bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2026–01–18
43 papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. CD8+ T cell aging, senescence, and related disease.
  2. The ubiquitin ligase KLHL6 drives resistance to CD8+ T cell dysfunction.
  3. PTMA safeguards mitochondrial integrity to sustain metabolic function and antitumor activity of CD8 T cells.
  4. Metabolic adaptation in CD4+ T cells promotes immunosuppression in sepsis.
  5. Latent Regulatory Programs Generate Synthetic T Cell States with Enhanced Therapeutic Potential.
  6. PARP inhibition generates enhanced CD8+ central memory T cells by transcriptional and metabolic reprogramming.
  7. Fine-tuning BACH2 dosage balances stemness and effector function to enhance antitumor T cell therapy.
  8. Multi-omics Analysis of Human Blood Cells Reveals Unique Features of Age-associated Type2 CD8 Memory T cells.
  9. Immunometabolism: Is cyanide a missing link between metabolic pathways and immune function?
  10. BACH2 dosage establishes the hierarchy of stemness and fine-tunes antitumor immunity in CAR T cells.
  11. Microbiota-induced T cell plasticity enables immune-mediated tumour control.
  12. Publisher Correction: Tissue-resident exhausted and memory CD8+ T cells have distinct ontogeny, function and roles in disease.
  13. T Cell Exhaustion in Cancer Immunotherapy: Heterogeneity, Mechanisms, and Therapeutic Opportunities.
  14. Selection for Postponed Senescence in Drosophila melanogaster Reveals Distinct Metabolic Aging Trajectories Modifiable by the Angiotensin-Converting Enzyme Inhibitor Lisinopril.
  15. CD38 Inhibition Ameliorates Age-Related Cognitive Decline via a Choroid Plexus-Cerebrospinal Fluid-Hippocampus Axis.
  16. CD8+ T cell aging is associated with macular neovascularization area change in neovascular age-related macular degeneration: a prospective cohort study.
  17. Metabolic adaptations rewire CD4+ T cells in a subset-specific manner in human critical illness with and without sepsis.
  18. Aging of the Hematopoietic System: Mechanisms, Consequences, and Systemic Interactions.
  19. BACH2 regulates T cell lineage state to enhance CAR T cell function.
  20. Metabolites as signalling molecules in the tumour immune microenvironment.
  21. Senescent cell accumulation is associated with T-cell imbalance in the skin.
  22. Senescent fibroblasts drive CD8+ T cell dysfunction in colorectal cancer via CD36-mediated lipid transfer and peroxidation.
  23. Metformin inhibits nuclear egress of chromatin fragments in senescence and aging.
  24. Hypoxia-driven remodeling of SELENOP+ macrophages shapes T cell dynamics and promotes ovarian cancer metastasis.
  25. Transcriptomic profiling of T cell exhaustion mechanisms in cervical cancer pathogenesis.
  26. Enhanced antitumor efficacy of next-generation B7-H3 chimeric antigen receptor T cells containing CD28, CD137 and CD27 costimulatory domains in multiple myeloma.
  27. Spontaneous somatic Pten loss contributes to functional heterogeneity of T cells.
  28. Single-Chain IL-23 Secretion by CAR T Cells Improves Tumor Control and Persistence Against Solid Tumors.
  29. CCL20-CCR6 signaling alters the metabolic reprogramming to promote the pathogenic Th17 cell differentiation.
  30. NMNAT1 Activates Autophagy to Delay D-Galactose-Induced Aging in Cochlear Hair Cells.
  31. Real-time multimodal phenotyping reveals distinct tumour cell dynamics and immune escape mechanisms in T cell therapies.
  32. Purinosomes and mitochondria: Dynamic interactomes at the crossroads of metabolism, cell structure, and disease.
  33. To the nines: IL-9 boosts T cell function.
  34. Targeting the N-acetyltransferase 10/DKK2 axis enhances CD8+ T cell antitumor activity in colorectal cancer models.
  35. IL-15 overexpression promotes memory program and anti-tumor activity of CD64 CAR T cells in a preclinical AML model.
  36. A Closed Computational-Experimental Loop Identifies Metabolic Collapse at the Root of Macrophage Dysfunction due to Zinc Dyshomeostasis.
  37. Longitudinal T-Cell Phenotypic Dynamics During Sustained Antiretroviral Therapy in People With HIV.
  38. GLP-1 receptor agonism counteracts omics aging in mice.
  39. Targeting the Mapk13-Tcf1-Slc7a5 Axis via One-Carbon Metabolic Regulation to Prevent Chronic Allograft Vasculopathy.
  40. Quercetin rejuvenates aged adipose progenitor cells by attenuating inflammatory pathways.
  41. CD4+ T cells mediate CAR-T cell-associated immune-related adverse events after BCMA CAR-T cell therapy.
  42. Ex Vivo Zinc Nanoparticle Conditioning Primes T Cells for Potent Antitumor Activity in Ovarian Cancer Patient-Derived Xenografts.
  43. IL7-TBRII, a Dual Cytokine Modulator Targeting IL-7 and TGF-β Pathways, Inhibits Tumor Progression and Metastasis.
  1. Sci China Life Sci. 2026 Jan 05.
    CD8+ T cell aging, senescence, and related disease.
    Zhe He, Fei Guo, Qifan Zhao, Wei Lu.
      CD8+ T cells are the primary killer cells that fight infections and malignantly transformed cells in vivo. In response to various stimuli, activated CD8+ T cells differentiate into effector and memory CD8+ T cells, which eliminate target cells and provide long-term protective immunity, respectively. Aberrant CD8+ T cell function induced by aging can lead to immune-related disorders. Both endogenous and exogenous stress affect the aging process of CD8+ T cells. CD8+ T cell aging results in cell senescence, characterized by disrupted cell proliferation, and impairs many other CD8+ T cell-related immune responses. It is now well-established that the aging of immune cells, including CD8+ T cells, exacerbates the body's inflammation and promotes cell senescence in distant tissues, thereby accelerating the onset and progression of age-related diseases. Therefore, clarifying the genetic characteristics, molecular mechanisms, and specific markers of aged CD8+ T cells is crucial for delivering precise and effective therapeutic interventions for age-related diseases, particularly those induced by CD8+ T cell aging.
    Keywords:  CD8+ T cells; aging; immune-related diseases; infection
    DOI:  https://doi.org/10.1007/s11427-025-3101-7
  2. Nature. 2026 Jan 14.
    The ubiquitin ligase KLHL6 drives resistance to CD8+ T cell dysfunction.
    Hongcheng Cheng, Yapeng Su, Xiaoli Pan, Yue Xu, Ermei Xie, Jing Du, Daniel G Chen, Xiaomeng Dai, Raphael Gottardo, Philip D Greenberg, Guideng Li.
      The multifaceted dysfunction of tumour-infiltrating T cells, including exhaustion and mitochondrial dysfunction, remains a major obstacle in cancer immunotherapy1-6. Transcriptomic and epigenomic regulation of T cell dysfunction have been extensively studied7-9, but the role of proteostasis in regulating these obstacles remains less defined. Here we combined computational analyses of atlases of T cell exhaustion and mitochondrial fitness with performed targeted in vivo CRISPR screens, which identified the E3 ubiquitin ligase KLHL6 as a dual-negative regulator of both T cell exhaustion and mitochondrial dysfunction. Mechanistically, KLHL6 expression promoted TOX poly-ubiquitination and subsequent proteasomal degradation, thereby attenuating the transition of progenitor exhausted T cells towards terminal exhaustion. Simultaneously, KLHL6 maintained mitochondrial fitness by constraining the excessive mitochondrial fission that occurs during chronic T cell receptor stimulation by means of post-translational regulation of the PGAM5-Drp1 axis. However, KLHL6 is naturally downregulated by T cell receptor ligation, mitigating its potentially beneficial ubiquitin ligase activities during exposure to chronic stimulation. Enforcing KLHL6 expression in T cells markedly improved efficacy and long-term persistence against tumours and during viral infections in vivo. These findings uncover KLHL6 as a multifunctional, clinically actionable target for cancer immunotherapy, and highlight the potential of modulating proteostasis and ubiquitin modification to improve immunotherapy.
    DOI:  https://doi.org/10.1038/s41586-025-09926-8
  3. Sci Immunol. 2026 Jan 23. 11(115): eadz7275
    PTMA safeguards mitochondrial integrity to sustain metabolic function and antitumor activity of CD8 T cells.
    Keling Huang, Xiaoxue Li, Wenhua Liang, Shuyao Wu, Youqiong Ye, Yan Lu, Junke Zheng, Weifang Wang, Qifan Zheng, Guo Fu, Song Gao, Feng Wang.
      Immune checkpoint blockade (ICB) has transformed cancer treatment, yet its efficacy is often limited by the progressive exhaustion of tumor-reactive CD8 T cells. By analyzing transcriptomes of CD8 T cells from patients treated with ICB across cancer types, we found that prothymosin alpha (PTMA) is highly expressed in progenitor exhausted T (TPEX) cells and is associated with treatment response. PTMA expression was directly controlled by T cell factor 1 (TCF1), a central regulator of TPEX cell maintenance in the tumor microenvironment. In mice, genetic deletion of Ptma from T cells compromised CD8 T cell persistence in tumors and abolished the therapeutic effect of programmed cell death protein 1 (PD-1) blockade. PTMA preserved mitochondrial DNA integrity through interaction with mitochondrial transcription factor A (TFAM), sustaining T cell oxidative phosphorylation under metabolic stress. Our findings identify the TCF1-PTMA axis as a molecular link between mitochondrial fitness and durable T cell-mediated antitumor immunity, offering insights and potential directions for future therapeutic strategies to boost immunotherapy efficacy.
    DOI:  https://doi.org/10.1126/sciimmunol.adz7275
  4. Nat Immunol. 2026 Jan 15.
    Metabolic adaptation in CD4+ T cells promotes immunosuppression in sepsis.
    Nicole M Chapman, Hongbo Chi.
      
    DOI:  https://doi.org/10.1038/s41590-025-02403-4
  5. bioRxiv. 2026 Jan 08. pii: 2026.01.07.698190. [Epub ahead of print]
    Latent Regulatory Programs Generate Synthetic T Cell States with Enhanced Therapeutic Potential.
    Brandon M Pratt, Genevieve N Mullins, Nolan Brown, William D Green, Jennifer Modliszewski, Fucong Xie, Lara van Rooyen, Vasyl Zhabotynsky, Alexander N Jambor, Gabrielle Cannon, Jarred M Green, Andrew Kennedy, Coral Del Mar Alicea Paunto, Huitong Shi, Emily Merritt, Takeshi Egawa, Ashwin Somasundaram, Wei Wang, Jessica E Thaxton, Gianpietro Dotti, H Kay Chung, J Justin Milner.
      Transcription factors (TFs) govern cell fate through coordinated gene-regulatory networks, yet the full potential of these networks to generate non-native, therapeutically advantageous cell states in vivo remains largely unexplored. We hypothesized that systematic gain-of-function (GOF) overexpression of TFs in CD8⁺ T cells, central mediators of immune protection, could reveal latent, or "hidden," regulatory programs capable of generating synthetic T cell states with therapeutic utility. To test this, we developed single-cell GOF sequencing (scGOF-seq), a multiplexed platform for unbiased, in vivo mapping of GOF effects on T cell fate in immunocompetent mouse models of infection and cancer. scGOF-seq uncovered unexpected regulators of T cell differentiation and accumulation, including SOX2, OCT4, and GATA2, which are normally silenced during T cell differentiation. Notably, outside its native regulatory context, supraphysiologic cMyc GOF reprogrammed CD8⁺ T cells into a synthetic stem-effector hybrid state, enabling >5,000-fold antigen-dependent expansion and antitumor activity, contrasting sharply with its native function in driving terminal differentiation. scGOF-seq further identified TF modules that cooperate with cMyc GOF to promote robust CD8⁺ T cell responses in solid tumors. Together, these findings establish GOF perturbation as a powerful strategy for revealing latent immune regulatory programs and engineering synthetic immune states with therapeutic potential.
    One-Sentence Summary: In vivo single-cell gain-of-function screening reveals latent transcriptional programs that can reprogram T cells into highly functional synthetic states.
    DOI:  https://doi.org/10.64898/2026.01.07.698190
  6. Nat Immunol. 2026 Jan 12.
    PARP inhibition generates enhanced CD8+ central memory T cells by transcriptional and metabolic reprogramming.
    Wael Traboulsi, Pankaj Gaur, Subhadip Kundu, Zainab Ramlaoui, Christopher Priestley-Milianta, Aishwariya Iyengar, Nour Shobaki, Dareen Sarhan, Min-Jung Lee, Jung-Min Lee, George N Pavlakis, Mikayel Mkrtichyan, Viia E Valge-Archer, Simon T Barry, Vivek Verma, Seema Gupta, Samir N Khleif.
      CD8+ central memory T (TCM) cells provide stronger antitumor immunity than more-differentiated effector memory counterparts. Here we show that poly(ADP-ribose) polymerase (PARP) inhibition induces CD8+ TCM cells with superior memory by activating the SIRT-1-FOXO1 pathway and inducing metabolic and transcriptional switches through inhibition of enzymatic activity and enhanced PARP trapping. Together, this results in suppression of the cell cycle and upregulation of memory and fatty acid oxidation gene expression, and reprogramming CD8+ T cells into TCM cells with enhanced metabolic fitness and substantially higher recall capabilities. PARP inhibitor treatment of tumor-bearing mice resulted in an increase in the number of 'superior TCM' cells within the tumor microenvironment and enhanced immune-mediated antitumor responses. PARP inhibitor-treated CD8+ T cells were more effective in adoptive cell therapy. Furthermore, the frequency of CD8+ memory T cells and the expression of their memory markers was increased in patients with cancer treated with PARP inhibitor. Together, these data show that PARP inhibition directly reprograms CD8+ T cells, enhancing metabolic fitness and generating highly effective therapeutically superior memory cells.
    DOI:  https://doi.org/10.1038/s41590-025-02383-5
  7. Nat Immunol. 2026 Jan 16.
    Fine-tuning BACH2 dosage balances stemness and effector function to enhance antitumor T cell therapy.
    Alberto G Conti, Alexander C Evans, Teresa von Linde, Christian Deo T Deguit, Sarah K Whiteside, Alexander J Wesolowski, Charlotte J Imianowski, Yumi Yamashita-Kanemaru, Layla Dahmani, Jack Chapman, Ardon M Pillay, Aws Al-Deka, Randy Greaves, Oliver Burton, Panagiota Vardaka, Shienny Sampurno, Iván Pérez-Núñez, Nicole Y L Saw, Jie Yang, Andrew J M Howden, Klaus Okkenhaug, Suman Mitra, Bartlomiej Swiatczak, Ian A Parish, Rahul Roychoudhuri.
      Adoptive T cell therapies are limited by poor persistence of transferred cells. Attempts to enhance persistence have focused on genetic induction of constitutively hyperactivated but potentially oncogenic T cell states. Physiological T cell responses are maintained by quiescent stem-like/memory cells dependent upon the transcription factor BACH2. Here we show that quantitative control of BACH2 dosage regulates differentiation along the continuum of stem and effector CD8⁺ T cell states, enabling engineering of synthetic states with persistent antitumor activity. While conventional high-level overexpression of BACH2 enforces quiescence and hinders tumor control, low-dose BACH2 expression promotes persistence without compromising effector function, enhancing anticancer efficacy. Mechanistically, low-dose BACH2 partially attenuates Jun occupancy at highly AP-1-dependent genes, restraining terminal differentiation while preserving effector programs. Similarly, dose optimization enables effective deployment of quiescence factor FOXO1. Thus, quantitative control of gene payloads yields qualitative effects on outcome with implications for quiescence factor deployment in cell therapy.
    DOI:  https://doi.org/10.1038/s41590-025-02389-z
  8. bioRxiv. 2026 Jan 07. pii: 2025.12.23.696247. [Epub ahead of print]
    Multi-omics Analysis of Human Blood Cells Reveals Unique Features of Age-associated Type2 CD8 Memory T cells.
    Hiroyuki Matsui, Marlene Cervantes, Mir M Khalid, Alan Tomusiak, Varun Dwaraka, Jorge Landgrave-Gomez, Prasanna Vadhana Ashok Kumaar, Qingwen Chen, Jesica Lasky-Su, Jake Stone, Ritesh Tiwari, Ryan Kwok, Shuntaro Ichikawa, Benjamin D Ambrose, Rebeccah R Riley, Genesis Vega Hormazabal, Ariel Floro, Andreea Cristina Alexandru, Ryan Smith, Birgit Schilling, Herbert G Kasler, Eric Verdin.
      Aging impacts immune function, but the mechanisms driving age-related changes in immune cell subsets remain unclear. To explore age-dependent changes in immune cell populations, we analyzed human peripheral blood mononuclear cells (PBMCs) from a cohort of healthy donors aged 20-82 years using a 36-color spectral flow cytometry panel focused on T cells. We identified a unique population of memory CD8 T cells, which lack CXCR3 and produce a Th2-like cytokine response, accumulate with age. We discovered an age-dependent bias in naïve CD8 T cells toward Th2 cytokine production, accompanied by transcriptional and epigenetic changes supporting this phenotype. Moreover, health outcome association analysis linked the accumulation of these unique CXCR3- central memory CD8 T cells to asthma, chronic liver conditions, and type 2 diabetes. Together, our results support the model that an age-dependent drift in epigenetic regulation towards a Th2-like phenotype drives a pathogenic Th2-like immune population.
    DOI:  https://doi.org/10.64898/2025.12.23.696247
  9. Biochem Pharmacol. 2026 Jan 08. pii: S0006-2952(26)00025-0. [Epub ahead of print]245 117694
    Immunometabolism: Is cyanide a missing link between metabolic pathways and immune function?
    Brian J Day.
      Immunometabolism is an emerging field that explores how metabolic pathways shape immune cell function, fate, and response. Immune cells undergo dynamic metabolic reprogramming to meet the energetic and biosynthetic demands of activation, differentiation, and effector activity. While glycolysis and oxidative phosphorylation (OxPhos) are well-established regulators of immune responses, recent discoveries suggest that endogenously produced cyanide may serve as a novel modulator of mitochondrial metabolism. Traditionally viewed as a toxic compound, cyanide is now being recognized for its potential role in regulating OxPhos through inhibition of complex IV in the electron transport chain, thereby influencing the balance between glycolysis and mitochondrial respiration. This review synthesizes current knowledge on the metabolic regulation of immune cells-including T cells, macrophages, dendritic cells, B cells, and natural killer (NK) cells-and highlights the role of core pathways such as glycolysis, fatty acid oxidation (FAO), and amino acid metabolism. It also explores how cyanide formation and metabolism intersect with innate immunity, particularly through the generation of thiocyanate and its role in antimicrobial defense. Furthermore, the review discusses how nutritional status integrate with metabolic cues to fine-tune immune responses. Finally, the clinical implications of immunometabolic regulation are examined in the context of autoimmune diseases, cancer, infections, and metabolic disorders. The potential of cyanide as a therapeutic modulator of immune metabolism is considered, offering new perspectives on immune regulation and disease intervention.
    Keywords:  Cancer; Immunity; Infection; Inflammation; Metabolic disorders; Metabolic switch; Therapeutics
    DOI:  https://doi.org/10.1016/j.bcp.2026.117694
  10. Nat Immunol. 2026 Jan 16.
    BACH2 dosage establishes the hierarchy of stemness and fine-tunes antitumor immunity in CAR T cells.
    Taidou Hu, Ziang Zhu, Ying Luo, Safuwra Wizzard, Jonathan Hoar, Sejal S Shinde, Kiddist Yihunie, Chen Yao, Tuoqi Wu.
      Stem-like T cells promote the efficacy of immunotherapy and are heterogeneous in stemness, with long-term (LT) stem-like T cells at the apex of this hierarchy. How the stemness hierarchy is regulated in chimeric antigen receptor (CAR) T cells and how it affects antitumor function are unclear. Here we show that BACH2 dose-dependently regulates LT stem-like differentiation and antitumor immunity of CAR T cells. LT stem-like CAR T cells that appear before infusion and re-emerge after tumor clearance have superior antitumor immunity and the greatest BACH2 expression. BACH2 promotes the antitumor response of CAR T cells and the LT stem-like transcriptional program. Temporal and quantitative induction of BACH2 expression in CAR T cells during manufacturing using chemical switches fine-tunes the degree of stemness and imprints greater control of solid tumors. Together, these data show that BACH2 dosage defines stemness hierarchy in CAR T cells and can be temporally and tunably controlled to optimize differentiation and antitumor efficacy.
    DOI:  https://doi.org/10.1038/s41590-025-02388-0
  11. Nature. 2026 Jan 14.
    Microbiota-induced T cell plasticity enables immune-mediated tumour control.
    Tariq A Najar, Yuan Hao, Yuhan Hao, Gabriela Romero-Meza, Alexandra Dolynuk, Emma Almo, Dan R Littman.
      Therapies that harness the immune system to target and eliminate tumour cells have revolutionized cancer care. Immune checkpoint blockade (ICB), which boosts the anti-tumour immune response by inhibiting negative regulators of T cell activation1-3, is remarkably successful in a subset of cancer patients. Yet a significant proportion do not respond to treatment, emphasizing the need to understand factors influencing the therapeutic efficacy of ICB4-9. The gut microbiota, consisting of trillions of microorganisms residing in the gastrointestinal tract, has emerged as a critical determinant of immune function and response to cancer immunotherapy, with several studies demonstrating association of microbiota composition with clinical response10-16. However, a mechanistic understanding of how gut commensal bacteria influence the efficacy of ICB remains elusive. Here we use a gut commensal microorganism, segmented filamentous bacteria (SFB), which induces an antigen-specific T helper 17 (TH17) cell effector program in the small intestine lamina propria (SILP)17, to investigate how colonization with this microbe affects the efficacy of ICB in restraining distal growth of tumours sharing antigen with SFB. We find that anti-programmed cell death protein 1 (PD-1) treatment effectively inhibits the growth of implanted SFB antigen-expressing melanoma only if mice are colonized with SFB. Through T cell receptor (TCR) clonal lineage tracing, fate mapping and peptide-major histocompatability complex (MHC) tetramer staining, we identify tumour-associated SFB-specific T helper 1 (TH1)-like cells derived from the homeostatic TH17 cells induced by SFB colonization in the SILP. These gut-educated ex-TH17 cells produce high levels of the pro-inflammatory cytokines interferon (IFN)-γ and tumour necrosis factor (TNF) within the tumour microenvironment (TME), enhancing antigen presentation and promoting recruitment, expansion and effector functions of CD8+ tumour-infiltrating cytotoxic lymphocytes and thereby enabling anti-PD-1-mediated tumour control. Conditional ablation of SFB-induced IL-17A+CD4+ T cells, precursors of tumour-associated TH1-like cells, abolishes anti-PD-1-mediated tumour control and markedly impairs tumour-specific CD8+ T cell recruitment and effector function within the TME. Our data, as a proof of principle, define a cellular pathway by which a single, defined intestinal commensal imprints T cell plasticity that potentiates PD-1 blockade, and indicate targeted modulation of the microbiota as a strategy to broaden ICB efficacy.
    DOI:  https://doi.org/10.1038/s41586-025-09913-z
  12. Nat Immunol. 2026 Jan 13.
    Publisher Correction: Tissue-resident exhausted and memory CD8+ T cells have distinct ontogeny, function and roles in disease.
    Simone L Park, Mark M Painter, Sasikanth Manne, Victor Alcalde, Maura McLaughlin, Matthew A Sullivan, Divij Mathew, Leonel Torres, Yinghui J Huang, David B Reeg, Naomi R Douek, Trenton Campos, Max Klapholz, Maria A Cardenas, Victoria Fang, Shin Foong Ngiow, Wumesh Kc, Rishi R Goel, Amy E Baxter, Jennifer E Wu, Melody Tan, Corbett T Berry, Christoph T Ellebrecht, Alexander C Huang, Emily Papazian, Ying Liu, Karthik Rajasekaran, Robert M Brody, Erica R Thaler, Devraj Basu, Ahmed Diab, Josephine R Giles, E John Wherry.
      
    DOI:  https://doi.org/10.1038/s41590-026-02420-x
  13. Adv Sci (Weinh). 2026 Jan 12. e20634
    T Cell Exhaustion in Cancer Immunotherapy: Heterogeneity, Mechanisms, and Therapeutic Opportunities.
    Yang Yu, Xiaoyu Yao, Qingyang Wang, Mengrui Yang, Runze Li, Jiangjiang Qin, Jing Zhuang, Changgang Sun.
      T cell exhaustion represents a pivotal mechanism of immune escape in cancer, with its inherent heterogeneity and dynamic plasticity being key determinants of the variable responses and resistance to immune checkpoint inhibitors (ICIs). This review comprehensively delineates the multifaceted heterogeneity of exhausted T (TEX) cells, tracing their developmental trajectory from precursor exhausted T (TPEX) cells to terminally differentiated exhausted T (TEX -term) cells. We highlight both distinct and shared exhaustion features across diverse cancer types and spatial niches within the tumor microenvironment. Furthermore, we examine the multi-layer biomarkers that drive and define this state, including characteristic surface inhibitory receptors, core transcription factors, and metabolism-associated molecules. Grounded in this mechanistic understanding, we discuss emerging therapeutic strategies aimed at reversing T cell exhaustion. These range from the optimized application of ICIs and rational combination therapies involving epigenetic or metabolic interventions, to next-generation engineered cell therapies such as chimeric antigen receptor T cell (CAR-T), T cell receptor-engineered T cell (TCR-T), and tumor-infiltrating lymphocytes (TILs), alongside emerging modalities including oncolytic viruses and bispecific antibodies. Finally, we discuss prevailing challenges and future directions, emphasizing that deciphering the heterogeneous landscape of TEX cells, identifying precise biomarkers, and developing temporally controlled combination regimens are imperative to effectively reverse T cell exhaustion and broaden the therapeutic efficacy of cancer immunotherapy.
    Keywords:  T cell exhaustion; cancer immunotherapy; combination therapy; immune checkpoint inhibitors; tumor microenvironment
    DOI:  https://doi.org/10.1002/advs.202520634
  14. Aging Cell. 2026 Feb;25(2): e70375
    Selection for Postponed Senescence in Drosophila melanogaster Reveals Distinct Metabolic Aging Trajectories Modifiable by the Angiotensin-Converting Enzyme Inhibitor Lisinopril.
    Denise Vecchié, Robert R H Anholt, Trudy F C Mackay, Maria De Luca.
      Aging is accompanied by profound changes in energy metabolism, yet the underlying drivers and modulators of these shifts remain incompletely understood. Here, we investigated how life-history evolution shapes metabolic aging and pharmacological responsiveness by leveraging Drosophila melanogaster lines divergently selected for reproductive timing. We measured organismal oxygen consumption rate and performed untargeted metabolomics in young and old flies of both sexes from long-lived "O" lines (selected for female late-life reproduction) and unselected "B" control lines. Males and females from the O lines maintained stable metabolic rates and largely preserved metabolite profiles with age, whereas B line flies showed age-related increases in oxygen consumption, citrate accumulation, and elevated levels of medium- and long-chain fatty acids, hallmarks of mitochondrial inefficiency and impaired lipid oxidation. Aged B flies also displayed elevated S-adenosylmethionine, reduced sarcosine, and diminished heme levels, indicating dysregulation of one-carbon metabolism and impaired heme biosynthesis. Furthermore, Vitamin B6 metabolites, pyridoxamine, pyridoxal, and 4-pyridoxate, increased with aging only in B line females. Motivated by evidence implicating the renin-angiotensin system in metabolic aging, we treated flies with the angiotensin-converting enzyme (ACE) inhibitor lisinopril. Lisinopril prevented the age-related rise in metabolic rate in B line females, aligning their metabolic phenotype with that of O line flies. This suggests that ACE inhibition may buffer against age-associated increases in metabolic rate and contribute to enhanced metabolic stability. Our results show that selection for delayed reproduction and increased lifespan modifies age-related metabolic trajectories and modulates physiological responses to pharmacological intervention.
    Keywords:  energy metabolism; longevity; metabolomics; postponed reproductive senescence; renin‐angiotensin system blockade
    DOI:  https://doi.org/10.1111/acel.70375
  15. Res Sq. 2026 Jan 06. pii: rs.3.rs-8330519. [Epub ahead of print]
    CD38 Inhibition Ameliorates Age-Related Cognitive Decline via a Choroid Plexus-Cerebrospinal Fluid-Hippocampus Axis.
    Eric Verdin, Jingqi Fang, Rebeccah Riley, Kevin Schneider, Rosalba Perrone, Prasanna Kumaar, Christina King, Grant Kauwe, Andrea Roberts, Genesis Vega Hormazabal, Yini Zhang, Ethan Millard, Xinran Liu, Wendy Jara, Carlos Galicia Aguirre, Harrison Baker, Natalia Murad, Ben Ambrose, Tommy Tran, Nicolas Martin, Ran Zhang, Durai Sellegounder, Simon Melov, David Furman, Tara Tracy, Akos Gerencser, Birgit Schilling, Lisa Ellerby.
      Age-related cognitive decline represents a major and unresolved challenge of human aging. Here, we identify the NAD⁺-consuming enzyme CD38 as a central regulator of cognitive aging acting through a choroid plexus-cerebrospinal fluid (CSF)-hippocampus axis. CD38 expression increases with age and localizes primarily to pericytes in the choroid plexus, where it depletes NAD⁺, impairs mitochondrial function, and promotes cellular senescence. Genetic ablation or pharmacological inhibition of CD38 restores NAD⁺ levels, suppresses senescence markers, and improves choroid plexus function, resulting in a rejuvenated CSF proteomic and metabolomic profile characterized by reduced inflammatory signaling and enhanced neurotrophic support. These changes propagate to the hippocampus, reversing age-related transcriptional signatures and enhancing synaptic plasticity. A novel, brain-penetrant CD38 inhibitor, NTX-748, reproduced the benefits of CD38 deficiency-elevating systemic and brain NAD⁺ levels, improving long-term potentiation, and enhancing multiple domains of cognition in aged mice. Collectively, these findings identify the choroid plexus as a metabolic gatekeeper of brain aging and establish CD38 inhibition as a promising therapeutic strategy to promote cognitive resilience and healthy brain aging.
    DOI:  https://doi.org/10.21203/rs.3.rs-8330519/v1
  16. BMC Ophthalmol. 2026 Jan 10.
    CD8+ T cell aging is associated with macular neovascularization area change in neovascular age-related macular degeneration: a prospective cohort study.
    Alexander Kai Thomsen, Maria Abildgaard Steffensen, Kathrine Gotfredsen, Henrik Vorum, Bent Honoré, Mogens Holst Nissen, Torben Lykke Sørensen.
      
    Keywords:  Age-related macular degeneration; Choroidal neovascularization; Immunosenescence; Inflammation; Macular neovascularization; Macular neovascularization area; Neovascular age-related macular degeneration; Systemic inflammation; T cells; Treatment response
    DOI:  https://doi.org/10.1186/s12886-025-04570-2
  17. Nat Immunol. 2026 Jan 15.
    Metabolic adaptations rewire CD4+ T cells in a subset-specific manner in human critical illness with and without sepsis.
    Matthew T Stier, Allison E Sewell, Erin L Mwizerwa, Chooi Ying Sim, Samantha M Tanner, Casey M Nichols, Heather H Durai, Erin Q Jennings, Paul Lindau, Erin M Wilfong, Sarah N Obeidalla, V Eric Kerchberger, Dawn C Newcomb, Julie A Bastarache, Lorraine B Ware, Jeffrey C Rathmell.
      Metabolic and immunologic dysfunction, including pathological CD4+ T cell immunosuppression, are archetypal in critical illness, but whether these factors are mechanistically linked remains incompletely defined. Here we characterized the metabolic properties of human CD4+ T cells from critically ill patients with and without sepsis and healthy adults. CD4+ T cells in critical illness showed subset-specific metabolic plasticity, with regulatory T (Treg) cells preferentially acquiring glycolytic capacity that associated with sustained cellular fitness and worsened clinical illness. Adapted Treg cells were more metabolically flexible and stabilized suppressive markers FOXP3 and TIGIT under mitochondrial stress. Single-cell transcriptomics suggested reactive oxygen species (ROS) and kynurenine metabolism as drivers of Treg cell remodeling. Subsequent inhibition of ROS and kynurenine metabolism attenuated glycolytic adaptation and suppressive rewiring, respectively, in Treg cells. These findings indicate that metabolic dysfunction was a contributor to CD4+ T cell remodeling in critical illness and suggest avenues to restore effective immunity.
    DOI:  https://doi.org/10.1038/s41590-025-02390-6
  18. Aging Cell. 2026 Feb;25(2): e70385
    Aging of the Hematopoietic System: Mechanisms, Consequences, and Systemic Interactions.
    Masashi Miyawaki, Seiji Hashimoto, Sumito Ogawa, Yoshitaka Kase.
      The aging of the hematopoietic system is central to physiological aging, with profound consequences for immune competence, tissue regeneration, and systemic health. Age-related changes manifest as altered blood cell composition, functional decline in hematopoietic stem cells (HSCs), and deterioration of the bone marrow niche. Beyond hematologic dysfunction, hematopoietic aging acts as a systemic amplifier of age-related diseases through clonal hematopoiesis and inflammatory remodeling. This review integrates recent insights into the mechanisms and systemic impacts of hematopoietic aging, reframing it as a modifiable axis of systemic aging. We highlight emerging rejuvenation strategies-senolytics, metabolic reprogramming, and microbiota-targeted therapies-that aim to restore hematopoietic and immune function, offering promising avenues to improve healthspan and reduce age-related multimorbidity.
    Keywords:  aging; healthspan; hematopoiesis; hematopoietic stem cells; inflammation
    DOI:  https://doi.org/10.1111/acel.70385
  19. Nat Immunol. 2026 Jan 16.
    BACH2 regulates T cell lineage state to enhance CAR T cell function.
    Tien-Ching Chang, Amanda Heard, John Lattin, John M Warrington, Amanda Barrett, Jack H Landmann, Yangdon Tenzin, Vishaal Ganesh, Bryant Thompson, Sadia Afrin, Deepesh Kumar Gupta, Ju-Fang Chang, Julie Ritchey, Mehmet Emrah Selli, Yu-Sung Hsu, Haorui Song, A J Federico, Avery Horn, Michael P Meers, Evan W Weber, Thomas J Wandless, Jeremy Chase Crawford, Paul G Thomas, John F DiPersio, Stephen Gottschalk, Nathan Singh.
      Nearly all chimeric antigen receptors (CARs) signal in the absence of antigen, referred to as 'tonic signaling'. Tonic signaling of CARs containing 41BB domains enhances T cell fitness and function, in contrast to the exhaustion driven by CD28-containing CARs. Here we show that 41BB induces BACH2, a transcriptional regulator that directs stem and memory programs. Overexpression of BACH2 successfully prevented exhaustion but locked CAR T cells in a quiescent state. We linked BACH2 to a degradation domain to tune BACH2, enabling us to prevent exhaustion while enabling potent effector function that broadly enhanced the long-term efficacy of CAR T cells targeting liquid and solid tumors. Through interrogation of clinical CAR products, we further found an association between BACH2 activity and clinical outcomes in patients with leukemia. These data identify a central function for BACH2 in regulating CAR T cell efficacy.
    DOI:  https://doi.org/10.1038/s41590-025-02391-5
  20. Nat Rev Immunol. 2026 Jan 12.
    Metabolites as signalling molecules in the tumour immune microenvironment.
    Youxiang Mao, Wenjun Xia, Peng Jiang.
      Alterations in key metabolic pathways are required for tumour development and the adaptation of tumour cells to intrinsic or extrinsic stresses, as well as for the regulation of immune cell fate and immune responses in the tumour microenvironment. In particular, the dysregulation or alteration of certain metabolites produced by tumour cells has been shown to be important in creating the immunosuppressive tumour microenvironment. Recent studies have broadened our understanding of the interactions between metabolites and antitumour immunity. Here we highlight how, beyond their metabolic role, metabolites can function as signalling molecules to modulate the behaviours of immune cells and tumour cells. We also discuss potential therapeutic strategies targeting specific metabolites and future research directions in metabolite sensing.
    DOI:  https://doi.org/10.1038/s41577-025-01258-y
  21. Vavilovskii Zhurnal Genet Selektsii. 2025 Dec;29(7): 1137-1144
    Senescent cell accumulation is associated with T-cell imbalance in the skin.
    K S Matveeva, S K Kolmykov, T S Sokolova, D R Salimov, D V Shevyrev.
      Organismal aging is accompanied by the accumulation of senescent cells - damaged, non-functional cells that exhibit cell cycle arrest, resistance to apoptosis, metabolic dysfunction, and production of a wide range of pro-inflammatory substances. The age-related accumulation of these cells is associated with impaired tissue function, contributes to chronic inflammation (inflammaging), and promotes the development of various age-associated diseases. Conversely, the elimination of senescent cells restores tissue functions and positively affects overall metabolism. Under normal conditions, senescent cells are removed by the innate immune system; however, the efficiency of this process declines with age. The involvement of adaptive immunity and the role of T cells in the clearance of senescent cells remain poorly understood. The aim of this study was to identify alterations in local T cell immunity associated with the accumulation of senescent cells in human skin. The analysis was performed on publicly available single-cell RNA-sequencing data from skin biopsies, and the senescent status was assessed using the SenePy algorithm with Gaussian mixture models. It was found that the emergence of senescent cells occurs heterogeneously across cell types within the tissue. The accumulation of these cells is associated with alterations in the CD4+ to CD8+ T cell ratio, as well as with an increased abundance of regulatory T cells. Functional analysis revealed that these quantitative age-related shifts were accompanied by more pronounced activation of regulatory T cells together with features of anergy and exhaustion in CD8+ T cells, whereas functional changes in CD4+ T cells were heterogeneous. These findings underscore the importance of adaptive immunity in maintaining tissue homeostasis and suggest potential age-related dysfunction of tissue-resident T cells. Understanding the mechanisms underlying the interaction between adaptive immunity and senescent cells is crucial for the development of senolytic vaccines and other immunological approaches aimed at enhancing endogenous elimination of senescent cells.
    Keywords:  adaptive immunity; aging; genetic signatures; regulatory T cells; senescence; senescent cell elimination; single-cell transcriptome; skin; tissue-resident T cells
    DOI:  https://doi.org/10.18699/vjgb-25-118
  22. J Transl Med. 2026 Jan 14.
    Senescent fibroblasts drive CD8+ T cell dysfunction in colorectal cancer via CD36-mediated lipid transfer and peroxidation.
    Mengxiao Ge, Shuangyi Sun, Wentong Chen, Zhenxiao Xu, Deyi Kang, Zeqin Wang, Yumeng Guo.
      
    Keywords:  CD8+ T cell; Colorectal tumor; Lipid transfer; Patient-derived organoids; Senescent fibroblasts
    DOI:  https://doi.org/10.1186/s12967-025-07636-3
  23. Nat Aging. 2026 Jan 16.
    Metformin inhibits nuclear egress of chromatin fragments in senescence and aging.
    Takuya Kumazawa, Yanxin Xu, Yu Wang, Ji-Won Lee, Tara C O'Brien, Chia-Kang Ho, Murat Cetinbas, Aaron Weiner, Konrad Hochedlinger, Ruslan I Sadreyev, Nabeel Bardeesy, Chia-Wei Cheng, Bin He, Zhixun Dou.
      Chronic inflammation promotes aging and age-associated diseases. While metabolic interventions can modulate inflammation, how metabolism and inflammation are connected remains unclear. Cytoplasmic chromatin fragments (CCFs) drive chronic inflammation through the cGAS-STING pathway in senescence and aging. However, CCFs are larger than nuclear pores, and how they translocate from the nucleus to the cytoplasm remains uncharacterized. Here we report that chromatin fragments exit the nucleus via nuclear egress, a membrane trafficking process that shuttles large complexes across the nuclear envelope. Inactivating critical nuclear egress proteins, the ESCRT-III or Torsin complex, traps chromatin fragments at the nuclear membrane and suppresses cGAS-STING activation and senescence-associated inflammation. Glucose limitation or metformin inhibits CCF formation through AMPK-dependent phosphorylation and autophagic degradation of ALIX, an ESCRT-III component. In aged mice, metformin reduces ALIX, CCFs, and cGAS-mediated inflammation in the intestine. Our study identifies a mechanism linking metabolism and inflammation and suggests targeting the nuclear egress of chromatin fragments as a strategy to suppress age-associated inflammation.
    DOI:  https://doi.org/10.1038/s43587-025-01048-0
  24. Nat Commun. 2026 Jan 12.
    Hypoxia-driven remodeling of SELENOP+ macrophages shapes T cell dynamics and promotes ovarian cancer metastasis.
    Qing Liu, Chenzhao Feng, Tianhao Wu, Siyang Zhang, Xinyi Wang, Qian Zhao, Xueying Song, Shuangyan Liu, Linru Quan, Yuli Zhang, Shimin Zhang, Bin Yang, Jixin Li, Gang Chen, Xuanzhang Huang, Chaoyang Sun, Xin Zhou.
      High-grade serous ovarian cancer (HGSOC) is characterized by extensive transcoelomic dissemination and the accumulation of ascites. However, how site-specific tumor microenvironment (TME) drives progression remains unknown. Here we show the co-occurrence and spatial co-localization of SELENOP+ macrophages and precursor exhausted CD8+ T cells and demonstrate that SELENOP+ macrophages activate T cells via selenoprotein P in vitro and in vivo. We further identify a dynamic transition in the SELENOP+/SPP1+ macrophage populations as tumor metastasis, driven by increased hypoxia malignant epithelial cells through VEGFA-EPHB2 signaling. We also reveal that anti-VEGFA intervention controls ovarian tumor growth by increasing SELENOP+ macrophages and cytotoxicity of CD8+ T cells in vivo. Taken together, these findings spotlight the role of tumor-induced TME remodeling in subverting immune-mediated tumor control and thus facilitating HGSOC metastasis in females. Collectively, our results provide a foundation for the development of targeted therapeutic interventions aimed at impeding HGSOC metastatic trajectory.
    DOI:  https://doi.org/10.1038/s41467-025-67859-2
  25. Discov Oncol. 2026 Jan 16.
    Transcriptomic profiling of T cell exhaustion mechanisms in cervical cancer pathogenesis.
    Caixia Li, Hong Lin, Hegan Zhang.
      
    Keywords:  Bioinformatics; Cervical cancer; Hub genes; Immune microenvironment; T cell exhaustion
    DOI:  https://doi.org/10.1007/s12672-026-04423-4
  26. Cytotherapy. 2025 Nov 26. pii: S1465-3249(25)00910-7. [Epub ahead of print]28(3): 102014
    Enhanced antitumor efficacy of next-generation B7-H3 chimeric antigen receptor T cells containing CD28, CD137 and CD27 costimulatory domains in multiple myeloma.
    Krissada Natungnuy, Piriya Luangwattananun, Kamonlapat Supimon, Pornpimon Yuti, Punchita Rujirachaivej, Jatuporn Sujjitjoon, Mutita Junking, Seiji Okada, Pa-Thai Yenchitsomanus.
       BACKGROUND: Multiple myeloma (MM) remains an incurable disease despite significant advancements in treatment strategies. Chimeric antigen receptor (CAR) T cell therapies targeting B-cell maturation antigen have demonstrated clinical promise; however, their effectiveness is often limited by disease relapse, partly due to CAR T cell exhaustion. B7-homolog 3 (B7-H3), an immune checkpoint molecule that is overexpressed in MM and may suppress T cell function, represents a potential alternative target to improve CAR T cell efficacy and enhance disease control.
    METHODS: We engineered and characterized three generations of B7-H3-specific CAR T cells, second (B7H3.CAR2), third (B7H3.CAR3) and next-generation (B7H3.CAR-NG), each incorporating distinct costimulatory domains. B7H3.CAR2 contains the CD28 costimulatory domain, B7H3.CAR3 combines CD28 and CD137, and B7H3.CAR-NG incorporates CD28, CD137, and CD27 costimulatory modules. Their expression and function were evaluated in vitro using MM cell lines with differential B7-H3 expression. CAR T cell phenotype, cytotoxic activity, persistence and cytokine secretion were assessed through both short- and long-term coculture assays.
    RESULTS: B7-H3 expression levels varied across MM cell lines, with MM.1S exhibiting the highest and NCI-H929 the lowest expression. Second-, third- and next-generation B7-H3-specific CAR T cells (B7H3.CAR2, B7H3.CAR3, and B7H3.CAR-NG) were successfully generated, with CAR expression rates of 31.27 ± 8.63%, 29.90 ± 8.86% and 37.27 ± 8.69%, respectively. All three CAR T cell types selectively lysed B7-H3-positive MM.1S cells in an antigen density-dependent manner while sparing B7-H3-negative SupT1 cells. Among them, B7H3.CAR-NG T cells showed the highest cytotoxicity, lysing 53.22 ± 9.28% of MM.1S cells at a 1:1 effector-to-target ratio, compared to 11.66 ± 1.62% of SupT1 cells. In long-term cocultures, CAR-NG T cells demonstrated superior tumor control and persistence, likely due to a higher frequency of central memory T cells. Cytokine analysis revealed elevated secretion of effector molecules by CAR-NG T cells, indicating enhanced antitumor functionality.
    CONCLUSIONS: B7-H3-specific CAR T cells exhibit potent antitumor activity against MM, with the next-generation construct (B7H3.CAR-NG) demonstrating superior cytotoxicity, persistence and cytokine production. These findings support the potential of B7H3.CAR-NG T cells as a promising therapeutic strategy for MM.
    Keywords:  B7-H3; CAR T cells; adoptive cell therapy; chimeric antigen receptor; immune checkpoint; multiple myeloma
    DOI:  https://doi.org/10.1016/j.jcyt.2025.102014
  27. Sci Rep. 2026 Jan 12.
    Spontaneous somatic Pten loss contributes to functional heterogeneity of T cells.
    Allen Y Chen, Alexander Y Rudensky.
      We found that healthy mice harbor T cells with heritable low Pten expression and that monoallelic Pten loss in CD4 T cells causes a bias in their differentiation toward T follicular helper cells during acute viral infection. These results suggest that somatically induced mono- or biallelic loss of expression of signaling-related genes in T cells can impact the quality of population-level T cell responses-without conspicuous pathological sequelae such as autoimmune and inflammatory manifestations or lymphomagenesis.
    DOI:  https://doi.org/10.1038/s41598-025-34754-1
  28. Mol Ther. 2026 Jan 10. pii: S1525-0016(26)00008-0. [Epub ahead of print]
    Single-Chain IL-23 Secretion by CAR T Cells Improves Tumor Control and Persistence Against Solid Tumors.
    John T Keane, David A Degaramo, Heather M Sosnoski, Shawna K Brookens, Hyeon-Gyu S Lewis, Fang Liu, Avery D Posey.
      Chimeric antigen receptor (CAR) T cell therapy achieves durable remissions in hematological malignancies, yet its success against solid tumors is blunted in part by the tumors' highly immunosuppressive microenvironment. Fourth-generation "armored" CAR T cells are engineered to secrete pro-inflammatory molecules to counteract this barrier. Here, we engineered TnMUC1-targeted CAR T cells that constitutively secrete either single-chain interleukin-12 (scIL-12) or single-chain interleukin-23 (scIL-23). Both cytokine-armored CAR T cell formats improved effector function in vitro, increasing interferon-gamma production and cytotoxicity compared with their unarmored counterparts. scIL-12- and scIL23-secreting CAR T cells significantly delayed tumor growth and prolonged survival in mouse xenograft models of human breast and prostate cancer, while scIL-23 secretion led to increases in vivo persistence and retention of early differentiation states. These findings nominate scIL-23 armoring as a promising strategy to extend CAR T cell therapy to solid tumors.
    DOI:  https://doi.org/10.1016/j.ymthe.2026.01.007
  29. iScience. 2026 Jan 16. 29(1): 114385
    CCL20-CCR6 signaling alters the metabolic reprogramming to promote the pathogenic Th17 cell differentiation.
    Heikrujam Thoihen Meitei, Neeraja Kulkarni, Amey Shirolkar, Srikanth Rapole, Praveen Kumar Sharma, Vikkarasan Rehman Mujeeb, Sharad Srivastava, Girdhari Lal.
      CCR6 is a G-protein-coupled receptor that binds to its ligand CCL20. Th17 and Foxp3+CD4+ T cells express CCR6, enabling their migration to inflamed tissues with unique metabolic environments. The factors that regulate their metabolic adaptation and functional roles in these tissues remain unclear. Using inflammatory bowel disease patient samples and experimental colitis models in mice, we demonstrated that the intrinsic signaling of CCL20-CCR6 in CD4+ T cells promotes the differentiation of inflammatory Th1-like Th17 cells (T-bet+RORγt+) during colitis. This signaling induces the rapamycin-sensitive phosphorylation of PI3K, Akt, mTORC1, and STAT3 in a CCR6-dependent manner. RNA-seq and proteomics analysis revealed that the addition of CCL20 during Th17 differentiation affects several metabolic pathways, including energy metabolism. CCL20 significantly increased glycolysis and inhibited oxidative phosphorylation, thereby driving the differentiation of pathogenic Th17 cells. Our findings suggest that alterations in CCR6-induced changes in Th17 metabolism offer an interesting therapeutic target for gut inflammation and autoimmunity.
    Keywords:  Biological sciences; Components of the immune system; Immunology
    DOI:  https://doi.org/10.1016/j.isci.2025.114385
  30. Aging Cell. 2026 Feb;25(2): e70373
    NMNAT1 Activates Autophagy to Delay D-Galactose-Induced Aging in Cochlear Hair Cells.
    Yongjie Wei, Wenqing Yang, Han Wu, Mengdie Kong, Dachuan Fan, Yuhua Zhang, Nan Cheng, Jiawei Du, Lingna Guo, Yuyang Li, Ye Zhang, Qian Dai, Wei Cao, Jianming Yang, Qiaojun Fang.
      With an aging population, the incidence of age-related hearing loss (ARHL) continues to increase. Aging cells exhibit reduced nicotinamide adenine dinucleotide (NAD+) levels and impaired autophagy; however, the mechanisms underlying these processes remain largely unclear. In our study, we assessed the role of nicotinamide nucleotide adenylate transferase 1 (NMNAT1) in cochlear hair cell aging using D-galactose (D-gal)-induced aging HEI-OC1 cells and cochlear explants. We observed a significant reduction in NMNAT1 expression in HEI-OC1 cells and cochlear hair cells treated with D-gal. Notably, NMNAT1 overexpression activated autophagy and decelerated hair cell aging. Metabolomic analysis revealed a dysregulated tricarboxylic acid cycle in Nmnat1-knockout cells, indicating that NMNAT1 regulates autophagy and metabolic pathways that affect hair cell aging. These findings offer novel insights into the association between autophagy and metabolism during aging and highlight NMNAT1 as a potential therapeutic target for the prevention and treatment of ARHL.
    Keywords:  NMNAT1; TCA cycle metabolism; age‐related hearing loss; autophagy; cochlear hair cell
    DOI:  https://doi.org/10.1111/acel.70373
  31. Nat Biomed Eng. 2026 Jan 12.
    Real-time multimodal phenotyping reveals distinct tumour cell dynamics and immune escape mechanisms in T cell therapies.
    Shengjie Chen, Kunru Yu, Shengsen Zhang, Xiaoliang Guo, Rong Zhu.
      Adoptive T cell transfer therapy remains limited by the inability to monitor live tumour cell dynamics during treatment. Here we introduce a real-time, label-free phenotyping system that integrates electrical impedance spectroscopy, Raman spectroscopy and microscopy to analyse live tumour cells undergoing therapy. This system enables simultaneous tracking of metabolic activity, membrane integrity and cytoplasmic properties at single-cell resolution. First, analysis of glycolysis reveals that tumour-infiltrating lymphocytes suppress lactate production early, reducing tumour aggressiveness, while chimaeric antigen receptor T cells trigger tumour silent escape early and delay metabolic inhibition until later stages, culminating in cell death. Second, membrane profiling shows early phospholipid and cholesterol depletion under tumour-infiltrating lymphocyte treatment, with partial recovery, whereas chimaeric antigen receptor T cells cause progressive and irreversible membrane damage. Third, cytoplasmic analysis identifies early protein structural disruption and ionic imbalance under tumour-infiltrating lymphocyte therapy, while chimaeric antigen receptor T cells trigger delayed metabolic collapse and cytoplasmic contraction. These findings uncover distinct immune killing mechanisms and escape phases, offering mechanistic insights into tumour-immune interactions and informing the design of personalized therapeutic strategies.
    DOI:  https://doi.org/10.1038/s41551-025-01582-7
  32. Pharmacol Res. 2026 Jan 10. pii: S1043-6618(26)00011-3. [Epub ahead of print]224 108096
    Purinosomes and mitochondria: Dynamic interactomes at the crossroads of metabolism, cell structure, and disease.
    Andrea Mancini, Elisabetta Betterini, Matteo Bordi, Francesco Cecconi.
      Mitochondria are central hubs of cellular metabolism, integrating nutrient catabolism, ATP production, redox balance, and biosynthetic precursor supply. Recent work has revealed that their influence extends beyond canonical bioenergetics to include intimate connections with cytosolic multi-enzyme assemblies. Among these, the purinosome, the complex dedicated to de novo purine biosynthesis, has emerged as a paradigmatic example of how metabolic pathways achieve efficiency through spatial and functional coupling. This Review highlights the dynamic interplay between purinosomes and mitochondria. We describe how mitochondrial metabolism supplies key substrates, including aspartate, glycine, and formate, while oxidative phosphorylation provides the ATP required for nucleotide synthesis. We discuss how purinosomes assemble through liquid-liquid phase separation, position near mitochondria in response to energetic stress, and act as adaptive metabolic hubs that sense and integrate growth and nutrient signals. Finally, we examine how disruption of this mitochondrion-purinosome axis contributes to disease, from rare neurodevelopmental disorders to cancer and neurodegeneration.
    Keywords:  Cancer biology; Metabolons; Mitochondria metabolism; Nucleotide metabolism; Organelle contact sites; Purine synthesis
    DOI:  https://doi.org/10.1016/j.phrs.2026.108096
  33. Immunity. 2026 Jan 13. pii: S1074-7613(25)00562-X. [Epub ahead of print]59(1): 14-16
    To the nines: IL-9 boosts T cell function.
    Elizabeth Wickman, Maksim Mamonkin.
      IL-9 is canonically associated with anti-helminth and allergic immunity. However, in this issue of Immunity, Jiang et al. and Castelli et al. demonstrate how integrating IL-9 signaling in T cells enhances their persistence and anti-tumor function in solid cancer models.
    DOI:  https://doi.org/10.1016/j.immuni.2025.12.006
  34. J Clin Invest. 2026 Jan 16. pii: e196722. [Epub ahead of print]136(2):
    Targeting the N-acetyltransferase 10/DKK2 axis enhances CD8+ T cell antitumor activity in colorectal cancer models.
    Mengmeng Li, Xiaoya Zhao, Jun Wu, Shimeng Zhou, Yao Fu, Chen Chen, Zhuang Ma, Jiawen Xu, Yun Qian, Zhangding Wang, Bo Wang, Qiang Wang, Qingqing Ding, Changyu Chen, Honggang Wang, Xiaozhong Yang, Weijie Dai, Wenjie Zhang, Shouyu Wang.
      Despite overexpression of N-acetyltransferase 10 (NAT10) in colorectal cancer (CRC), its immunomodulatory role in the tumor microenvironment remains elusive. Here, we reveal that NAT10 promotes immune evasion through N4-acetylcytosine-dependent (ac4C-dependent) mRNA stabilization. Using syngeneic mouse models (MC38/CT-26), intestinal epithelial-cell specific Nat10 conditional KO (Nat10cKO) mice, patient-derived organoids, and clinical specimens, we show that Nat10 ablation enhanced CD8+ T cell-mediated antitumor immunity. Single-cell RNA-seq revealed increased cytotoxic CD8+ T cell infiltration in Nat10cKO tumors, which was corroborated by the inverse correlation of tumoral NAT10 expression and CD8+ T cell number in clinical specimens. Multi-omics integration analysis identified DKK2 as the predominant NAT10-regulated transcript. NAT10 stabilized DKK2 mRNA via ac4C modification, leading to high expression of the DKK2 protein. Secreted DKK2 engaged LRP6 receptors to activate AKT-mTOR signaling, inducing cholesterol accumulation in CD8+ T cells and impairing their cytotoxicity. Pharmacological NAT10 inhibition (Remodelin treatment) or DKK2 neutralization restored CD8+ T cell function and synergized with anti-PD-1 therapy. Our findings establish the NAT10/DKK2/LRP6/AKT-mTOR/cholesterol axis as a critical regulator of CD8+ T cell dysfunction in CRC, positioning NAT10/DKK2 as a potential target to enhance immunotherapy efficacy.
    Keywords:  Cancer immunotherapy; Colorectal cancer; Epigenetics; Gastroenterology; Immunology; Oncology
    DOI:  https://doi.org/10.1172/JCI196722
  35. Commun Biol. 2026 Jan 15.
    IL-15 overexpression promotes memory program and anti-tumor activity of CD64 CAR T cells in a preclinical AML model.
    Lingling Shan, Chuo Li, Ting Li, Chongkai Wang, Haidong Cui, Aiming Pang, Xiaoming Feng.
      The prognosis of relapsed or refractory acute myeloid leukemia (r/r AML) patients remains poor due to lack of novel therapies. We previous demonstrated that chimeric antigen receptor (CAR) T cells targeting CD64 have the potential to treat AML with minimal toxicity to hematopoietic stem/progenitor cells. However, the efficacy was limited in AML mouse models. Interleukin-15 (IL-15), a cytokine that promotes T cell survival and proliferation, has been shown to enhance CAR T cell activity. Here, we engineer CD64 CAR T cells with overexpression of IL-15 and evaluate the function. IL-15-armed CAR T cells exhibit enhanced cytolytic activity against AML cells, improve expansion and persistence in vitro, and favor a memory phenotype while reducing exhaustion and apoptosis. In mouse model, IL-15-armed CAR T cells show robust expansion, prolong mouse survival, and no obvious toxicity. These findings suggest that IL-15-armed CD64 CAR T cells may be a promising strategy for r/r AML.
    DOI:  https://doi.org/10.1038/s42003-026-09528-8
  36. bioRxiv. 2026 Jan 11. pii: 2026.01.09.698698. [Epub ahead of print]
    A Closed Computational-Experimental Loop Identifies Metabolic Collapse at the Root of Macrophage Dysfunction due to Zinc Dyshomeostasis.
    Sunayana Malla, Deandra R Smith, Ashley M Peer, Derrick R Samuelson, Daren L Knoell, Rajib Saha.
      Zinc plays a crucial role in immune regulation, the oxidative stress response, and epithelial barrier integrity, yet zinc's precise role in regulating metabolic and immunological functions in myeloid cells remains poorly understood. Here, we employ a systems biology approach using constraint-based modeling to elucidate the consequences of myeloid-specific loss of ZIP8 on macrophage metabolic function and antibacterial capabilities. We demonstrate that macrophage populations in the lung of ZIP8 knockout ( Zip8 KO) mice exhibit widespread metabolic disruption, spanning glycolysis, butanoate metabolism, amino acid metabolism, and mitochondrial function. Specifically, Zip8 KO macrophages exhibit impaired nutrient uptake and dysregulated energy metabolism, which is exacerbated following Streptococcus pneumoniae infection. Genome-scale metabolic modeling and flux analysis revealed a paradoxical pattern of metabolic suppression prior to infection, followed by overcompensation post-infection, potentially driving immune dysfunction. Consistent with these predictions Zip8 KO bone marrow-derived macrophages displayed increased ATP demand and disrupted mitochondrial energetics, compromising their ability to control infection. Importantly, we identified succinate, and kynurenic acid as metabolites capable of restoring immune responses and validated their ability to enhance bacterial clearance in Zip8 KO BMDMs. Together, these findings establish ZIP8 as a central regulator of immune-metabolic homeostasis and suggest potential therapeutic avenues to restore immune function in settings of zinc deficiency.
    DOI:  https://doi.org/10.64898/2026.01.09.698698
  37. Open Forum Infect Dis. 2026 Jan;13(1): ofaf775
    Longitudinal T-Cell Phenotypic Dynamics During Sustained Antiretroviral Therapy in People With HIV.
    Christophe Vanpouille, Alan Wells, Victor DeGruttola, Miranda Lynch, Xinlian Zhang, Xin M Tu, Antoine Chaillon, Brendon Woodworth, Noah Gaitan, Stephen A Rawlings, Alan Landay, Kathleen M Weber, Eileen P Scully, Jonathan Karn, Sara Gianella.
       Background: Antiretroviral therapy (ART) suppresses HIV replication and partially restores immune function, but immunologic abnormalities often persist.
    Methods: We performed longitudinal multiparametric flow cytometry on peripheral blood mononuclear cells from 79 people with HIV-1 (51 women, 28 men) who were virologically suppressed and followed over a median 6 years of ART. We assessed T-cell counts and expression of activation (CD38⁺HLA-DR⁺), cycling (Ki67⁺), exhaustion (TIGIT⁺PD-1⁺), cytotoxicity (CD107a⁺), and regulatory (FoxP3⁺CD25⁺) markers across memory subsets, and we examined associations with sex and HIV reservoir size and activity.
    Results: CD4⁺ T-cell counts increased and CD8⁺ T-cell counts declined over time, improving CD4/CD8 ratios. Immune activation and cycling markers decreased in both T-cell compartments. TIGIT/PD-1 expression declined significantly in CD4⁺ memory subsets but not in CD8⁺ T cells, while CD107a expression remained elevated in effector memory CD8⁺ and CD4⁺ T cells. Regulatory CD4⁺ T cells declined over time, and no significant associations were observed between T-cell phenotypes and HIV reservoir measures or between sexes.
    Conclusions: Long-term ART promotes partial immune normalization, including reduced activation and reversal of CD4⁺ T-cell exhaustion. However, persistent expression of CD8⁺ T-cell surrogate markers of exhaustion and stable cytotoxic profiles suggest ongoing antigenic stimulation, potentially driven by HIV or chronic coinfections.
    Keywords:  HIV; T cell; flow cytometry; long-term ART
    DOI:  https://doi.org/10.1093/ofid/ofaf775
  38. Nat Aging. 2026 Jan 15.
    GLP-1 receptor agonism counteracts omics aging in mice.
    Anna Kriebs.
      
    DOI:  https://doi.org/10.1038/s43587-025-01063-1
  39. Adv Sci (Weinh). 2026 Jan 15. e20815
    Targeting the Mapk13-Tcf1-Slc7a5 Axis via One-Carbon Metabolic Regulation to Prevent Chronic Allograft Vasculopathy.
    Wang Yi, Di Wu, Jing Liu, Shi Chen, Liu Song, Bin Xie, Aini Xie, Peixiang Lan, Zhishui Chen.
      Chronic allograft vasculopathy (CAV) is driven in part by stem-like CD4+ T cells, but how these cells sustain their progenitor programs during chronic rejection remains unclear. Here, a metabolic-epigenetic axis is identified in which Mapk13 phosphorylates Tcf1 at T289, enabling Tcf1 to activate the amino acid transporter Slc7a5 and enhance methionine uptake. This rewires one-carbon metabolism and increases H3K4me3 enrichment at the Tcf7 locus, thereby maintaining stem-like CD4+ T cells within rejecting grafts. Disruption of this circuit-via genetic deletion of Mapk13 or Slc7a5, or through dietary methionine restriction-reduces Tcf1+ CD4+ T cell stemness and prevents CAV in mouse models. These findings reveal the Mapk13-Tcf1-Slc7a5 axis as a critical metabolic dependency of pathogenic T cells and highlight one-carbon metabolism as a promising target to promote long-term graft survival.
    Keywords:  TCF1; chronic allograft vasculopathy; methionine restriction; one‐carbon metabolism; stem cell‐like T cells
    DOI:  https://doi.org/10.1002/advs.202520815
  40. Exp Gerontol. 2026 Jan 08. pii: S0531-5565(26)00005-7. [Epub ahead of print]214 113027
    Quercetin rejuvenates aged adipose progenitor cells by attenuating inflammatory pathways.
    Junwan Fan, Ling Zhou, Run Song, Fuqiang Yang, Yingjie Geng, Xueyu Zhang, Qiuhua Yu, Zirui Li, Yan Wang, Wenyan He.
      The mass of inguinal white adipose tissue (iWAT) decreases with age, and its dysfunction contributes to systemic effects, including chronic inflammation, ectopic lipid deposition, and insulin resistance. However, the molecular and functional characteristics of aged adipose progenitor cells (APCs), as well as effective strategies to rejuvenate their adipogenic potential, remain poorly understood. In this study, we found that aged mice exhibited a reduced frequency of APCs, increased inflammatory activity, and impaired adipogenic differentiation capacity. Strikingly, while quercetin exerted concentration-dependent effects on the vitality and function of APCs, only moderate doses specifically restored the adipogenic differentiation of aged APCs. Mechanistically, this rejuvenating effect was primarily mediated through the suppression of pro-inflammatory pathways. Together, our findings provide novel mechanistic insights into APCs aging in iWAT and identify quercetin as a promising rejuvenative agent for the treatment of adipose tissue dysfunction and related metabolic disorders in aging.
    Keywords:  Adipogenic differentiation; Adipose progenitor cells; Aging; Quercetin
    DOI:  https://doi.org/10.1016/j.exger.2026.113027
  41. Nat Med. 2026 Jan 15.
    CD4+ T cells mediate CAR-T cell-associated immune-related adverse events after BCMA CAR-T cell therapy.
    Matthew Ho, Luca Paruzzo, Julia Han Noll, Federico Stella, Pooja Devi, Sonia Ndeupen, Yael A Day, Gregory M Chen, Ivan J Cohen, Angel Ramirez-Fernandez, Adam Waxman, Shivani Kapur, Fang Chen, Rong Xu, Andrew Huff, Danuta Jarocha, Vrutti Patel, Audrey C Bochi-Layec, Ranjani Ramasubramanian, Shan Liu, Riemke Bouvier, Vitor B de Souza, Heta Patel, Ziyu Li, Alberto Carturan, Peter Michener, Caitlin R Hopkins, Owen Koucky, Janna Minehart, Alex Dimitri, Neel R Nabar, Zainul S Hasanali, Bryan T Ciccarelli, Putzer Hung, Erik Williams, Robert Bartoszek, Maya Lavorando, Suyash Mohan, Vanessa E Gonzalez, Patrizia Porazzi, Vijay G Bhoj, Sokratis A Apostolidis, Dan T Vogl, David L Porter, John Scholler, Caroline Diorio, Aoife M Roche, John K Everett, Frederic D Bushman, Katherine L Nathanson, Edward A Stadtmauer, Sandra P Susanibar-Adaniya, Alfred L Garfall, Marco Ruella, Adam D Cohen, Joseph A Fraietta.
      B cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of multiple myeloma but can cause unique toxicities, including cranial nerve palsy, parkinsonism and enterocolitis, which we refer to collectively as CAR T cell therapy-associated immune-related adverse events (CirAEs). Among 198 patients treated with ciltacabtagene autoleucel or idecabtagene vicleucel (June 2021-December 2024), 27 (13.6%) developed CirAEs. This included one remarkable case with three distinct CirAEs in association with an extreme CD4+ CAR T cell expansion (peak lymphocytes: 197 × 103 per microliter), which was abrogated in vitro by CCR5 inhibition. CirAEs were associated with significantly higher non-relapse mortality (hazard ratio = 5.2, P = 0.006), and independent risk factors included ciltacabtagene autoleucel (odds ratio = 4.5, P = 0.058), peak absolute lymphocyte count ≥ 2.4 × 103 per microliter in the first 14 days post-infusion (odds ratio = 4.3, P < 0.001) and apheresis CD4:CD8 ratio > 1 (odds ratio = 2.6, P = 0.048). We identified marked CD4+ CAR T cell infiltration in all available CirAE tissues, including cerebrospinal fluid during neurologic CirAEs, implicating CD4+ CAR T cell therapy as a key mediator of these toxicities.
    DOI:  https://doi.org/10.1038/s41591-025-04121-8
  42. Mol Pharm. 2026 Jan 13.
    Ex Vivo Zinc Nanoparticle Conditioning Primes T Cells for Potent Antitumor Activity in Ovarian Cancer Patient-Derived Xenografts.
    Zhangyun Gong, Kai Chen, Aoran Luo, Jie Zhang, Haixing Yi, Xiangyuan Xie, Kaixin Dai, Zhimin Lu, Yiran Xie.
      T-cell dysfunction imposed by the tumor microenvironment limits the durability of cellular immunotherapies, motivating interventions that strengthen effector programs before infusion. Here we describe an ex vivo pretreatment that uses zinc nanoparticles (Zn NPs) as a transient intracellular Zn2+ modulator to condition T cells without altering receptor engineering. Brief priming with Zn NPs yielded T cells with consistently improved tumor-cell killing across effector-to-target ratios and increased IL-2, IFN-γ, and TNF-α secretion while avoiding rises in intracellular ROS. In murine melanoma models, adoptive transfer of primed T cells delayed tumor growth and prolonged survival without toxicity; combination with Galectin-9 blockade further enhanced control. Translational relevance was supported in an ovarian cancer patient-derived xenograft model, where primed CAR T cells achieved superior tumor control, showed greater intratumoral CAR T infiltration, and again benefited from Galectin-9 inhibition. Transcriptome profiling of primed T cells revealed coordinated remodeling of metal-ion response, consistent with reinforced signaling and stress resilience. This study establishes Zn NP-enabled priming as a practical, drop-in step for T-cell manufacturing that enhances effector function and cooperates with galectin-axis inhibition to overcome microenvironmental suppression and improve therapeutic potency.
    Keywords:  CAR T cell therapy; T-cell priming; galectin-9 blockade; ovarian cancer patient-derived xenograft; zinc nanoparticles
    DOI:  https://doi.org/10.1021/acs.molpharmaceut.5c01508
  43. Immune Netw. 2025 Dec;25(6): e42
    IL7-TBRII, a Dual Cytokine Modulator Targeting IL-7 and TGF-β Pathways, Inhibits Tumor Progression and Metastasis.
    Youngsik Oh, Sora Kim, Ji-Hae Kim, Kun-Joo Lee, Dain Moon, Chaerim Jeong, Hyun Gyung Kim, Seung-Min Chun, Mi-Sun Byun, Seung-Woo Lee.
      Tumor-infiltrating CD8+ T cells are a key determinant of anti-tumor efficacy in immunotherapy. IL-7 has been explored as a cytokine therapy to expand CD8+ T cells, showing promising anti-tumor effects in preclinical models. However, clinical outcomes remain limited, likely due to the immunosuppressive tumor microenvironment. To enhance the efficacy of IL-7 therapy, we reanalyzed publicly available single-cell RNA-sequencing (scRNA-seq) data of tumors treated with IL-7, identifying elevated TGF-β signaling in CD8+ T cells following treatment. As TGF-β impairs CD8+ T cell function and antagonizes IL-7 signaling, we developed a bifunctional fusion protein, recombinant human IL-7 (rhIL-7)-hyFc-sTBRII (IL7-TBRII), by fusing a TGF-β trap (Fc-TBRII) to rhIL-7-hyFc (IL7-Fc). We evaluated the binding affinities and functionalities of each domain in vitro and in vivo, and assessed anti-tumor effects in the MC38 colon cancer model. IL7-TBRII demonstrated superior anti-tumor efficacy compared to IL7-Fc or Fc-TBRII alone, primarily through increased infiltration of cytotoxic CD8+ T cells into tumors. Also, IL7-TBRII expanded the number of activated CD44+ CD8+ T cells. Furthermore, IL7-TBRII reduced metastasis in the 4T1 breast cancer model by reshaping the immune cell composition, and demonstrated synergistic efficacy when combined with radiotherapy or anti-CTLA-4 therapy in the EMT6 breast tumor model. These findings suggest that dual modulation of the IL-7 and TGF-β pathways by IL7-TBRII effectively reprograms the immune microenvironment in both primary and metastatic tumors, particularly by promoting CD8+ T cell activation and infiltration, thus offering a promising strategy to improve clinical responses to immunotherapy.
    Keywords:  Immunotherapy; Interleukin-7; Recombinant fusion proteins; Transforming growth factor beta
    DOI:  https://doi.org/10.4110/in.2025.25.e42
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