.202541
  18. Nat Aging. 2026 Jun 09.
    Systematic review assesses link between physical activity and epigenetic age.
    Anna Kriebs.
      
    DOI:  https://doi.org/10.1038/s43587-026-01155-6
  19. bioRxiv. 2026 Jun 05. pii: 2026.06.04.730166. [Epub ahead of print]
    Preserved CD4 + T cell helper function and coordinated antiviral immunity in people with HBV/HIV co-infection on long-term therapy.
    Aljawharah Alrubayyi, Anucha Preechanukul, Yinru Zhang, Jonida Kokici, Tanu Kamat, Jessica Davies, Indrajit Ghosh, Fiona Burns, Sabine Kinloch, Pedro Simoes, Sanjay Bhagani, Patrick T F Kennedy, Mala K Maini, Upkar S Gill, Dimitra Peppa.
       Background & Aims: People with HBV/HIV co-infection on antiretroviral therapy achieve higher rates of HBV functional cure than those with HBV mono-infection, yet the immunological basis remains poorly characterised. HBV-specific CD4 + T cell responses are critical for viral control and functional cure but have been scarcely examined in HBV/HIV co-infection. Our previous studies in HBV/HIV co-infection demonstrated preserved stem-like CD8 + T cells and NK cell functional responses, but whether CD4 + T cell helper function is similarly maintained is unknown.
    Methods: We analysed CD4 + T cell responses in 72 participants (HBV n=26, HBV/HIV n=24, HIV n=22) on suppressive antiviral therapy, using multiparameter flow cytometry, virus-specific CD4 + T cell functional assays and proliferation assays.
    Results: People with HBV/HIV co-infection had significantly higher HBV envelope- and core-specific CD4 + T cell responses, with IL-2 production particularly discriminating between groups. CD4 + T cell responses to CEF (CMV, EBV, and Influenza) were comparable, confirming antigen specificity. Granzyme B-expressing cytotoxic CD4 + T cells and TCF-1 + CD127 + PD-1 + CD4 + T cells were enriched in co-infection. CD4 + and CD8 + T cell responses were more frequently coordinated within donors in co-infection than in mono-infection (envelope 83% vs 50%; core 94% vs 60%), where they were more often uncoupled. IL-2 producing CD4 + T cells correlated with CD8 + T cell responses and the CD4:CD8 ratio in co-infection. HBV-specific proliferative capacity was enhanced in co-infection.
    Conclusions: People with HBV/HIV co-infection mount functional HBV-specific CD4 + T helper responses that are coordinated with CD8 + T cell immunity at the individual level. Together with our prior findings of preserved NK and CD8 + T cell responses in this cohort, these data identify treated HBV/HIV co-infection as a setting of integrated, rather than compromised, antiviral immunity.
    Impact and Implications: People with HBV/HIV co-infection can achieve HBV functional cure more frequently than people with HBV mono-infection, but the immune mechanisms remain unclear. This study shows that treated HBV/HIV co-infection is characterised by functional HBV-specific CD4⁺ helper responses and coordinated CD4⁺/CD8⁺ antiviral immunity. These responses were most strongly associated with the CD4:CD8 ratio, a routinely available clinical marker, rather than with CD4 count alone. These findings argue that people with HBV/HIV co-infection should be prioritised in, not excluded from, HBV cure immunotherapy trials.
    DOI:  https://doi.org/10.64898/2026.06.04.730166
  20. Dev Comp Immunol. 2026 Jun 06. pii: S0145-305X(26)00102-3. [Epub ahead of print] 105646
    Distinct T cell lineages marked by expression of cd4 paralogues in medaka.
    Norimasa Iwanami, Yosuke Yoshida, Yuta Saito, Hiyori Sakaguchi, Chikako Yokoyama, Masaru Matsuda, Taro Tachibana.
      T lymphocytes are classified into CD4+ and CD8+ T cells based on the glycoproteins expressed on their cell surface. Teleosts possess two CD4 paralogs, CD4-1 and CD4-2; however, their functional roles in T cell differentiation remain unclear. We generated fish mutant lines lacking the two cd4 paralog genes and genes encoding the two components of the CD8 co-receptor. The resulting phenotypes were analyzed using polyclonal antisera specific to medaka (Oryzias latipes) CD4-1 and CD8α, raised using a DNA immunization strategy. Our results indicate that cd4-2 deficiency does not affect the development of CD4-1+ T cells, providing genetic evidence for their distinct functions. Interestingly, in cd4-1 deficient mutants, the smaller compartment of CD4-1+ T cells was accompanied by a relative increase of CD8α+ T cells. Reciprocally, the lack or reduction of CD8α+ T cells caused by the deletion of cd8 genes was accompanied by a greater preponderance of CD4-1+ T cells. For the first time, our study provides direct genetic evidence for the interconnected differentiation programs of CD4+ and CD8+ T cells in teleost.
    Keywords:  CD4; CD8; T cells; antisera; genome editing; medaka
    DOI:  https://doi.org/10.1016/j.dci.2026.105646
  21. Front Aging. 2026 ;7 1832962
    An overview of current research on exercise interventions in aging and aging-related disease.
    Arad Jain, Campbell Johnston, Yiyu Zhang, Janice Oh, Carolyn Tsung, Eric Kent, Hongji Zhang.
      Global declines in physical activity have contributed to an acceleration in immune aging, characterized by systemic inflammation (inflammaging) and impaired immune regulation (immunosenescence). This narrative review provides an overview of the evidence in both preclinical and clinical models supporting exercise as a critical intervention to counteract immune aging and its related diseases. Regular physical activity modulates systemic inflammation, reduces neutrophil extracellular trap (NET) formation, and promotes favorable shifts in immune cell populations, including T cell and natural killer (NK) cell subsets. Exercise interventions have been associated not only with maintaining immune health but also in mitigating autoimmune disease progression, improving metabolic regulation, enhancing tumor immune surveillance, and reducing neuroinflammation. Emerging studies highlight the role of exercise in promoting vascular normalization within the tumor microenvironment, alleviating tumor hypoxia and acidosis, and restoring T and NK cell function. In the elderly, appropriately prescribed multimodal exercise regimens may lower infection risk without clear evidence of immunodepression, supporting exercise as a potentially safe and effective strategy for immune rejuvenation. Furthermore, novel mechanistic insights, including the modulation of NET burden, IGF-1 signaling, kynurenine metabolism, and microbiome composition, suggest that exercise influences key biological pathways underlying age-related immune decline. While exercise offers broad clinical benefits, future research should prioritize mechanistic studies to optimize exercise prescriptions and inform the development of exercise-mimetic therapeutics. Taken together, investigating the exercise regimens employed in these studies remains a promising intervention for promoting healthy immune aging and improving resilience against chronic inflammatory, metabolic, infectious, and malignant diseases.
    Keywords:  aerobic training; aging; cognitive function; endurance training; exercise; exercise intervention; functional performance; immune aging
    DOI:  https://doi.org/10.3389/fragi.2026.1832962
  22. Cell Rep. 2026 Jun 09. pii: S2211-1247(26)00588-7. [Epub ahead of print]45(6): 117510
    Peptide-MHC-targeted engineered virus-like particles enable selective priming and gene editing of tumor-specific T cells.
    Brian H Shim, Q Henry Zhao, Jack A Queenan, Blake E Smith, Michael E Birnbaum, David R Liu.
      Tumor-infiltrating lymphocyte (TIL) therapies harness tumor-specific T cells endogenous to a patient's repertoire but their efficacy is limited by challenges such as low frequencies of tumor-specific clonotypes and dysfunctional T cell phenotypes. These challenges necessitate technologies to engineer and reprogram endogenous tumor-specific TILs ex vivo. Here, we present a strategy using engineered virus-like particles (eVLPs) pseudotyped with peptide-major histocompatibility complexes (pMHCs) as a programmable, single-effector platform for selective and coordinated priming, expansion, and genome editing of rare antigen-specific CD8+ T cells among their endogenous polyclonal repertoires. We demonstrate that pMHC-pseudotyped eVLPs (pMHC-eVLPs) deliver T cell function-enhancing base editors to arm polyclonal lymphocytes with enhanced anti-tumor cytotoxicity by selectively expanding and engineering the tumor-specific T cell compartment. Our work establishes pMHC-eVLPs as a platform for enhancing TIL therapy with precision gene edits without the risks of bystander T cell engineering associated with polyclonal TIL engineering approaches.
    Keywords:  CP: cancer; TIL therapy; gene editing; genomics; targeted delivery; virus-like particles
    DOI:  https://doi.org/10.1016/j.celrep.2026.117510
  23. bioRxiv. 2026 Jun 01. pii: 2026.05.28.728503. [Epub ahead of print]
    Jump-starting the T cell response in established tumors.
    Tyler R McCaw, Mingyong Liu, Christopher D Scharer, Jeremy M Boss, Tian Mi, Alexander F Rosenberg, Mei Li, Rebecca C Arend, Donald J Buchsbaum, James Markert, Troy D Randall.
      Checkpoint blockade only works in 10-20% of patients. Consequently, investigators are testing checkpoint inhibitors in combination with drugs like the class I histone deacetylase inhibitor, entinostat (ENT). Unfortunately, the combination of ENT and checkpoint blockade fared poorly in patients with breast or ovarian cancer, despite promising pre-clinical results. Here we show that ENT enhances CD8 + T cell responses by maintaining a progenitor-like population of CD8 + T cells that supplies activated effector T cells to tumors for prolonged periods. Surprisingly, the anti-tumor effects of ENT are only experienced when delivered during a narrow window that occurs after T cell activation and before T cell exhaustion-a window that is likely closed in most patients. However, by first "jump-starting" the T cell response using an oncolytic virus, the anti-tumor activity of ENT and PD1 blockade is restored. These data establish a general paradigm, independent of tumor type, to rationally manipulate anti-tumor immunity.
    DOI:  https://doi.org/10.64898/2026.05.28.728503
  24. Cancer Immunol Res. 2026 Jun 11.
    Topical resiquimod elicits systemic protection and improves anti-PD1 therapy in melanoma via priming of CD8+ T cells.
    Shujing Liu, Alain H Rook, Alexander C Huang, Amit Maity, Zhiyuan Qin, Yeqing Chen, Delu Song, Yanxiang Deng, Zhi Huang, Giorgos C Karakousis, Tara C Mitchell, Ravi K Amaravadi, Lynn M Schuchter, Zev A Binder, Donald M O'Rourke, Meenhard Herlyn, Wei Guo, Xiaowei Xu.
      The Toll-like receptor (TLR) 7/8 agonist resiquimod shows promise for treating cutaneous T cell lymphoma and actinic keratosis, yet its mechanism of action remains unclear. We demonstrated that topical resiquimod significantly inhibited melanoma growth across various genetic and syngeneic mouse models, prolonged survival, and reduced lymph node metastasis in vivo. Resiquimod suppressed B16 melanoma growth, with an effect superior to that of imiquimod. The therapeutic effect was CD8+ T cell-dependent, as evidenced by the loss of efficacy upon CD8+ T cell depletion or in Rag2-/- mice. Resiquimod increased intratumoral CD45+ inflammatory cells, particularly antigen-experienced PD1+CD62L-CD8+ effector T cells, and enhanced their Ki-67 and Granzyme B expression. Resiquimod significantly expanded Pmel- and Trp2-specific CD8+ T cells in the presence of dendritic cells. Topical treatment of melanoma-bearing mice induced systemic protection in rechallenge experiments. In addition, combining topical resiquimod with anti-PD-1 antibodies led to superior inhibition of tumor growth and metastasis across multiple melanoma models. Proteomic analysis revealed increased Granzyme B and CD26, and decreased phosphorylated FOXO3a, post-treatment. In patient-derived organoids and melanoma slice cultures, resiquimod induced significant tumor killing and CD8+ T cell activation, further augmented by PD-1 antibodies. Our findings support the conclusion that resiquimod promotes CD8+ T-cell priming via dendritic cells and enhances the therapeutic efficacy of anti-PD-1 checkpoint blockade in melanoma.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-25-0998
  25. Int Immunopharmacol. 2026 Jun 06. pii: S1567-5769(26)00828-3. [Epub ahead of print]185 116982
    Local delivery of GPC3-CAR T cells in a thermosensitive hydrogel enhances antitumor efficacy in hepatocellular carcinoma.
    Yu Fu, Weibin Chen, Yuanyuan Zhou, Shichao Zhang, Xiongwei Zheng, HongYi Liu, Yilin Zhao.
      CAR T cell therapy has demonstrated remarkable antitumor efficacy in hematologic malignancies, but its application in solid tumors remains challenging. This is primarily due to the suppressive tumor microenvironment, which impedes T cell infiltration and reduces their functionality. Compared with standard intravenous administration, localized delivery strategies offer significant promise for CAR T therapy in solid tumors. Nevertheless, most reported approaches rely on complex biomaterials and are mainly applied in immune-privileged tissues. Here, we developed an injectable, thermosensitive chitosan/β-glycerophosphate/gelatin (CS/G/GP) hydrogel for local delivery of GPC3-CAR T cells and the cytokine IL-15 to enhance therapeutic efficacy against solid tumors. This hydrogel not only supported in vitro survival and proliferation of CAR T cells but also limited passive diffusion of IL-15, thereby sustaining GPC3-CAR T cell activity, expansion, and cytotoxicity. In an in vivo NCG mouse model of hepatocellular carcinoma (HCC), hydrogel-mediated local injection markedly enhanced CAR T cell infiltration and antitumor activity within tumor tissues, without apparent systemic toxicity. Overall, our hydrogel platform offers a safe, feasible, and effective strategy for localized CAR T cell therapy, improving treatment efficacy in solid tumors.
    Keywords:  GPC3-CAR T cells; Hepatocellular carcinoma; Interventional injection; Thermosensitive hydrogel
    DOI:  https://doi.org/10.1016/j.intimp.2026.116982
  26. Innovation (Camb). 2026 Jun 01. 7(6): 101274
    HBV-driven expansion of CXCR6+-exhausted T cells and CXCL16+ macrophage interaction: Implications for immunotherapy in HCC.
    Ranzhiqiang Yang, Congyu Lu, Qian Jian, Yinghui Song, Bo Sun, Wei He, Jieqiong Li, Fan Yang, Xiaohui Wang, Zhiguo Tan, Jiajin Yang, Chunzhao Yu, Chuang Peng, Yulong Yin, Yuan Gao, Liuqin He, Lianhong Zou, Sulai Liu.
      Hepatitis B virus (HBV) may alter immunotherapy responsiveness in HBV-positive hepatocellular carcinoma (HCC) patients. However, the underlying immune mechanisms remain unclear. To characterize the immune determinants underlying the enhanced immunotherapy response observed in HBV+ HCC patients, we comprehensively analyzed 528 HCC patients who received immunotherapy, encompassing diverse hepatitis infections. We performed an analysis incorporating single-cell RNA sequencing, spatial transcriptomics, and tissue microarray validation to map the tumor immune landscape. An adoptive T cell transfer combined with anti-programmed death-1 (PD-1) therapy in a syngeneic HCC mouse model was performed to validate key findings. HBV+ HCC patients exhibited superior responses to immunotherapy and prolonged overall survival. Remarkably, HBV+ HCC patients harbored an elevated proportion of exhausted CD8+ T cells, and these cells concurrently exhibited enhanced immune activity and cytotoxic potential. Our study spotlighted a novel subset of exhausted CD8+ T cells, termed PD-1+ CXCR6+ CD8+ T cells. In untreated cases, high levels of PD-1+ CXCR6+ CD8+ T cells correlated with poor prognosis. In contrast, among patients receiving immunotherapy, their enrichment was associated with markedly better outcomes. In vivo, adoptive transfer of CXCR6+ T cells markedly augmented the antitumor efficacy of anti-PD-1 therapy. Moreover, PD-1+ CXCR6+ CD8+ T cells demonstrated a prominent interaction with CXCL16+ macrophages in HBV+ HCC. Taken together, we identified a novel exhausted T cell subset, PD-1+ CXCR6+ CD8+ T cells, that are enriched in HBV+ HCC patients and maintained by CXCL16+ macrophages. The enrichment of PD-1+ CXCR6+ CD8+ T cells and their interaction with CXCL16+ macrophages may contribute to the enhanced immunotherapy response observed in HBV+ HCC.
    Keywords:  exhausted T cells; hepatitis virus; hepatocellular carcinoma; immunotherapy; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.xinn.2026.101274
  27. Front Immunol. 2026 ;17 1742866
    In vitro generation of RORγt+ regulatory T cells reveals enhanced immunosuppressive function and OXPHOS-dependent metabolism.
    Marcella Cipelli, Eloísa Martins da Silva, Lais Cavalieri Paredes, Mariana Abrantes do Amaral, Barbara Nunes Padovani, Luísa Menezes-Silva, Vinicius Andrade-Oliveira, Niels Olsen Saraiva Camara.
       Background: RORγt+ regulatory T cells (Treg) play a crucial role in immune regulation, particularly in the gut. However, most current knowledge about this subset derives from in vivo studies, as in vitro investigation has been limited by the lack of protocols capable of preserving their phenotype.
    Methods: Here, we developed and optimized an in vitro differentiation protocol to efficiently generate RORγt+ Treg cells. The protocol was evaluated based on the frequency of RORγt+ Treg cells generated, their suppressive function compared to conventional induced Treg (iTreg), and their metabolic profile.
    Results: The optimized protocol increased the frequency of RORγt+ Treg cells in vitro by up to 70%, providing a robust system for their study. Functionally, in vitro-differentiated RORγt+ Treg cells displayed enhanced immunosuppressive activity compared to conventional iTreg, effectively inhibiting effector CD4⁺ T cell proliferation. Metabolic analyses further revealed a reliance on oxidative phosphorylation (OXPHOS) in this subset.
    Conclusion: This protocol enables the efficient in vitro generation of RORγt+ Treg cells, facilitating functional and metabolic studies of this population and opening new avenues for potential therapeutic applications in immune-mediated diseases.
    Keywords:  RORγt; T cell differentiation; T cell function; Treg; immunometabolism
    DOI:  https://doi.org/10.3389/fimmu.2026.1742866
  28. Biomark Res. 2026 Jun 11.
    Mitochondrial transfer between tumor and immune cells: a nexus of metabolic adaptation and immune dysfunction.
    Jianqiang Yang, Yunqi Li, Soumya Vijaya Kumar, Nabil F Saba, Chloe Shay, Yong Teng.
      The tumor microenvironment (TME) is a dynamic and highly interactive ecosystem that fuels cancer progression through coordinated cellular crosstalk. Recent studies have uncovered intercellular mitochondrial transfer as a critical adaptive mechanism within this niche. Here, we synthesize current evidence supporting a paradigm in which mitochondria function as "shared organelles", whose bidirectional trafficking reshapes tumor and immune cell states. We discuss the mechanisms by which cancer cells acquire functional mitochondria from stromal compartments to enhance bioenergetic fitness, metabolic plasticity, and resistance to therapy. Conversely, we highlight the transfer of damaged or dysfunctional mitochondria from tumor cells to immune populations, a process that contributes to immune suppression and impaired anti-tumor responses. We further delineate the molecular and cellular networks regulating mitochondrial exchange, including tunneling nanotubes, extracellular vesicles, and cytoskeletal dynamics. Finally, we evaluate emerging therapeutic strategies aimed at disrupting mitochondrial trafficking and reprogramming TME metabolism. Collectively, this review positions mitochondrial transfer as a fundamental driver of tumor progression and a promising, yet underexplored, target for cancer therapy.
    Keywords:  Antitumor therapy; Mitochondrial transfer; TME; Tumor immunity; Tumor-stromal cell interactions
    DOI:  https://doi.org/10.1186/s40364-026-00955-7
  29. Science. 2026 Jun 11. 392(6803): 1194-1199
    Placental nicotinamide adenine dinucleotide modulates the timing of labor.
    Erin J Ciampa, Luana M Machado, Kathy J Lee, Amanda J Clark, Kyle Q Vu, Nawal A Khan, Sarah Kispert, Samantha Armstrong, Yunping Li, Ginger L Milne, Ashley Solmonson, S Ananth Karumanchi, Samir M Parikh.
      Labor is mediated proximately by prostaglandin signaling within gestational tissues and must be tightly regulated for birth to occur after appropriate fetal development. Metabolic changes accompanying gestational aging have been postulated as a determinant of birth timing, but specific nutrients, sensors, and messengers remain obscure. We report that placental nicotinamide adenine dinucleotide (NAD+) dynamically tunes gestational length. Depletion of placental NAD+ in mice provoked labor onset, mediated by the role of NAD+ as a cofactor for 15-hydroxy prostaglandin dehydrogenase, an enzyme responsible for suppressing prostaglandin accumulation. Augmentation of placental NAD+ prolonged gestation at baseline and in a model of preterm labor. These findings suggest a central role for metabolic exhaustion in provoking labor and reveal potential therapeutic avenues for preterm labor and the optimization of labor induction.
    DOI:  https://doi.org/10.1126/science.adz1624
  30. Hepatol Commun. 2026 Jul 01. pii: e0973. [Epub ahead of print]10(7):
    Depletion of NAT10 in T cells attenuates metabolic dysfunction-associated steatohepatitis in mice.
    Yanying Yang, Jie Lu, Mingyue Ma, Jing Zhou, E Wang, Yan Lu, Zhe Dai, Bing Zhou, Yao Li.
       BACKGROUND: Metabolic dysfunction-associated steatohepatitis (MASH) is a leading cause of chronic liver disease, yet its pathogenesis remains incompletely understood. Immune dysregulation, particularly intrahepatic T-cell responses, is implicated in disease progression; however, the specific roles of T-cell subsets and their regulatory mechanisms are not fully defined.
    METHODS: We performed single-cell RNA sequencing (scRNA-seq) on human liver tissues from patients with varying severities of metabolic dysfunction-associated steatotic liver disease (MASLD). To establish causality, we generated T cell-specific NAT10 knockout mice. The molecular mechanism was elucidated using acetylated RNA immunoprecipitation sequencing (acRIP-seq) and mRNA stability assays.
    RESULTS: scRNA-seq revealed a marked increase in NAT10 expression in intrahepatic effector CD8+ T cells from patients with severe MASLD. In mice, T cell-specific deletion of NAT10 significantly attenuated MASH progression, reducing hepatocyte injury, fibrosis, and intrahepatic CD8+ T cell accumulation. NAT10 deficiency suppressed CD8+ T cell cytotoxicity, evidenced by decreased production of IFN-γ, TNF-α, and GZMB. Mechanistically, NAT10 stabilizes Fhit mRNA through ac4C modification, enhancing its expression.
    CONCLUSIONS: Our study identifies NAT10 as a critical regulator of CD8+ T cell-mediated immunopathology in MASH. By stabilizing Fhit mRNA, NAT10 promotes the expression of inflammatory factors, shaping the pro-inflammatory hepatic microenvironment. Targeting NAT10 presents a promising therapeutic strategy to modulate intrahepatic immunity and arrest MASH progression.
    Keywords:  N-acetyltransferase 10; N4-acetylcytidine; fibrosis; liver disease; single-cell
    DOI:  https://doi.org/10.1097/HC9.0000000000000973
  31. Nat Commun. 2026 Jun 11.
    Tumor-resident T cells and dendritic cells form an in situ archetype during immunotherapy response in melanoma.
    Andrea Di Pietro, Lewis Au, Patrick Crock, Niko Thio, Angela Pizzolla, Thu Ngoc Nguyen, Sean Macdonald, Hugh Chalmers, Ruiqing Zhu, Alessia Airaghi, Tristan Molden-Hauer, Marina Bacac, Petra Schwalie, Ramona Schlenker, Mitchell P Levesque, Sonia Mailer, Kristy Barnes-Cullen, Karen Winch, Joanna Chan, George Au Yeung, Lavinia Spain, Aparna D Rao, Shahneen Sandhu, David E Gyorki, Grant A McArthur, Laura K Mackay, Paul J Neeson.
      Tumor-resident (TR) T cells, known as tissue-resident memory (TRM) T cells in mice, play a central role in melanoma immunosurveillance, yet their contribution to immune checkpoint inhibitor (ICI) therapy has not been comprehensively explored. We performed spatial and single-cell profiling on 32 metastatic melanoma lymph node samples, from treatment-naïve, ICI-resistant and ICI-responsive patients. Here we show that tumor areas in ICI-responders were enriched for both CD8+ and CD4+ TR. CD8+ TR cells were clonally expanded, and both CD8+ and CD4+ TR cells upregulated cytotoxicity-related gene expression, suggesting functional anti-tumor immunity. Conversely, ICI-resistant tumors displayed chronic IFN-γ response pathways, linked to T cell exhaustion. We further identified a spatially organized immune triad composed of CD8⁺ TR, CD4⁺ TR, and type-3 dendritic cells (DC3) that is exclusive to responding tumors. These findings define coordinated cellular interactions within the tumor microenvironment that underpin successful immunotherapy and provide a framework for spatial biomarkers of response.
    DOI:  https://doi.org/10.1038/s41467-026-74076-y
  32. Front Immunol. 2026 ;17 1833034
    Deviation from physiologically appropriate oxygen levels alters proliferation, cytokine production and proximal antigen receptor signalling in CD4+ memory T cells.
    Elizabeth Clay, Graham R Wallace, Stephen P Young.
       Background: Immune cells must adapt to highly variable oxygen levels encountered across different tissues of the body. Under inflammatory conditions, oxygen levels may reach further extremes, for example healthy synovial joints display oxygen levels of 6-10%, which drop to <5% in rheumatoid arthritis. In contrast, most in vitro experiments are performed under atmospheric oxygen (~21%), raising concerns that experimental conditions do not accurately reflect the physiological microenvironment of the disease being modelled.
    Aim: To explore the role of oxygen levels (21%, 8.5%, 3% and 1% oxygen) on human memory CD4+ T cell function.
    Results: At oxygen levels reflective of physiologically healthy conditions we observed increased proliferative capacity and reduced pro-inflammatory cytokine production of CD4+ memory T cells. Altered patterns were observed in both hyperoxic and hypoxic conditions. A critical component of TCR proximal signaling, Lck phosphorylation, was altered in resting T cells equilibrated to varying oxygen levels. The highest 'activated' state was seen at physiologically healthy oxygen levels, suggesting prior oxygen exposure can determine subsequent signaling responses.
    Conclusion: We conclude that environmental oxygen levels significantly influence CD4+ memory T cell responses, with implications for their function in inflammatory sites in vivo. These differences need to be taken into account when designing or interpreting in vitro experiments, as well as harnessing T cells therapeutically.
    Keywords:  CD4+ memory T cell; T cell signaling; hypoxia; in vitro culture; physiological oxygen levels; redox
    DOI:  https://doi.org/10.3389/fimmu.2026.1833034
  33. Cancers (Basel). 2026 May 29. pii: 1786. [Epub ahead of print]18(11):
    Mitochondrial Metabolic Reprogramming in Colorectal Cancer-Associated Fibroblasts: An Up-to-Date Review.
    Ying Li, Dipanjan Chanda, Seong-Woo Jeon, Jae-Han Jeon, Min-Ji Kim.
      Colorectal cancer (CRC) progression stems from dynamic metabolic crosstalk between malignant cells and the tumor microenvironment (TME). Among stromal components, cancer-associated fibroblasts (CAFs) have emerged as pivotal metabolic drivers rather than mere structural elements. Specifically, evidence indicates that mitochondrial reprogramming in CAFs significantly orchestrates tumor growth, therapeutic resistance, and immune evasion in CRC. This review synthesizes recent insights into how CAF mitochondrial dynamics and metabolic reprogramming dictate CRC biology. We first examine the functional diversity of CAF subpopulations and their distinct mitochondrial requirements. We then contrast mitochondrial dynamics-including fission-fusion balance and mitophagy-between CRC cells and CAFs, highlighting how tumor-derived signals modulate stromal mitochondrial function. We systematically evaluate key regulatory pathways of CAF mitochondrial reprogramming, including TGF-β/HIF-1α, ROS-NF-κB, PI3K-AKT-mTOR, AMPK-PGC-1α, YAP/TAZ mechanotransduction, and mtDNA-mediated cGAS-STING signaling. Furthermore, we discuss how remodeled CAF mitochondria foster metabolic symbiosis via lactate, ketone, and glutamine shuttling; maintain redox homeostasis through the NADPH-glutathione axis and UCP2; and establish immunosuppressive niches via mitochondrial stress signaling. Collectively, these mechanisms drive resistance to chemotherapy, targeted agents, radiotherapy, and immunotherapy. By integrating mitochondrial metabolism, stromal signaling, and clinical responses, this review identifies CAF mitochondria as an actionable target within the CRC TME. Targeting these CAF-specific pathways offers a novel strategy to disrupt tumor-stroma metabolic cooperation and overcome treatment resistance in colorectal cancer.
    Keywords:  cancer-associated fibroblasts; colorectal cancer; metabolic reprogramming; mitochondria; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers18111786
  34. Cancer Immunol Res. 2026 Jun 11.
    DNA hypomethylating agents preserve T cell stemness and potentiate the efficacy of CD3-bispecific antibodies.
    Mark Aleynick, Qingqing Wang, Jennifer E Wu, Samantha Lemus, Matthew Chaimowitz, Hannan Mir, Jacqueline J Warsaw, Chunguang Guo, Lynn E Macdonald, Janelle C Waite, Nikos Kourtis, Dimitris Skokos.
      Bispecific antibodies targeting tumor-associated antigens and CD3 are promising therapeutic agents for both solid and hematologic cancers. CD3-bispecifics induce T cell activation and cytotoxicity; however, prolonged TCR stimulation can lead to chromatin rewiring and T cell dysfunction, thereby limiting their full therapeutic potential. Here, we investigate the combination of CD3-bispecifics with the DNA hypomethylating agent decitabine and observe enhanced synergistic tumor growth inhibition in various preclinical models. Utilizing a PSMAxCD3 bispecific antibody for treatment of prostate carcinoma and in vivo humanized mouse disease models, we catalog, at the single-cell level, the dynamics of T cell epigenetic states during bispecific therapy and in combination with decitabine. Importantly, this combination strategy preserves a TCF-1+ T cell population and delays acquisition of a dysfunctional state at both chromatin and protein levels. At the DNA methylation level, TCR stimulation in the presence of decitabine maintains a naive-like pattern in gene loci associated with T cell stemness. This study provides a resource for understanding the evolution of T cell states during immunotherapy and mechanistic support for combining epigenetic modifiers with CD3-bispecifics in the clinic.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-25-1420
  35. Res Sq. 2026 Jun 02. pii: rs.3.rs-9520035. [Epub ahead of print]
    Time-restricted feeding rejuvenates cerebrovascular function and preserves cognition during aging.
    Stefano Tarantini, Madison Milan, Sharon Negri, Rakesh Rudraboina, Eva Troyano-Rodriguez, Jennifer Ihuoma, Aleksandra Kosmider, Shantipriya Awasthi, Woncheol Jung, Hassan Abushukair, Rohan Varshney, Gregory Mullen, Raghavendra Nagaraja, Niharika Uppari, Mohiuddin Ahmad, Priya Balasubramanian, Shannon Conley, Andriy Yabluchanskiy, Anna Csiszar, Zoltan Ungvari, Audrey Cleuren, Michael Rudolph, Mickael Tanter, Tae Gyu Oh, Rafael de Cabo.
      Cerebromicrovascular dysfunction is a key driver of age-related cognitive decline, yet interventions targeting microvascular aging remain limited. Here, we show that time-restricted feeding (TRF) preserves cognitive function and rejuvenates cerebrovascular physiology in aged mice. TRF improves resting cerebral blood flow and neurovascular coupling while attenuating blood-brain barrier disruption, neuroinflammation, and endothelial senescence. Mechanistically, TRF enhances metabolic flexibility and restores mitochondrial bioenergetic capacity in cerebromicrovascular endothelial cells. Ketone bodies elevated by TRF recapitulate key mitochondrial and vascular effects, improving endothelial respiration, membrane potential, and redox balance in aged mice and primary human brain endothelial cells, but do not fully reproduce neurovascular unit protection. These findings identify endothelial mitochondrial reprogramming as a central mechanism linking dietary timing to cerebrovascular resilience and cognitive preservation, and suggest that metabolic interventions can partially reverse key features of vascular brain aging.
    DOI:  https://doi.org/10.21203/rs.3.rs-9520035/v1
  36. Front Reprod Health. 2026 ;8 1801173
    Unraveling the intricate link: gut microbiota and recurrent spontaneous abortion.
    Dan Li, Xiaoqiang Liu, Zhaogang Teng, Chenxi Yang, Xiaoxia Chen, Ping Tan.
      Recurrent spontaneous abortion (RSA) affects 1%-5% of reproductive-age couples, and nearly 50% of cases remain unexplained. This review summarizes recent evidence to elucidate the association between gut microbiota dysbiosis and RSA. We confirm that RSA patients exhibit decreased alpha diversity, reduced levels of Bacteroidetes, Lactobacillus, and Bifidobacterium, and elevated Proteobacteria and Escherichia-Shigella. Gut dysbiosis contributes to RSA through three core pathways: disrupted T helper 17/regulatory T cell balance leading to maternal-fetal immune intolerance; insufficient short-chain fatty acid production and elevated trimethylamine N-oxide causing metabolic disorders; and disrupted estrogen and progesterone metabolism via microbial hydroxysteroid dehydrogenases triggering endocrine dysfunction. We also clarify the bidirectional causal relationship between gut dysbiosis and RSA, summarize inconsistent findings across studies, and highlight the potential of probiotics and dietary interventions. This review provides mechanistic insights and clinical implications for microbiota-targeted strategies in unexplained RSA.
    Keywords:  gut microbiota; immune regulation; inflammation; metabolites; recurrent spontaneous abortion
    DOI:  https://doi.org/10.3389/frph.2026.1801173
  37. Res Sq. 2026 Jun 01. pii: rs.3.rs-9261217. [Epub ahead of print]
    HIRA-mediated H3.3 deposition preserves hepatocyte cell identity during liver aging.
    Peter Adams, Rouven Arnold, Marcos Teneche, Xue Lei, Armin Gandhi, Christina Shi, Jessica Proulx, Adarsh Rajesh, Aaron Havas, Shiqi Su, Annanya Sethiya, Shanshan Yin, Hiroshi Tanaka, Zong Chua, Andrew Davis, Laurence Haddadin, Michael Alcaraz, Irene Huang, Angela Liou, Anaïs Equey, Nirmalya Dasgupta, Karl Miller, Margaret Tulessin, Buddy Charbono, Adriana Charbono, Siva Varanasi, K Evensen, April Williams Wehner, Rebecca Porritt, Guillermina Garcia, Sakshi Chauhan, Brian Egan, Michael Choob, Carolin Mogler, Kevin Y Yip, Keiko Ozato, Susan Kaech, Yu Xin Wang.
      Age-associated functional decline is partly driven by progressive chromatin degeneration. Maintenance of chromatin integrity preserves cell identity and promotes healthy aging, but through different mechanisms in proliferating and non-proliferating cells. However, specific mechanisms of chromatin maintenance and their compensatory capacity in proliferating and non-proliferating cells are undefined. The histone chaperone HIRA deposits the histone variant H3.3 in a DNA replication-independent manner, leading to its accumulation in aging, non-proliferating cells. Here, we show that hepatocyte-specific loss of HIRA causes loss of cell identity, metabolic dysfunction, and accelerated fibrotic pathology with age. Transcriptomic and epigenomic analyses indicate that HIRA-H3.3 preserves chromatin integrity and sustains transcription of highly expressed genes, including cell identity genes. Partial hepatectomy, associated with induced proliferation, restores identity of HIRA knockout livers with compensatory deposition of canonical histones H3.1/2. Together, these results demonstrate that HIRA-mediated H3.3 deposition is essential for safeguarding cell identity and tissue function during aging of non-proliferating cells, but this function can be rescued by tissue regeneration and associated cell proliferation.
    DOI:  https://doi.org/10.21203/rs.3.rs-9261217/v1
  38. J Immunol Methods. 2026 Jun 11. pii: S0022-1759(26)00055-4. [Epub ahead of print] 114079
    Intracellular CD3 and surface CD8β distinguish activated human T cells from natural killer cells after αCD3/αCD28 stimulation.
    Cade M McDonald, Sofia C Alzugaray Orellana, Susan E Murray.
      Many studies of human T cell function involve activating primary T cells in vitro to assess functional outcomes. A common model of human T cell activation is polyclonal stimulation with αCD3/αCD28 antibodies. However, subsequent identification of these stimulated T cells in a mixed population is complicated by surface CD3 loss. In particular, both cytotoxic T cells and natural killer (NK) cells can appear CD3-CD8α+, leading to misidentification of NK cells as cytotoxic T cells. To address this limitation, we investigated incorporating intracellular CD3 and surface CD8β staining following αCD3/αCD28 stimulation to improve discrimination between cytotoxic T cells and NK cells. We found that intracellular CD3 staining completely recovers lost CD3 expression. When intracellular staining is not amenable to downstream applications in which live cells are required, we found that CD8β more accurately identifies cytotoxic T cells while excluding NK cells than does the more common CD8α staining. We validated CD8β as a more faithful marker of cytotoxic T cells by comparing cytokine profiles of CD8α or CD8β gated PBMC to those of purified T cells, showing that CD8β most closely mimics the cytokine profile of cytotoxic T cells within a purified T cell population. We conclude that i) intracellular CD3 staining is ideal when cell fixation and permeabilization is possible and ii) surface CD8β staining is best when intracellular CD3 staining is not possible, e.g., when recovery of live cells from fluorescence-activated cell sorting is necessary.
    Keywords:  CD3 downregulation; CD8α; CD8β; Human; Natural killer cells; T cell activation
    DOI:  https://doi.org/10.1016/j.jim.2026.114079
  39. Front Immunol. 2026 ;17 1828801
    Neutrophil immunometabolism in ACLF and sepsis: mechanisms, dysfunction, and therapeutic opportunities.
    Sonali Mukherjee, Takhellambam Malemnganba, Pragyan Acharya.
      Innate immune cells, undergo profound metabolic changes in critical illnesses. In both, acute-on-chronic liver failure (ACLF) and sepsis, these alterations underpin the paradoxical coexistence of hyperinflammation and immune dysfunction. Here, we present a comparative framework to examine how immune metabolic circuits are reshaped across these two syndromes. We focus primarily on neutrophil function while also considering contributions from other immune cell types, highlighting shared pathways, divergent mechanisms, and their clinical implications. We first delineate shared features of neutrophil activation in critical illness, including glycolysis-driven metabolic reprogramming, excessive reactive oxygen species (ROS) generation, and neutrophil extracellular trap (NET) formation, all processes that amplify tissue injury and propagate systemic inflammation. However, fundamental differences emerge in the baseline immune state, trajectory, and underlying immunometabolic programming of the two diseases. Sepsis arises as an acute insult in a previously homeostatic immune system, triggering a rapid transition from hyperactivation to mitochondrial dysfunction and eventual metabolic exhaustion. In contrast, ACLF develops on a background of chronic liver disease, where immune cells are already primed and metabolically stressed, resulting in a constrained and dysfunctional response from the outset. By placing ACLF and sepsis side by side, this review highlights the metabolic regulation of innate immunity, particularly neutrophils, as both a unifying principle and a disease-specific vulnerability. This comparative perspective deepens mechanistic understanding and provides a framework for precision immunometabolic interventions in critical illness.
    Keywords:  NEtosis; acute on chronic liver failure (ACLF); immune dysfunction; immune reprogramming; immunometabolism; inflammation; metabolic exhaustion; sepsis
    DOI:  https://doi.org/10.3389/fimmu.2026.1828801
  40. Virol J. 2026 Jun 07.
    Single-cell characterization of the CD8+ T cell landscape and repertoire in HIV-1 Infection following antiretroviral therapy.
    Jun Lei, Jialingfang, Aifang Xu.
      Although antiretroviral therapy (ART) effectively suppresses HIV-1 viremia, immune dysfunction often persists. Here, we integrated single-cell RNA and T cell receptor (TCR) sequencing data to delineate the alterations of CD8⁺ T cells. Based on cross-sectional samples from different individuals (healthy donors, treatment-naïve individuals, and ART-treated individuals), we found ART promoted the transition of CD8⁺ T cells from exhausted toward naïve and memory-like subsets. Weighted gene co-expression network analysis identified distinct modules, including three (SM2-SM4) highly expressed in treatment-naïve individuals and one (SM6) significantly elevated post-ART. The reduced TCR diversity and increased clonality observed post-infection were not fully restored by ART, although ART partly altered clonal structure and CDR3 length. We established a predictive model based on the TCR features of CD8⁺ T cells, which accurately distinguished healthy donors, treatment-naïve individuals, and ART-treated individuals. These findings clarify the complex landscape of CD8⁺ T cell reconstitution, and identify key transcriptional networks and clonal dynamics during ART.
    DOI:  https://doi.org/10.1186/s12985-026-03212-3
  41. J Hepatol. 2026 Jun 05. pii: S0168-8278(26)02622-X. [Epub ahead of print]
    Dysregulated transcription in core- and pol-specific CD8 T cells can be targeted by HDAC inhibition to improve T-cell function in chronic hepatitis B.
    Camilla Ceccatelli Berti, Ilaria Montali, Sara Doselli, Benedetta Farina, Simona Schivazappa, Andrea Vecchi, Marzia Rossi, Valentina Reverberi, Anna Montali, Dana Sambarino, Alessio Pelagatti, Francesca Ferraglia, Valeria Barili, Floriana Facchetti, Elisabetta Degasperi, Diletta Laccabue, Amalia Penna, Marie-Laure Plissonnier, Fabien Zoulim, Pietro Lampertico, Carolina Boni, Gabriele Missale, Marco Morselli, Carlo Ferrari, Paola Fisicaro.
       BACKGROUND & AIMS: Virus-specific T cell dysfunction is a hallmark of chronic hepatitis B (CHB) and its correction can represent a potential option for HBV cure. A deeper understanding of T cell correlates of infection persistence and control is needed to clarify the CD8 T cell roles in CHB pathogenesis, and to identify new therapeutic targets for efficient T cell reconstitution.
    METHODS: Core- and polymerase-specific CD8 cells from untreated highly viremic HBeAg-negative CHB patients were studied by RNA-sequencing, compared to patients who achieved functional cure after nucleos(t)ide-analog treatment (rNUC) or acute hepatitis B (rACU). Histone acetylation levels, cytokine production, and cytotoxicity were evaluated on T cells from chronic patients in the presence of HDAC inhibition.
    RESULTS: A 101-gene "resolution signature" characterizing both resolution groups compared to CHB patients was identified, as well as 41 genes whose deregulation was not reversed in rNUC. Although most of deregulated genes showed similar behavior in core- and pol-specific CD8 cells of CHB patients, 30% of them were not concordant. Targeting deregulated DNA transcription with entinostat significantly improved histone acetylation levels and T cell function.
    CONCLUSIONS: Mechanisms of dysfunction in core- and polymerase-specific CD8 cells are only partially shared by both T cell subsets; without a clear hierarchy of exhaustion severity between pol- and core-specific cells. A transcriptional scar-like signature of chronicity was maintained even after HBsAg loss. The resolution gene signature shared by pol- and core-specific CD8 cells from rNUC and rACU patients pointed to histone deacetylase inhibition as a promising immunotherapeutic intervention for CHB.
    Keywords:  CD8 T cell antigen specificity; CD8 T cell dysfunction; Chronic hepatitis B; HBV-specific CD8 T cell transcriptome; T cell restoration
    DOI:  https://doi.org/10.1016/j.jhep.2026.05.020
  42. Mol Ther Oncol. 2026 Jun 18. 34(2): 201234
    mRNA-LNP vaccine providing antigen and co-stimulation in the tumor microenvironment enhances CAR T cell function (CART-Vac).
    Ikumi Nakashima, Shoji Saito, Jingbo Zhao, Miyuki Tanaka, Eiichi Akahoshi, Aiko Hasegawa, Mitsuko Sugano-Ishihara, Shigeki Yagyu, Yozo Nakazawa.
      Despite advances in multimodal therapies, outcomes for pediatric patients with relapsed or refractory cancers remain poor. Chimeric antigen receptor (CAR) T cell therapy has demonstrated limited efficacy in solid tumors due to the immunosuppressive tumor microenvironment (TME), which promotes T cell exhaustion and restricts CAR T cell expansion. This study evaluated a combinatorial approach to enhance CAR T function by reprogramming the TME to overexpress target antigens (TAs) and co-stimulatory molecules (CSMs) through a lipid nanoparticle-based CAR-T vaccination (CART-Vac). As proof of concept, rhabdomyosarcoma cells (Rh30) engineered to overexpress TAs and CSMs (Rh30-TACS) were examined. EPHB4-directed CAR T cells demonstrated enhanced cytotoxicity, proliferation, and cytokine secretion in vitro, and superior tumor control with increased T cell infiltration in Rh30-TACS tumors in vivo compared with Rh30 tumors. To induce TA and CSM expression in the TME, CART-Vac was designed to deliver mRNAs encoding truncated EPHB4, CD80, and CD137L. CART-Vac effectively mediated transient expression, significantly enhancing CAR T expansion and antitumor activity in both models. These findings suggest that CART-Vac can modulate the TME, offering a promising strategy to improve the therapeutic efficacy of CAR T cells in solid tumors.
    Keywords:  EPHB4; chimeric antigen receptor; co-stimulatory molecules; gene therapy; intratumor injection; lipid nanoparticles; mRNA; rhabdomyosarcoma; target antigens; vaccine
    DOI:  https://doi.org/10.1016/j.omton.2026.201234
This page is being maintained by Thomas Krichel. It was last updated on 2026‒06‒14 at 5:09.