bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2026–04–05
fifty papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. CD8+ T cell exhaustion driven by metabolic reprogramming.
  2. T cell adaptation in chronic infections and tumors.
  3. Sulfur partitioning from cysteine controls T cell proliferation and effector function.
  4. Memory T cell aging and rejuvenation.
  5. Krüppel-like factors 2 and 3 regulate T cell exhaustion by directing T cell residency and migration.
  6. Mitochondrial ATP production promotes T cell differentiation and function by regulating chromatin accessibility.
  7. Genetic disruption of Pdcd-1 upstream enhancer boosts T cell function and antitumor responses.
  8. CLOCK is an Epigenetic Integrator of Circadian Rhythm and T Cell Immunity.
  9. Mitochondrial metabolism and signaling direct dendritic cell function in antitumor immunity.
  10. Unveiling the molecular architecture of T cells and immune synapses with cryo-expansion microscopy.
  11. Repurposing rosmarinic acid as an anti-colorectal cancer agent through bolstering T cell anti-tumor immunity by enhancing activation of MEK1-mediated TCR signaling.
  12. Irgm1 Restrains CD8+ T Cell Cytokine Production and Apoptosis via Cell-Extrinsic Regulation of Type I Interferon Signaling.
  13. Engineering metabolite-sensing NK and T cells to target solid tumors.
  14. Regulatory T cell-derived TGF-β signaling governs the differentiation and maintenance of tumor-infiltrating bystander CD8+ T cells.
  15. Acute and chronic infections drive distinct trajectories in human memory CD4+ T cell formation.
  16. Lymphodepleting preconditioning impairs host antitumor immunity induced by adoptive T cell therapy in mouse models.
  17. Th17 cells require the DNA repair sensor xeroderma pigmentosum complementation Group C to control oxidative DNA damage in a murine model.
  18. The CD4+ T cell population partners with Tpex CD8+ T cells to mediate antitumor immunity in the tumor microenvironment.
  19. Expansion and mobilization of virus-specific stem-like CD8 T cells in chronic viral infection after treatment with a long-acting IL-7, NT-I7.
  20. Solving the puzzle of CD8 T cell positive selection.
  21. Dual-targeted lipid nanoparticles for TET3 siRNA delivery: nanobiotechnology strategy to remodel tumor immune microenvironment in hepatocellular carcinoma.
  22. Nebivolol prevents exhausted T cells and enhances cytotoxicity against MCF-7 breast cancer cells in a β2-adrenergic receptor-dependent manner.
  23. Fundamental Cell-Intrinsic Mechanism Underlying Age-Dependent Accumulation of Senescent Cells.
  24. Persistent IFN-I signaling inhibits mitochondrial oxidative metabolism in CD8+ T cells during HIV-1 infection under cART.
  25. Chromosome 1 Open Reading Frame 35 Drives Colorectal Cancer Progression by Enhancing Tumor-Intrinsic Proliferation and CD8+ T Cell Suppression.
  26. Epstein-Barr virus orchestrates spatial reorganization and immunomodulation in the classic Hodgkin lymphoma tumor microenvironment.
  27. mRNA lipid-nanoparticle-mediated mitochondrial apoptosis augments adoptive T cell immunotherapy.
  28. Abortive infection: T cells as early, antibody-independent defenders.
  29. Targeting the sensory-sympathetic axis for cancer immunotherapy.
  30. Cytotoxic T cell recognition of α-synuclein drives pathogenic immune responses in multiple system atrophy.
  31. Hematopoietic Stem Cell Senescence and Opportunities for Intervention.
  32. Metformin drives HIF-1α-mediated dual metabolic reprogramming to enhance γδ T cell therapy in triple-negative breast cancer.
  33. Targeting PI3Kδ suppresses pancreatic cancer by dual disruption of fibrosis and immune evasion.
  34. Advances in Metabolic Reprogramming and Immune Regulatory Mechanisms in Lung Cancer.
  35. Autophagy meets tissue-resident memory: Emerging crosstalk and therapeutic opportunities in cutaneous melanoma.
  36. Engineering T cell therapies for lung cancer.
  37. ER-localized ceramide accumulation contributes to replicative senescence.
  38. NAD+ Homeostasis and Mitochondrial Modifiability: Resilience in Alzheimer's Disease.
  39. Stem cell therapy might improve aging frailty.
  40. A unique CD4⁺ T cell subset expressing granzyme K is regulated by transcription factor EOMES and important for T cell-mediated intestinal inflammation.
  41. Chimeric CD3ζ chains containing CD28 signalling motifs enhance antigen-specific IL-2 production and expansion of human TCR-engineered T cells in vitro.
  42. NEK8 kinase-mediated lactate increase impairs antitumor immunity decreasing radiotherapy sensitivity in colorectal cancer.
  43. Transdermal bicarbonate buffer therapy increases intratumoral pH and elicits antitumor responses in bladder cancer.
  44. Zinc-coordination-driven mitochondrial nanodisruptors to ablate cancer stemness for potentiating immunotherapy in colorectal malignancies.
  45. Distinct tissue niches contribute to prostate tissue-resident memory CD8+ T cell differentiation and heterogeneity.
  46. Visualizing the metabolic battleground: the role of PET imaging in understanding immunometabolism and the tumor microenvironment.
  47. Correction to "Type I Interferons Induce CD8+ T Cell Chemotaxis Through Regulating Melanocyte but Not Keratinocyte CXCL9/10/11 Secretion in the Initiation of Vitiligo".
  48. Taming Autoimmunity: Alpha-1 Antitrypsin Overexpressing Mesenchymal Stem/Stromal Cells Promote Regulatory T Cell Crosstalk to Reverse Diabetes.
  49. Targeting Mitochondrial Stress Responses: Terbinafine and Miglustat as Novel Lifespan and Healthspan Modulators.
  50. New Vistas for Withania somnifera in Signal Transduction of Inflammation and Aging.
  1. Cancer Cell Int. 2026 Apr 03.
    CD8+ T cell exhaustion driven by metabolic reprogramming.
    Wenzhi Deng, Chunhong Li, Qiang Wang, Xiulin Jiang, Yongzhi Xie.
      
    Keywords:  CD8⁺ T cells; Fatty acid oxidation; Glycolysis; Immunotherapy; Metabolic reprogramming; Mitochondrial metabolism; T cell exhaustion; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s12935-026-04287-2
  2. Cell Mol Immunol. 2026 Mar 30.
    T cell adaptation in chronic infections and tumors.
    Hendrik Luxenburger, Robert Thimme, Maike Hofmann.
      Chronic viral infections and cancer challenge immune control by enforcing sustained antigen exposure, which profoundly alters the fate and function of CD8+ T cells. In contrast to acute infections, which induce robust effector differentiation and durable immune memory, persistent infections and tumors drive CD8+ T cells into distinct states of functional adaptation. The best studied chronic adaptation is T cell exhaustion, which is characterized by impaired effector functions, reduced proliferative capacity, sustained expression of inhibitory receptors, and stable transcriptional and epigenetic reprogramming. T cell exhaustion is not a uniform or terminal condition but comprises heterogeneous and dynamic cellular states, including stem-like/precursor populations that retain self-renewal capacity and therapeutic responsiveness. These insights have reshaped our understanding of immune regulation in chronic disease and underpin the success of immune checkpoint blockade therapies. However, heterogeneous and often transient clinical responses highlight critical gaps in our mechanistic understanding of exhausted T cell biology. This review synthesizes recent advances in the cellular and molecular profiling of chronically stimulated CD8+ T cells across chronic viral infection and cancer, focusing on regulatory networks, defining factors, and tissue-specific cues that govern functional adaptation and exploring emerging therapeutic reprogramming strategies.
    Keywords:  Chronic infections; Immune checkpoint blockade (ICB); T cell exhaustion; TME; Tumors
    DOI:  https://doi.org/10.1038/s41423-026-01405-y
  3. Cell. 2026 Mar 31. pii: S0092-8674(26)00279-5. [Epub ahead of print]
    Sulfur partitioning from cysteine controls T cell proliferation and effector function.
    Beth Kelly, Minsun Cha, Tatjana Gremelspacher, Jacob L Martin, Massimo Andreis, Isha Maloo, Gustavo E Carrizo, Mia Gidley, Michal A Stanczak, Petya Apostolova, Joseph Longo, Lisa M DeCamp, Eric H Ma, Ryan D Sheldon, Russell G Jones, David E Sanin, Ananya Majumdar, Erika L Pearce.
      Delineating how acquired nutrients are partitioned into different intracellular pathways and how these various fates support distinct functions in T cells is limited. We show that CD8+ T cells acquire cysteine to serve both as a substrate for glutathione (GSH) production, which modulates effector functions, and to cede its sulfur for NFS1-dependent FeS cluster synthesis, which supports proliferation. NFS1 deletion in activated CD8+ T cells promotes exhaustion and dampens anti-cancer immunity, whereas blocking cysteine flux into GSH or enforcing FeS metabolism enhances tumor control. This role for disrupted FeS metabolism in T cell exhaustion is echoed in data from human hepatocellular carcinoma. Elucidating how different intracellular pathways use cysteine enables targeted control of cysteine flux to retain the beneficial effects of cysteine while abolishing those that restrain function. We illustrate this concept for one metabolite, cysteine, but it is likely to apply to other metabolites relevant for immune cell function.
    Keywords:  CD8+ T cells; Fe-S clusters; T cell exhaustion; anti-tumor immunity; cysteine; glutathione; immunometabolism; iron uptake; lipid peroxidation; mitochondria
    DOI:  https://doi.org/10.1016/j.cell.2026.03.012
  4. Immunity. 2026 Mar 30. pii: S1074-7613(26)00088-9. [Epub ahead of print]
    Memory T cell aging and rejuvenation.
    Sarah Adamo, Joel G Rurik, Claire E Gustafson, Marcus Buggert.
      Aging reshapes T cell immunity, as evidenced by eroding naive diversity and remodeled memory hierarchies. This generates an experienced yet constrained repertoire, with weakened protection against novel infections and malignancies and blunted vaccine responsiveness. However, the pace and extent of decline vary widely between individuals. Such heterogeneity signals a recalibration of immune priorities that favors persistence over plasticity of memory T cells. Here, we discuss how aging shapes memory T cell compartments-from repertoire contraction and differentiation to altered metabolic, transcriptional, and epigenetic states. We further examine how chronic inflammation, antigen persistence, and niche remodeling converge to drive dysfunction or resilience. Finally, we outline strategies to rejuvenate T cell immunity during aging to preserve adaptive competence across the lifespan.
    Keywords:  T cells; adaptive competence; aging; memory; rejuvenation
    DOI:  https://doi.org/10.1016/j.immuni.2026.02.018
  5. Immunity. 2026 Mar 27. pii: S1074-7613(26)00091-9. [Epub ahead of print]
    Krüppel-like factors 2 and 3 regulate T cell exhaustion by directing T cell residency and migration.
    Jian Shen, Ryan J Brown, Yuqi Zhang, Kexin Gai, Ashley K Brown, Ashley M Bauer, Ashley Zhu, Siying Lin, Hongshen Niu, Arjun Kharel, Ziyang Xu, Gregory S Cohen, Taylor A Depauw, Eric Fagerberg, Geoffrey S Kansas, Nikhil S Joshi, Stephen C Jameson, Weiguo Cui.
      During chronic viral infection, CD8+ progenitor exhausted T (Tpro) cells give rise to either cytotoxic effector-like exhausted T (Teff) cells that are migratory or terminally exhausted T cells (Texh) that reside in the tissue parenchyma. Here, we explored how cellular localization influences exhausted T cell fate. We found that Krüppel-like factor 2 (KLF2) promoted the expression and chromatin accessibility of migratory genes, whereas its counterpart, KLF3, limited these programs and promoted tissue residency. Forcing CD8+ T cells out of the tissue environment biased differentiation from the Texh toward the Teff cell trajectory, suggesting that cellular localization can actively influence cell-fate decisions. Mechanistically, KLF2 induced KLF3, which, in turn, constrained Klf2 transcription and competed for shared chromatin-binding sites. In summary, KLF2 and KLF3 form a reciprocal regulatory circuit that governs CD8+ T cell migration and exhaustion during chronic viral infection.
    Keywords:  KLF2; KLF3; T cell differentiation; T cell exhaustion; T cell migration; chromatin accessibility; chronic viral infection; sphingosine-1-phosphate signaling; tissue residency; transcriptional regulation
    DOI:  https://doi.org/10.1016/j.immuni.2026.02.021
  6. bioRxiv. 2026 Mar 28. pii: 2026.03.27.714789. [Epub ahead of print]
    Mitochondrial ATP production promotes T cell differentiation and function by regulating chromatin accessibility.
    Charles Ng, Tak Shun Fung, Dayi Li, Korbinian N Kropp, Luis F Somarribas Patterson, Alexandria Markovitz, Daniel N Weinberg, Olivia Jones, Ji-Young Kim, Guoan Zhang, Richard Koche, Mara Monetti, Huayuan Tang, Yun He, Zhengshuang Xu, Xin Cai, Ziqi Yu, Geetha Bhagavatula, Sean P Colgan, Ya-Hui Lin, Zhuoning Li, Elizabeth M Steinert, Christopher A Klebanoff, Santosha A Vardhana, Navdeep S Chandel, Lin Wu, Craig B Thompson.
      Immune elimination of chronic infection or cancer requires cytotoxic CD8 + T cells that adopt and maintain an effector phenotype. Cytotoxic T cell function is a bioenergetically demanding process and T cells subjected to chronic antigen exposure have compromised effector function despite high rates of glycolysis. Here we report the ability of the short-chain α-hydroxy acid, D-α-hydroxybutyrate, to act as a signaling molecule that increases mitochondrial ATP production and drives the conversion of proliferating T cells into cytotoxic effector cells. DAHB signaling switches ATP production from glycolysis to oxidative phosphorylation supported by fatty acid oxidation, even in glucose-replete media. This conversion suppresses both AMPK phosphorylation and the integrated stress response (ISR) in activated T cells while significantly elevating the level of the phosphagen, phosphocreatine (PCr). Both the PCr bioenergetic reserve and oxidative phosphorylation were required for T cell effector differentiation. DAHB-induction of CD8-effector gene transcription was coupled to bioenergetics by enhanced ATP-dependent remodeling of chromatin accessibility at effector gene loci. DAHB enhanced CD8 + T cell antitumor activity both in vitro and in vivo, and DAHB treatment of transferred T cells led to persistent in vivo antitumor effects. Together, these findings link cellular bioenergetics to the regulation of chromatin accessibility and gene expression required to support effector function.
    DOI:  https://doi.org/10.64898/2026.03.27.714789
  7. Immunol Lett. 2026 Mar 27. pii: S0165-2478(26)00044-1. [Epub ahead of print]280 107171
    Genetic disruption of Pdcd-1 upstream enhancer boosts T cell function and antitumor responses.
    Chandsultana Jerin, Wooseok Seo, Hiroyoshi Nishikawa.
      Programmed cell death 1 (PD-1) is an inhibitory receptor that drives T cell exhaustion in tumors, limiting antitumor immunity. Current PD-1 blockade therapies have shown limited success. To uncover new strategies for modulating PD-1, we investigated an upstream enhancer (UpEnh) of the Pdcd-1 gene using a CRISPR-Cas9 knockout mouse model. Deletion of the UpEnh reduced PD-1 expression across various T cell subsets. In a tumor setting, this deletion lowered PD-1 levels on intratumoral exhausted CD8⁺, conventional CD4⁺, Treg, and γδ T cells. This resulted in improved CD8⁺ and γδ T cell function and promoted stronger antitumor immunity. Our findings establish UpEnh as a critical regulator of PD-1, presenting a potential therapeutic target.
    Keywords:  Antitumor immunity; CRISPR-Cas9; PD-1; T cell; Upstream enhancer
    DOI:  https://doi.org/10.1016/j.imlet.2026.107171
  8. Res Sq. 2026 Mar 27. pii: rs.3.rs-9107841. [Epub ahead of print]
    CLOCK is an Epigenetic Integrator of Circadian Rhythm and T Cell Immunity.
    Khashayarsha Khazaie, Shirin Eyvazi, Abu Osman, Abdulrahman Saadalla, Mahendra Pal Singh, Cameron Marlow, Ali Keshavarzian, Faraz Bishehzari, Iradj Sobhani, Aleksey Matveyenko, Fotini Gounari.
      The circadian clock imposes a critical yet incompletely understood layer of regulation on adaptive immunity. T helper 17 (Th17) antimicrobial immune responses including expression of IL-17A by lamina propria CD4⁺ T cells, exhibit diurnal variation and are sensitive to circadian disruption. While the core circadian regulators CLOCK and BMAL1 canonically function as a heterodimer to drive rhythmic gene expression, emerging evidence suggests they may have distinct regulatory roles. Here we integrated ChIP-seq, ATAC-seq, and RNA-seq analyses in naïve CD4⁺ T cells to reveal that the CLOCK-BMAL1 complex controls circadian and metabolic programs through promoter binding, whereas exclusive CLOCK binding at promoters, together with CLOCK-BMAL1 binding at enhancers, regulates immune-associated genes. Using the mutant CLOCKΔ19, which lacks the transactivation domain, we observed disrupted circadian transcription and globally reduced chromatin accessibility, alongside increased accessibility at Th17-associated loci that their altered temporal regulation. Functionally, ClockΔ19 produces β-catenin stabilization in T cells, pronounced expansion of RORγt⁺ CD4⁺ T cells and Treg cells, impaired Treg suppression of Th17 responses, heightened Th17 responses, and reduced IFN-γ production during viral infection. Collectively, these findings define BMAL1 dependent and independent CLOCK functions that program naïve CD4⁺ T cell fate, restrain Th17 differentiation, and preserve immune homeostasis.
    DOI:  https://doi.org/10.21203/rs.3.rs-9107841/v1
  9. Science. 2026 Apr 02. 392(6793): eadv6582
    Mitochondrial metabolism and signaling direct dendritic cell function in antitumor immunity.
    Zhiyuan You, Jiyeon Kim, Chuansheng Guo, Haoran Hu, Nicole M Chapman, Xiaoxi Meng, Hao Shi, Yan Wang, Cliff Guy, Anil Kc, Jia Li, Jordy Saravia, Gustavo Palacios, Sherri Rankin, Camenzind G Robinson, Hongbo Chi.
      Antitumor immunity requires conventional type 1 dendritic cells (cDC1s). How cDC1s maintain functional fitness in the tumor microenvironment remains unclear. In this study, we established that intratumoral cDC1s exhibited discrete mitochondrial states and that OPA1-mediated mitochondrial energy and redox metabolism dictated cDC1 antitumor responses. Mechanistically, OPA1 orchestrated antigen presentation and the CD8+ T cell priming function of cDC1s by promoting nuclear respiratory factor 1 (NRF1) expression and electron transport chain integrity, thereby supporting bioenergetics and NAD+/NADH balance. During tumor progression, mitochondrial membrane potential and volume, as well as OPA1-NRF1 signaling, declined in intratumoral cDC1s. Furthermore, intratumoral administration of cDC1s with polarized mitochondria showed immunotherapeutic benefits in mice, particularly in combination with immune checkpoint blockade. Collectively, our findings reveal mitochondrial metabolism and signaling as putative targets to reinvigorate cDC1 function for cancer immunotherapy.
    DOI:  https://doi.org/10.1126/science.adv6582
  10. Cell Rep. 2026 Apr 01. pii: S2211-1247(26)00243-3. [Epub ahead of print]45(4): 117165
    Unveiling the molecular architecture of T cells and immune synapses with cryo-expansion microscopy.
    Florent Lemaître, Olivier Mercey, Isabelle Mean, Elise Paulin, Valérie Dutoit, Jan A Rath, Christine von Gunten, Denis Migliorini, Caroline Arber, Paul Guichard, Virginie Hamel, Benita Wolf.
      Cytotoxic T cell killing is executed at the immunological synapse, whose nanoscale organization underlies function but remains difficult to resolve in native states. Here, we apply cryo-expansion microscopy (cryo-ExM) to visualize the near-native three-dimensional architecture of human T cell synapses and cytotoxic organelles. Cryo-ExM preserves actin, microtubules, membranes, and fine membrane protrusions with high fidelity, enabling volumetric quantification of synapse morphogenesis. We identify an adhesion-dependent, dome-like membrane architecture beneath activated T cells that collapses upon ICAM-1 engagement, linking synapse topology to adhesive cues. Cryo-ExM further resolves intact lytic granules in primary human CD4 and CD8 T cells, revealing single-core and multi-core ultrastructures, spatial organization, and perforin and granzyme loading. Using tissue-adapted expansion microscopy, we map cytotoxic granule content in tumor-infiltrating T cells in FFPE human brain tumors. Together, these data establish a near-native structural framework for human T cell cytotoxicity and an imaging workflow bridging cell models and clinical tissues.
    Keywords:  3D ultrastructure; CP: immunology; T cell cytotoxicity; cryo-expansion microscopy; cytotoxic granule deployment; immune synapse; lytic granules; tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.1016/j.celrep.2026.117165
  11. Cancer Immunol Immunother. 2026 Apr 02. pii: 134. [Epub ahead of print]75(4):
    Repurposing rosmarinic acid as an anti-colorectal cancer agent through bolstering T cell anti-tumor immunity by enhancing activation of MEK1-mediated TCR signaling.
    Zhengchun Kang, Xu Li, Xiuzhu Ma, Feihu Yan, Zhen Wang.
      Activation of the T cell receptor (TCR) complex is fundamental to initiating adaptive immune responses, particularly in CD8⁺ cytotoxic T lymphocytes that mediate anti-tumor immunity. However, the immunosuppressive tumor microenvironment often impairs TCR signaling, limiting the efficacy of T cell-based cancer immunotherapies. Here, we report the identification of rosmarinic acid (RA), a naturally occurring polyphenolic compound, as a potent small molecule enhancer of TCR signaling. RA significantly augments IL-2 and IFN-γ production, promotes T cell proliferation, and enhances cytotoxicity of CD8⁺ T cells in vitro. Mechanistically, RA directly binds to MEK1, a key kinase in the MAPK/ERK pathway, with high affinity, leading to reduced MEK1 phosphorylation and downstream signaling activation. Transcriptomic and metabolic profiling of RA-treated CD8⁺ T cells revealed upregulation of genes associated with TCR signaling, calcium flux, PPAR signaling, and oxidative phosphorylation, indicating a broad remodeling of T cell effector function and metabolism. In vivo, RA treatment significantly suppressed tumor growth, increased tumor-infiltrating lymphocyte (TIL) frequency, and improved survival in MC38 tumor-bearing mice. These effects were abrogated upon CD8⁺ T cell depletion, confirming their central role. Furthermore, RA synergized with anti-PD-1 therapy and enhanced the efficacy of adoptively transferred OT-I T cells in colorectal tumor-bearing hosts. Collectively, our findings reveal RA as a novel immunomodulatory agent that boosts CD8⁺ T cell responses via MEK1-mediated TCR signaling enhancement, providing a promising strategy for drug repurposing in cancer immunotherapy.
    Keywords:  Cancer immunotherapy; Drug repurposing; MEK1; Rosmarinic acid; T cell receptor
    DOI:  https://doi.org/10.1007/s00262-026-04366-3
  12. Eur J Immunol. 2026 Apr;56(4): e70113
    Irgm1 Restrains CD8+ T Cell Cytokine Production and Apoptosis via Cell-Extrinsic Regulation of Type I Interferon Signaling.
    Caitlyn T Molloy, Yazan Alwarawrah, Jonathan A Cohen, Brian E Fee, Jason K Whitmire, Gregory A Taylor, Nancie J MacIver.
      Immunity-related GTPases (IRGs) are a family of proteins that maintain cellular homeostasis by promoting autophagy and mitophagy. Mutations in human IRGM and genetic deletion of mouse Irgm1 have been linked to increased severity of inflammatory bowel disease, cancer, sepsis, and various infections. While IRGM/Irgm1 are known cell-intrinsic regulators of inflammation, their roles in T cell function remain poorly understood. We previously demonstrated that Irgm1 deficiency leads to increased production of proinflammatory mediators, including Granzyme B and interferon-γ, and increased apoptosis in CD8+ T cells. Here, we show that Irgm1 deficiency also alters Granzyme B production and impairs virus-specific CD8+ T cell responses during lymphocytic choriomeningitis virus (LCMV) infection. Using T cell-specific Irgm1 knockout mice and adoptive transfer experiments, we unexpectedly found that Irgm1 regulates CD8+ T cell responses through a cell-extrinsic mechanism. Transcriptomic and genetic analyses identified type I interferons (IFNs) as key mediators of this effect. These findings reveal a previously unrecognized, cell-extrinsic role for Irgm1 in regulating CD8+ T cell survival and function by modulating the inflammatory environment. Our results suggest that IRGM/Irgm1 acts as a critical immune rheostat, restraining pathological inflammation and modulating T cell responses in infection and autoimmunity.
    Keywords:  CD8+ T cells; apoptosis; immunity‐related GTPase M1 (Irgm1); inflammation; type I interferon
    DOI:  https://doi.org/10.1002/eji.70113
  13. Nat Immunol. 2026 Apr 03.
    Engineering metabolite-sensing NK and T cells to target solid tumors.
      
    DOI:  https://doi.org/10.1038/s41590-026-02500-y
  14. Cell Rep. 2026 Mar 27. pii: S2211-1247(26)00267-6. [Epub ahead of print]45(4): 117189
    Regulatory T cell-derived TGF-β signaling governs the differentiation and maintenance of tumor-infiltrating bystander CD8+ T cells.
    Yao Lin, Shuai Yue, Ding Qiu, Junjian He, Yang Yang, Shusen Ye, Wenwen Xi, Hairu Wang, Chunyang Xie, Texi Liang, Kaiyi Li, Xiaofan Yang, Yaxing Hao, Yuqing Li, Yi Yang, Teming Li, Song Wu, Lilin Ye, Xiangyu Chen.
      While indispensable for antitumor immunity, tumor-specific CD8+ T cells are numerically scarce and functionally exhausted in the tumor microenvironment (TME). In contrast, bystander memory CD8+ T (TBYS) cells that recognize pathogen-derived antigens but not tumor antigens are abundant in tumors and maintain polyfunctional effector capacity, yet their differentiation and maintenance mechanisms remain unclear. Here, we demonstrate that CD8+ TBYS cells comprise a heterogeneous population of TCM, TEM, and TRM subsets defined by distinct chromatin accessibility and transcriptional programs. These subpopulations follow a progressive TCM→TEM→TRM differentiation trajectory during tumor progression, with TRM cells exhibiting superior tissue retention and ultimately dominating the TBYS pool. We further identify TGF-β-derived from regulatory CD4+ T cells as the central instructor of this hierarchical differentiation, which promotes TBYS cell accumulation through suppression of KLF2. Our study elucidates a key mechanism of TBYS cell differentiation and maintenance, providing a foundation for the improved immunotherapies targeting this population.
    Keywords:  CP: cancer; CP: immunology; KLF2; TGF-β; bystander T cell; regulatory T cell; tissue-resident memory T cell
    DOI:  https://doi.org/10.1016/j.celrep.2026.117189
  15. Immunity. 2026 Apr 01. pii: S1074-7613(26)00119-6. [Epub ahead of print]
    Acute and chronic infections drive distinct trajectories in human memory CD4+ T cell formation.
    Matthias Reinscheid, Jill Weisser, Noah Pascual Maier, David B Reeg, Philipp L Hafkemeyer, Lara Kelsch, Giuseppe Rusignuolo, Jakob Arnold, Florian Emmerich, Andreas Walker, Yara Froehlich, Aparna Cherukunnath, Jörg Timm, Simone Picelli, Bertram Bengsch, Sagar, Robert Thimme, Tobias Boettler, Maike Hofmann.
      Virus-specific CD4+ T cells are essential for coordinating adaptive immunity during infection, but their differentiation and maintenance in chronic infection remain unclear. Using human hepatitis C virus (HCV) infection as a model, we assessed the determinants of virus-specific CD4+ T cell immunity in acute, spontaneously cleared, chronic, and therapeutically cured infections. During acute infection, multiple subsets of progenitor CD4+ T cells emerged, including subsets that are also found in chronic infection. In chronic infection, stem-like Bcl-2+ CD4+ T cells and T-bet+ effector CD4+ T cells existed in a progenitor/progeny relationship. Following therapy-mediated HCV cure, these cells retained their chronic signature but formed a stable memory pool that persisted for years and was distinct from HCV-specific CD4+ T cell memory after spontaneous clearance. Collectively, our findings highlight differences in CD4+ T cell fates that depend on infection outcomes and reveal common principles of CD4+ and exhausted CD8+ T cell maintenance during and after chronic infection.
    Keywords:  CD4+ T cell memory; CXCR5; PD-1; T cell differentiation trajectories; T cell exhaustion; T helper cell polarization; Tox; progenitor-progeny relationship; stem-like T cells
    DOI:  https://doi.org/10.1016/j.immuni.2026.03.008
  16. Nat Commun. 2026 Mar 31.
    Lymphodepleting preconditioning impairs host antitumor immunity induced by adoptive T cell therapy in mouse models.
    Diego Figueroa, Juan Pablo Vega, Andrés Hernández-Oliveras, Felipe Ardiles, Sofía Hidalgo, Ximena López, Vicente Saavedra, Catalina Bustamante, Daniela Malavé, Felipe Flores, Felipe Gálvez-Cancino, Hugo Gonzalez, Manuel Varas-Godoy, Maria Rosa Bono, Fabiola Osorio, Vincenzo Borgna, Alvaro Lladser.
      Adoptive T cell therapy (ACT) is effective against hematologic cancers, but the mechanisms underlying durable responses in solid tumors remain unclear. We show that adoptively transferred CD8+ T cells that eradicate established murine tumors promote expansion of host CD8+ T cells exhibiting tumor-reactive and tissue-resident phenotypes that contribute to tumor elimination. Mechanistically, tumor necrosis factor (TNF) from transferred cells induces dendritic cell (DC)-dependent expansion of host CD8+ T cells, conferring protection against ACT-resistant tumor cells lacking the targeted antigen. Lymphodepleting preconditioning promotes expansion of transferred cells and primary tumor eradication but impairs host antitumor immunity and abrogates protection against ACT-resistant tumors. In human tumors, increased TNF/DC/CD8+ T cell profiles correlate with favorable ACT responses and improved survival. These findings reveal a TNF-dependent interplay between transferred and host CD8+ T cells underlying durable antitumor immunity that is impaired by lymphodepleting preconditioning in mouse models, suggesting an underappreciated mechanism of ACT resistance.
    DOI:  https://doi.org/10.1038/s41467-026-71082-y
  17. Nat Commun. 2026 Apr 01. pii: 3157. [Epub ahead of print]17(1):
    Th17 cells require the DNA repair sensor xeroderma pigmentosum complementation Group C to control oxidative DNA damage in a murine model.
    Jefferson Antônio Leite, Natalia Notarberardino Bos, Luísa Menezes-Silva, Eloísa Martins da Silva, Giovana da Silva Leandro, Guilherme Comparotto Moreira de Goes, Patrick da Silva, Samuel Oliveira, Eder Soares de Almeida Santos, Hedden Ranfley, Ilaria Palagi, Magaiver Andrade-Silva, Camila Pontes Ferreira, José Arimatéa de Oliveira Nery Neto, Victor Yuji Yariwake, Marcella Cipelli, Beatriz Leocata, Talita Gonçalves, Anthony Gabry da Silveira, Sabrina Baroni, Howard L Weiner, Thomas G Hofmann, Stefanie Scheu, Bruno Junior Neves, Nadja Cristhina de Souza-Pinto, Leandro Machado Colli, Ari Waisman, Sandra Marcia Muxel, Carlos Frederico Martins Menck, Niels Olsen Saraiva Câmara.
      T helper 17 cells play essential roles in mucosal immunity and autoimmunity, yet the mechanisms that protect these cells from oxidative DNA damage remain poorly defined. Here we show, in a murine model, that the nucleotide excision repair sensor Xeroderma Pigmentosum Complementation Group C preserves genomic stability and metabolic fitness during T helper 17 cell differentiation. Loss of this factor reduces interleukin 17 production and increases mitochondrial reactive oxygen species and oxidative DNA damage, resulting in altered metabolic programs. Mechanistically, Xeroderma Pigmentosum Complementation Group C interacts with the base excision repair enzyme 8-oxoguanine DNA glycosylase, and its absence enhances oxidative lesion incision activity, indicating defective coordination between DNA repair pathways. Restoring antioxidant capacity rescues cytokine production and limits DNA damage in deficient cells. Together, these findings identify Xeroderma Pigmentosum Complementation Group C as a key coordinator of DNA repair and redox control required for T helper 17 cell function in inflammatory settings.
    DOI:  https://doi.org/10.1038/s41467-026-69914-y
  18. Nat Commun. 2026 Mar 28.
    The CD4+ T cell population partners with Tpex CD8+ T cells to mediate antitumor immunity in the tumor microenvironment.
    Shota Takei, Satoshi Yamasaki, Ou Yamaguchi, Atsuto Mouri, Ayako Shiono, Yu Miura, Kosuke Hashimoto, Hisao Imai, Kyoichi Kaira, Yoshinobu Ichiki, Hiroyuki Nitanda, Hirozo Sakaguchi, Tomoyuki Hishida, Katsuhisa Horimoto, Hiroshi Kagamu.
      CD4⁺ T cells support the priming, expansion, and function of CD8⁺ T cells through dendritic cells. Precursor exhausted T cells (Tpex) maintain self-renewal and supply cytotoxic CD8⁺ T cells in the tumor microenvironment (TME), but the identity of their CD4⁺ T-cell partners remains unclear. Here, we perform scRNA-seq, scTCR-seq, and mass cytometry analysis on peripheral blood, tumor, and lymph nodes primarily from lung cancer patients and, in part, renal cell carcinoma. We identify an IL-7Rhigh CCR6⁺ Th1-like CD4⁺ T cell-population, named Th7R, that is numerically and spatially partnered with Tpex. Th7R cells express lymphotoxin-β and CXCL13, correlate with high endothelial venules, and co-localize with Tpex in tertiary lymphoid structures. Th7R cell abundance correlates with Tpex numbers in the TME and lymph nodes, and adoptive transfer of Th7R increases Tpex in a preclinical mouse model. Intratumoral Th7R and Tpex associate with improved response to neoadjuvant PD-1 blockade therapy. These results suggest that Th7R cells act as partners of Tpex to sustain antitumor T-cell immunity.
    DOI:  https://doi.org/10.1038/s41467-026-71161-0
  19. Cell Rep. 2026 Mar 31. pii: S2211-1247(26)00282-2. [Epub ahead of print]45(4): 117204
    Expansion and mobilization of virus-specific stem-like CD8 T cells in chronic viral infection after treatment with a long-acting IL-7, NT-I7.
    Judong Lee, Christina Niavi, Eunseon Ahn, Haydn T Kissick, Rajesh M Valanparambil, Tahseen H Nasti, Donald J McGuire, Daniel Hua, Rebecca Obeng, Alexandra A Wolfarth, Danielle Borgonia, Sara Ferrando-Martinez, Donghoon Choi, Byung Ha Lee, Rafi Ahmed.
      PD-1+TCF1+ stem-like CD8 T cells are a progenitor population that provides a proliferative burst of effector CD8 T cells upon PD-1 blockade therapy, making them a key therapeutic target in antiviral and anticancer immunotherapy. Here, we show that IL-7 therapy preferentially expands these stem-like CD8 T cells, using NT-I7, a long-acting Fc-fused recombinant human IL-7 (efineptakin alfa). Gene profile analysis showed that a proliferating stem-like cluster induced by NT-I7 exhibited enrichment of genes related to lymphocyte migration. After NT-I7 treatment, proliferation of stem-like cells in the spleen was initiated within the white pulp, followed by egress into the red pulp. NT-I7 treatment led to an increase in stem-like CD8 T cells in circulation and peripheral tissues, contrasting with their resident property in lymphoid organs. These findings suggest NT-I7 as a promising strategy to expand and mobilize stem-like CD8 T cells to enhance antiviral and anticancer immunotherapies.
    Keywords:  CD8 T cells; CP: immunology; IL-7; T cell exhaustion; chronic infections and cancer; cytokines; immunotherapy; migration; progenitors of exhausted T cells; stem-like CD8 T cells
    DOI:  https://doi.org/10.1016/j.celrep.2026.117204
  20. Nat Immunol. 2026 Apr;27(4): 652-653
    Solving the puzzle of CD8 T cell positive selection.
    Juan Carlos Zúñiga-Pflücker, Anton Dobrin.
      
    DOI:  https://doi.org/10.1038/s41590-026-02476-9
  21. J Nanobiotechnology. 2026 Apr 01.
    Dual-targeted lipid nanoparticles for TET3 siRNA delivery: nanobiotechnology strategy to remodel tumor immune microenvironment in hepatocellular carcinoma.
    Wei Peng, Jin Zhou, Zhiliang Chen, Chengjia Tang, Jia Kuang, Wenke Li, Zhao Yang.
       BACKGROUND: Hepatocellular carcinoma (HCC) is characterized by a highly immunosuppressive tumor microenvironment (TME), where M2-polarized tumor-associated macrophages (TAMs) and exhausted CD8+ T cells limit immunotherapy efficacy. However, the upstream epigenetic mechanisms driving these phenotypes remain poorly defined, and effective nanotherapeutic strategies to reverse this immunosuppression are lacking. This study aimed to identify key epigenetic regulators of TME dysfunction and develop a targeted nanoplatform to restore antitumor immunity in HCC.
    RESULTS: Single-cell RNA sequencing identified ten-eleven translocation 3 (TET3) as highly expressed in M2 TAMs in HCC tissues. Mechanistically, TET3 promotes M2 polarization by enhancing interferon regulatory factor 4 (IRF4) transcriptional activity via hydroxymethylation, which in turn induces CD8⁺ T cell exhaustion through the CXCL12/CXCR4 axis. To target this pathway, we engineered dual-targeted lipid nanoparticles (TET3 siRNA@αmp-Lipo) modified with macrophage-specific peptides, enabling efficient and specific delivery of TET3 siRNA to M2 TAMs. In vitro experiments demonstrated the nanoparticles' excellent biocompatibility, stability, and ability to silence TET3, inhibiting M2 polarization and restoring CD8+ T cell function. In vivo studies confirmed that TET3 siRNA@αmp-Lipo significantly suppressed tumor growth, reduced M2 TAM infiltration, and reversed CD8+ T cell exhaustion in HCC models.
    CONCLUSIONS: This study identifies the TET3-IRF4 axis as a central epigenetic driver of immunosuppression in HCC and establishes TET3 siRNA@αmp-Lipo as a potent and translatable nanobiotechnology platform. By integrating targeted siRNA delivery with immune microenvironment remodeling, this strategy provides a promising approach to enhance immunotherapy for HCC and potentially other cancers with immunosuppressive TMEs.
    Keywords:  CD8⁺ T Cell Exhaustion; Hepatocellular Carcinoma Nanotherapy; Lipid Nanoparticles; TET3; Tumor-Associated Macrophage
    DOI:  https://doi.org/10.1186/s12951-026-04312-6
  22. Clin Exp Immunol. 2026 Mar 30. pii: uxag018. [Epub ahead of print]
    Nebivolol prevents exhausted T cells and enhances cytotoxicity against MCF-7 breast cancer cells in a β2-adrenergic receptor-dependent manner.
    Mehri Hajiaghayi, Fatemeh Gholizadeh, Niloufar Rahbari, Negaralsadat Emamnia, Steve C C Shih, Peter J Darlington.
       INTRODUCTION: Cancers often drive T cells toward an exhausted state characterized by impaired cytotoxicity and upregulation of inhibitory receptors (PD-1, TIM-3, CD38) and transcriptional regulators (TOX, NFATc1). Repeated stimulation in vitro is used to model this process, reflecting chronic antigen exposure in the tumor microenvironment. Stress-derived catecholamines further drive dysfunction through β-adrenergic receptor (β-AR) signaling. Here, we examined the impact of nebivolol, an atypical β1-AR blocker with β2-biased agonist activity, on T-cell exhaustion and cytotoxicity against breast cancer cells.
    METHODS: Human CD3+ T cells from healthy participants were activated once (early activation) or four times (repeated activation) using CD3/CD28/CD2 T cell activator. Cells were treated in vitro with nebivolol, terbutaline (β2-agonist), isoproterenol (β1/β2-agonist), and metoprolol (β1-blocker). Exhaustion markers, including PD-1, TIM-3, CD38, and TOX, were measured by flow cytometry and RT-qPCR; NFATc1 by western blot; TNF and IFN-γ by ELISA, and cytotoxicity against MCF-7 breast carcinoma cells by co-culture assays. Disruption of the β2-AR gene (ADRB2) was achieved using CRISPR/Cas9.
    RESULTS: Nebivolol reduced the proportion of TIM-3+CD38+PD-1+ T cells, downregulated TOX and nuclear NFATc1, and restored ADRB2 expression under repeated activation conditions. Nebivolol enhanced TNF secretion and improved cytotoxicity against MCF-7 cells. In contrast, terbutaline and isoproterenol had no significant effect on exhaustion markers or cytotoxicity. Metoprolol did not inhibit nebivolol's activity, indicating that its effects are not β1-AR-dependent. Disruption of ADRB2 indicated that nebivolol's anti-exhaustion effects are mediated by β2-AR.
    DISCUSSION: These findings show that nebivolol reinvigorates CD4+ and CD8+ T cells following repeated activation, restoring their cytotoxic function against breast cancer cells in vitro. The immunomodulatory activity of Nebivolol is independent of β1-AR and mediated through β2-AR, suggesting that biased β₂-AR signaling may represent a potential strategy for modulating T cell exhaustion in the tumor microenvironment.
    Keywords:  T cell exhaustion; cytotoxic T cells; nebivolol; tumor microenvironment; β₂-adrenergic receptors
    DOI:  https://doi.org/10.1093/cei/uxag018
  23. Aging Dis. 2026 Mar 20.
    Fundamental Cell-Intrinsic Mechanism Underlying Age-Dependent Accumulation of Senescent Cells.
    Pavel I Deryabin, Aleksandra V Borodkina.
      The accumulation of senescent cells during aging contributes to the progression of various age-related pathologies. Ineffective immune clearance, increased half-life of senescent cells, and bystander senescence are considered the primary drivers of this age-associated accumulation. Most of these causes stem from the aging of the immune system, which results in a prolonged persistence of damaged/nonfunctional cells within tissues and allows the internal senescence program to progress to a more severe phenotype. Here, we propose the existence of an additional immune-independent mechanism underlying the accumulation of senescent cells during aging. By reanalyzing existing experimental evidence, we show that cells of diverse identities and tissue origins become increasingly susceptible to senescence with age. The latter implies that epigenetic and molecular changes that cells acquire during aging create a permissive background for the activation of the senescence program. In light of our findings, senotherapeutic interventions alone may be insufficient to substantially alter the trajectory of organismal aging. Effective strategies may need to target upstream drivers of cellular dysfunction, including age-associated epigenetic alterations. Epigenetic rejuvenation could, in principle, enhance cellular stress resilience and thereby reduce the rate at which senescent cells emerge and accumulate.
    DOI:  https://doi.org/10.14336/AD.2026.0137
  24. Cell Mol Immunol. 2026 Apr 02.
    Persistent IFN-I signaling inhibits mitochondrial oxidative metabolism in CD8+ T cells during HIV-1 infection under cART.
    Liang Cheng, Guangming Li, Fei Luo, Wenwen Bi, Mengmeng Lu, Na Liu, Qiuchen Zhao, Runpeng Han, Hongyu Wang, Hao Yang, Jianping Ma, Wenjia Hu, Haisheng Yu, Wei Hou, Yong Xiong, Nilu Goonetilleke, R Brad Jones, Lishan Su.
      Persistent type I interferon (IFN-I) signaling contributes to immune exhaustion and promotes HIV-1 persistence. While we and others have demonstrated that blocking IFN-I signaling in vivo restores anti-HIV-1 T-cell function and reduces viral reservoirs, the underlying mechanism remains unclear. Here, we showed that in humanized mice (hu-mice) and cells from people living with HIV-1 (PLWH), IFN-I signaling impaired mitochondrial activity in CD8+ T cells during chronic HIV-1 infection with effective antiretroviral therapy. Reprogramming immunometabolism by transient inhibition of glycolysis with 2-deoxy-D-glucose (2-DG) rescued mitochondrial activity, reversed aberrant immune activation, and enhanced CD8+ T-cell activity in HIV-infected hosts, both ex vivo and in vivo. When combined with an HIV-1 reservoir-activating agent, 2-DG reduced the viral reservoir size in hu-mice and suppressed HIV-1 amplification in cells from PLWH. These findings indicate that 2-DG-mediated immunometabolic reprogramming represents a novel strategy to restore host immunity and control HIV-1 reservoirs.
    Keywords:  2-DG; CD8+ T cell; HIV-1; Immunometabolic reprogramming; Oxidative phosphorylation; Type I interferon
    DOI:  https://doi.org/10.1038/s41423-026-01398-8
  25. MedComm (2020). 2026 Apr;7(4): e70707
    Chromosome 1 Open Reading Frame 35 Drives Colorectal Cancer Progression by Enhancing Tumor-Intrinsic Proliferation and CD8+ T Cell Suppression.
    Shaosen Zhang, Changjiang Yang, Xunye Xu, Lan Lan, Ziyi He, Jiaoting Chen, Caihong Wang.
      The functional significance of Chromosome 1 open reading frame 35 (C1orf35) in colorectal cancer (CRC) remains poorly characterized. This study investigates its oncogenic role and underlying mechanisms. We report that C1orf35 is frequently upregulated in CRC clinical specimens, and its elevated expression correlates strongly with advanced tumor stage and serves as an independent prognostic indicator for reduced overall survival. Functional assays, including experiments in patient-derived organoids, demonstrate that C1orf35 is essential for driving tumor cell proliferation, migration, and expansion. Mechanistically, we identify C1orf35 as an upstream activator of the transcription factor c-Myc. This activation triggers the transcriptional upregulation of the metabolic enzyme pyrroline-5-carboxylate reductase 2 (PYCR2), a key node in proline biosynthesis that facilitates tumor growth. Furthermore, we uncover a distinct, non-cell-autonomous function of C1orf35 in shaping the tumor immune microenvironment. Through c-Myc, C1orf35 impairs the cytotoxic function of tumor-infiltrating CD8+ T cells. This inverse spatial relationship between C1orf35 expression and CD8+ T-cell infiltration is validated by multiplex immunohistochemistry in human CRC tissues. Thus, our work defines C1orf35 as a dual-function oncoprotein that promotes CRC progression by coordinately enhancing tumor-intrinsic growth via the c-Myc/PYCR2 axis and fostering an immune-suppressive niche. These findings nominate C1orf35 as a promising multi-faceted therapeutic target and prognostic biomarker in CRC.
    Keywords:  CD8+ T cells; chromosome 1 open reading frame 35; colorectal cancer; pyrroline‐5‐carboxylate reductase 2; tumor progression
    DOI:  https://doi.org/10.1002/mco2.70707
  26. Cell Rep Med. 2026 Mar 31. pii: S2666-3791(26)00139-4. [Epub ahead of print] 102722
    Epstein-Barr virus orchestrates spatial reorganization and immunomodulation in the classic Hodgkin lymphoma tumor microenvironment.
    Yao Yu Yeo, Huaying Qiu, Yunhao Bai, Bokai Zhu, Yuzhou Chang, Fabio Iannelli, Stephanie Pei Tung Yiu, Jason Yeung, Hendrik A Michel, Yuchen Wang, Yang Wang, Wenrui Wu, Kyle Wright, Muhammad Shaban, Sam Sadigh, Dingani Nkosi, Vignesh Shanmugam, Philip Rock, Precious Cramer, Julia Paczkowska, Pierre Stephan, Guanrui Liao, Amy Y Huang, Hongbo Wang, Han Chen, Leonie Frauenfeld, Louisa Kaufmann, Stefano Pileri, Bidisha Mitra, Benjamin E Gewurz, Bo Zhao, Garry P Nolan, Baochun Zhang, Alex K Shalek, Michael Angelo, Christian M Schürch, Faisal Mahmood, Roberto Chiarle, Qin Ma, W Richard Burack, Margaret A Shipp, Scott J Rodig, Sizun Jiang.
      Classic Hodgkin lymphoma (cHL) is composed of rare malignant Hodgkin and Reed-Sternberg (HRS) cells within a T-cell-rich tumor microenvironment (TME). Epstein-Barr virus (EBV) is present in ∼25% of cases, but its contribution to pathogenesis and immunomodulation remains unclear due to technical barriers. Using complementary spatial proteomics and transcriptomics across multi-institutional cohorts, we systematically map key EBV-linked TME reorganization. EBV-positive cHL exhibits distinct immunological features, including memory CD8 T cell enrichment, heightened T cell dysfunction spatially correlated with HRS proximity, and terminally exhausted T cell signatures contrasting with progenitor-exhausted patterns in EBV-negative disease. We identify EBV-encoded LMP1 as a factor in T cell dysfunction through enhanced HRS:CD8 interactions, and its expression level correlates with T cell terminal exhaustion in a distance-dependent manner. This spatial framework dissects viral-mediated immune evasion in the cHL TME, highlighting potential therapeutic opportunities to target virus-associated T cell dysfunction for precision immunotherapy in virus-associated malignancies.
    Keywords:  EBV; Hodgkin lymphoma; multiplexed imaging; spatial proteomics; spatial transcriptomics; systems immunology; tumor microenvironment; tumor virus
    DOI:  https://doi.org/10.1016/j.xcrm.2026.102722
  27. Cell Rep Med. 2026 Mar 30. pii: S2666-3791(26)00123-0. [Epub ahead of print] 102706
    mRNA lipid-nanoparticle-mediated mitochondrial apoptosis augments adoptive T cell immunotherapy.
    Jiayan Fu, Yaoqi Liu, Zhenyu Zhong, Benyuan Cao, Luna Ran, Zijia Guo, Haiyang Dong, Nengcheng Bao, Rongqing Pan, Jinqiang Wang, Yuanhui Mao, Yongfeng Jin.
      Adoptive T cell therapy (ACT) holds promise for cancer immunotherapy, yet its clinical efficacy against solid tumors remains suboptimal. An emerging strategy aims to enhance ACT by modulating mitochondrial apoptosis (mtApoptosis) priming of cancer cells. This study develops an mRNA-based combinational strategy that utilizes mRNA lipid nanoparticles encoding BH3 domains from activator-type proteins to trigger robust mtApoptosis, thereby augmenting antitumor immunity with ACT. This approach preferentially induces immunogenic cell death in cancer cells and remodels the immunosuppressive microenvironment. Combined with ACT, the formulation synergistically enhances tumor cell killing in vitro by lowering the apoptotic threshold. In vivo, the combination improves therapeutic efficacy by boosting endogenous T cell cytotoxicity and mitigating ACT-induced T cell dysfunction. Single-cell transcriptomics further reveals that the combination reprograms effector T cells toward memory-like states with expanded TCR diversity. Collectively, this study proposes a combinatorial mRNA-based strategy and provides mechanistic insights for augmenting ACT through mtApoptosis priming.
    Keywords:  adoptive T cell therapy; mitochondrial apoptosis; solid tumor; synergistic effect; therapeutic mRNA
    DOI:  https://doi.org/10.1016/j.xcrm.2026.102706
  28. Nat Rev Immunol. 2026 Apr 02.
    Abortive infection: T cells as early, antibody-independent defenders.
    Leo Swadling, Valeria Fumagalli, Mala K Maini, Matteo Iannacone.
      
    DOI:  https://doi.org/10.1038/s41577-026-01298-y
  29. Trends Pharmacol Sci. 2026 Mar 31. pii: S0165-6147(26)00063-5. [Epub ahead of print]
    Targeting the sensory-sympathetic axis for cancer immunotherapy.
    Wei-Lin Jin, Ming-Zhu Jin.
      How tumors manipulate neural circuits to evade immunity is unclear. In a recent study, Wei et al. reveal, in lung adenocarcinoma, a vagal sensory-brain stem sympathetic circuit that suppresses macrophages and CD8+ T cells via β2-adrenergic signaling. Disrupting this axis restores antitumor immunity, nominating β-blockers and neural modulation as promising therapies.
    Keywords:  ADRB2; cancer neuroscience; drug repurposing; immunosuppression; sensory–sympathetic axis; tumor–brain crosstalk
    DOI:  https://doi.org/10.1016/j.tips.2026.03.003
  30. Proc Natl Acad Sci U S A. 2026 Apr 07. 123(14): e2537271123
    Cytotoxic T cell recognition of α-synuclein drives pathogenic immune responses in multiple system atrophy.
    Jae-Seung Moon, Salvinaz I Moutusy, Mengrui Zhang, Alain Ndayisaba, Diego Rodriguez, Daniel N El Kodsi, Anastasia Kuzkina, Shady Younis, Shaghayegh Jahanbani, Laura S van Dam, Ya'el Courtney, Adi Netanel, Orr Sharpe, Mitchell G Miglis, Lawrence Steinman, Vikram Khurana, Fereshteh Jahanbani, William H Robinson.
      Multiple system atrophy (MSA) is a progressive neurologic disease, known as an α-synucleinopathy. There are currently no effective disease-modifying therapies for MSA. While neuroinflammation is a hallmark of MSA, the contribution of adaptive immune mechanisms remains poorly understood. Here, we profiled peripheral and central T cell responses in patients with MSA, in comparison with Parkinson's disease (PD) and healthy control cohorts, using single-cell transcriptomics, flow cytometry, and antigen-specific functional assays. We demonstrated that peripheral T cells from MSA patients are activated and skewed toward cytotoxic and inflammatory phenotypes. Single-cell transcriptomics further revealed clonal expansion of cytotoxic CD8+ T cells expressing GZMB, GNLY, and chemokine and integrin programs associated with brain homing. We also demonstrated that both CD4+ and CD8+ T cells from MSA patients recognize α-synuclein monomers and preformed fibrils in an HLA class I/II-dependent manner, driving proliferation, clonal expansion, and acquisition of cytotoxic features. Consistent with these peripheral responses, CD8+ T cell density was increased in the parietal cortex of postmortem MSA brain tissues, along with cytotoxic (GZMB+, GZMK+) and proinflammatory (IFNγ+) CD8+ T cells. Together, these findings demonstrate that cytotoxic T cells targeting α-synuclein are engaged in MSA, suggesting that their activity may contribute to neuroinflammation and disease progression, and highlighting this immune axis as a candidate therapeutic target for further investigation.
    Keywords:  antigen-specific T cell responses; cytotoxic T cells; multiple system atrophy; neuroinflammation; α-synuclein
    DOI:  https://doi.org/10.1073/pnas.2537271123
  31. Exp Hematol. 2026 Mar 30. pii: S0301-472X(26)00058-5. [Epub ahead of print] 105425
    Hematopoietic Stem Cell Senescence and Opportunities for Intervention.
    Aditya Barve, Preeti Dabas, Terri Cain, Shannon McKinney-Freeman.
      How the cellular state of senescence manifests in hematopoietic stem cells (HSCs) is currently poorly understood and likely orchestrated by a complex interplay of intrinsic and extrinsic factors, such as genetic instability, epigenetic reprograming, alterations in the stem cell niche and metabolic dysregulation. Accumulating senescence may contribute to the age-related functional decline of HSCs, which manifests as reduced self-renewal, impaired differentiation, altered hematopoietic regenerative potential, expansion of dysfunctional HSC clones, and increased susceptibility to hematological disorders. Recent work has advanced our understanding of the molecular hallmarks and signaling pathways that contribute to HSC senescence, nominating promising therapeutic targets to ameliorate age-associated hematopoietic dysfunction and malignancy. Here, we review the intrinsic and extrinsic factors that likely contribute to HSC senescence during homeostasis and pathological conditions. We further summarize senescence targeting strategies that may be leveraged to mitigate HSC senescence and restore hematopoietic function during aging or hematologic disease.
    DOI:  https://doi.org/10.1016/j.exphem.2026.105425
  32. Cancer Immunol Immunother. 2026 Apr 02. pii: 133. [Epub ahead of print]75(4):
    Metformin drives HIF-1α-mediated dual metabolic reprogramming to enhance γδ T cell therapy in triple-negative breast cancer.
    Xuping Qin, Haowen Zhong, Meize Liu, Tiantian Yu, Rong Ma, Ying Zhou, Jingyu Chen, Fen Liu, Xiwei Wang, Jianting Long.
      Triple-negative breast cancer (TNBC) lacks effective targeted treatments, rendering γδ T cell immunotherapy a promising therapeutic strategy. However, the function of these immune cells is often limited by exhaustion and immunosuppression. This study investigated whether metformin can enhance γδ T cell-mediated immunity against TNBC. Results demonstrated that metformin increased the cytotoxicity, proliferation, and cytokine production of γδ T cells while reducing their exhaustion markers. It differentially modulated cellular metabolism by enhancing oxidative phosphorylation (OXPHOS) and glycolysis in γδ T cells while suppressing these pathways in cancer cells through AMPK-HIF1-α signaling. Metformin also upregulated stress ligands on tumor cells, thereby improving immune recognition. In chemoresistant models, metformin restored γδ T cell function. Clinical data further showed that high AMPK activity and increased γδ T cell infiltration were associated with improved patient survival. These findings indicate that metformin remodels immunometabolism and enhances tumor immunogenicity, supporting its potential as a combinatory agent in γδ T cell-based immunotherapy for TNBC.
    Keywords:   γδ T cells; Metabolic reprogramming; Metformin; TNBC
    DOI:  https://doi.org/10.1007/s00262-026-04351-w
  33. Cell Rep. 2026 Mar 30. pii: S2211-1247(26)00266-4. [Epub ahead of print]45(4): 117188
    Targeting PI3Kδ suppresses pancreatic cancer by dual disruption of fibrosis and immune evasion.
    Maciej Garczyk, Gonçalo Outeiro-Pinho, Muthita Pitaktrairat, Bárbara Sofia Soares Da Silva, Giusy Di Conza, Karolina Niewola-Staszkowska, Marcel A Deken, Zoë Johnson, Asmita Thapa, Flavia Fico, Matteo Rossi Sebastiano, Inés Reynoso-Moreno, Daniele Pellegata, Giorgio Ramadori, Beat Gloor, Martin Wartenberg, Jürg Gertsch, Georgia Konstantinidou.
      Pancreatic ductal adenocarcinoma (PDAC) is characterized by dense stromal fibrosis that promotes immune exclusion and treatment resistance, yet the upstream drivers of this pro-fibrotic cascade remain poorly defined. Here, we identify phosphoinositide 3-kinase δ (PI3Kδ) as a previously unrecognized driver of fibrosis in PDAC. Pharmacological inhibition of PI3Kδ reduces collagen deposition while enhancing the infiltration of activated CD8+ T cells, thereby reprogramming the tumor microenvironment toward an antitumor state. Mechanistically, we reveal that PI3Kδ regulates the biosynthesis of lysophosphatidic acid (LPA), a key lipid mediator of stromal remodeling, by controlling phosphatidylcholine-derived precursors in both cancer cells and stromal fibroblasts. By regulating both LPA-driven stromal remodeling and immune suppression, PI3Kδ emerges as a central regulator of the PDAC tumor microenvironment. Co-inhibition of autotaxin, an enzyme contributing to LPA production, and PI3Kδ further amplifies stromal disruption and improves chemo-immunotherapy efficacy in preclinical PDAC models. These findings position PI3Kδ as a central therapeutic target in PDAC, offering a dual-action strategy to simultaneously dismantle stromal fibrosis and immune suppression.
    Keywords:  CP: cancer; CP: immunology; immunosuppression; pancreatic ductal adenocarcinoma; targeted therapies; tumor lipid metabolic regulation; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.celrep.2026.117188
  34. Oncol Res. 2026 ;34(4): 11
    Advances in Metabolic Reprogramming and Immune Regulatory Mechanisms in Lung Cancer.
    Xiaomeng Li, Xuejiao Li, Hongbo Wu, Rui Li.
      Lung cancer remains the leading cause of cancer-related mortality worldwide, primarily driven by metabolic reprogramming and immune evasion mechanisms within tumor cells. To adapt to the nutrient-deprived tumor microenvironment (TME), lung cancer cells undergo profound metabolic reprogramming, characterized by enhanced glycolysis (the Warburg effect), increased glutamine dependency (mediated by GLS1), and accelerated lipid synthesis (involving enzymes such as FASN). These metabolic alterations not only remodel the TME but also dampen antitumor immune responses by promoting immunosuppressive cell populations (e.g., Tregs and M2 macrophages) and inhibiting effector functions of CD8+ T cells and natural killer (NK) cells. Critically, a bidirectional crosstalk operates between tumor cell metabolism and the immunosuppressive TME: metabolic reprogramming drives immune suppression through metabolite accumulation, whereas the immunosuppressive TME, in turn, promotes tumor cell adaptability-thus forming a positive feedback loop that reinforces immune evasion and therapy resistance. This review elucidates key molecular pathways governing metabolic reprogramming in lung cancer-spanning glucose, amino acid, and lipid metabolism-and their dynamic crosstalk with immune regulation, including epigenetic modifications and non-coding RNA-mediated mechanisms. Additionally, it evaluates emerging therapeutic strategies targeting the metabolic-immune axis, such as inhibitors of HK2 or GLS1 combined with anti-PD-1/PD-L1 agents, which aim to reverse immunosuppression and improve clinical outcomes. By synthesizing recent advances, this work provides a theoretical framework for precision oncology interventions, highlighting the potential of metabolic immunotherapies and future directions integrating AI and multi-omics data to overcome resistance in lung cancer.
    Keywords:  Lung cancer; immune evasion; metabolic reprogramming; metabolic-immune axis; tumor microenvironment
    DOI:  https://doi.org/10.32604/or.2026.076176
  35. Biochim Biophys Acta Rev Cancer. 2026 Mar 30. pii: S0304-419X(26)00052-1. [Epub ahead of print] 189580
    Autophagy meets tissue-resident memory: Emerging crosstalk and therapeutic opportunities in cutaneous melanoma.
    Bogdan Toma, Mariana Pavel-Tanasa, Mihai Danciu.
      Melanoma is a highly immunogenic human cancer characterized by complex immune responses within the tumor microenvironment (TME). Among these, tumor-infiltrating lymphocytes (TILs) and tissue-resident memory T cells (TRM) are strongly associated with favorable prognosis and response to immune checkpoint blockade, reflecting their central role in sustaining anti-tumor immunity. Emerging evidence suggests that the activity and persistence of these T cell subsets are critically influenced by autophagy, a cellular process that maintains metabolic fitness, prevents exhaustion, and supports effector functions under nutrient-limited and stressful conditions typical of the TME. Understanding the autophagy-T cell axis may open new avenues for therapeutic strategies aimed at enhancing melanoma immunosurveillance and improving patient outcomes. In this review, we explore the intersection between TRM-cell biology and autophagy in cutaneous melanoma, outlining TRM differentiation and functions in the tumor setting, reviewing autophagy within melanoma cells, and examining evidence for their potential crosstalk. We further discuss how autophagy may shape TRM development, maintenance, and function, while tumor-intrinsic autophagy modulates TIL and TRM-mediated responses, and conclude by highlighting therapeutic opportunities, including those under investigation in registered clinical trials. By providing insights into this intricate interplay, the review aims to stimulate further investigation and support the development of targeted TRM-based therapeutic strategies for melanoma.
    Keywords:  Autophagy; Clinical trials; Melanoma; Tissue-resident memory T cells; Tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.1016/j.bbcan.2026.189580
  36. Mol Ther Oncol. 2026 Jun 18. 34(2): 201172
    Engineering T cell therapies for lung cancer.
    Hyatt Balke-Want, Vimal Keerthi, Steven A Feldman.
      
    DOI:  https://doi.org/10.1016/j.omton.2026.201172
  37. Cell Chem Biol. 2026 Mar 30. pii: S2451-9456(26)00073-5. [Epub ahead of print]
    ER-localized ceramide accumulation contributes to replicative senescence.
    Shweta Chitkara, Mengru Li, Natasha Gozali, Andrey Kuzmin, Artem Pliss, Paras Prasad, Yasemin Sancak, G Ekin Atilla-Gokcumen.
      Ceramides regulate diverse cellular processes through compartment-specific accumulation. While mitochondrial ceramide accumulation promotes apoptosis, its regulation and function during senescence remain incompletely understood. Here, we integrate lipidomics, transcriptomics, Raman spectroscopy, and biochemical characterizations to define sphingolipid remodeling in replicative senescence. Senescent cells exhibit elevated ceramide levels and depletion of very-long-chain sphingomyelins, despite unaltered sphingomyelin synthase 1 expression, implicating impaired ceramide-sphingomyelin turnover. Pharmacological inhibition of ceramide transfer protein (CERT), the ER-to-Golgi ceramide transporter, phenocopies sphingolipid remodeling and enhances senescence, suggesting disrupted ceramide trafficking as a driver of senescence. Raman spectroscopy suggests ceramide accumulation localized to the ER. In parallel, analysis of ER-enriched fractions confirms increased ceramide levels in ER fractions of senescent cells. Mechanistically, ceramide accumulation at the ER can contribute to ER stress. These findings identify altered ceramide trafficking as a contributor to ER stress and highlight ER-localized ceramide as a critical component of senescence-associated sphingolipid remodeling.
    Keywords:  ER stress; Raman BCA; ceramide; lipidomics; organelle enrichment; senescence; transcriptomics
    DOI:  https://doi.org/10.1016/j.chembiol.2026.03.003
  38. Front Biosci (Landmark Ed). 2026 Mar 19. 31(3): 49714
    NAD+ Homeostasis and Mitochondrial Modifiability: Resilience in Alzheimer's Disease.
    George B Stefano.
      Alzheimer's disease (AD) is increasingly associated with mitochondrial dysfunction and disrupted metabolism. Thus, the maintenance of nicotinamide adenine dinucleotide (NAD+) homeostasis is proposed as a potential therapeutic strategy. Toward this end, we suggest that AD-related mitochondrial dysfunction might be viewed as a regulatable, redox-dependent vulnerability rather than an inherently degenerative and irreversible process. This perspective advances an evolutionary model in which NAD+-mediated redox systems represent a conserved regulatory axis, and that destabilization of this axis during aging may increase susceptibility to degeneration. Here, we assess the potential of a therapeutic approach that combines this understanding of mitochondrial energy metabolism with results from preclinical studies demonstrating the impact of pharmacologic correction of NAD+ homeostasis (e.g., P7C3-A20) as contextual motivation. We explicitly elevate redox balance, rather than absolute NAD+ abundance, as the mechanistically dominant variable that shapes mitochondrial resilience, inflammatory tone, and neurovascular stability. Accordingly, the key unresolved issue is whether specific physiologic benefits might accrue from increased NAD+ availability per se or rather, the restoration of the NAD+/NADH redox ratio, with important implications for the interpretation of the results of directed metabolic interventions. Within this framework, metabolic failure in AD can be understood as an upstream permissive condition that explains, rather than replaces, canonical amyloid-β and tau-associated pathologies. While extended human lifespan may expose late-life vulnerabilities in otherwise conserved metabolic systems, claims of causal primacy, disease reversibility, and cross-neurodegenerative generalization remain premature, underscoring the need for redox-resolved, genetic, and clinical validation.
    Keywords:  Alzheimer’s disease; cognition; evolution; mitochondrial dysfunction; neurodegenerative diseases; neuroinflammatory diseases; nicotinamide adenine dinucleotide
    DOI:  https://doi.org/10.31083/FBL49714
  39. Nat Aging. 2026 Apr 01.
    Stem cell therapy might improve aging frailty.
    Isobel Leake.
      
    DOI:  https://doi.org/10.1038/s43587-026-01114-1
  40. Nat Immunol. 2026 Apr 02.
    A unique CD4⁺ T cell subset expressing granzyme K is regulated by transcription factor EOMES and important for T cell-mediated intestinal inflammation.
    Tian Xie, Yizhou Du, Qihan Wang, Hao Zhang, Kun Wei, Xinxin Chi, Xue Bai, Yujie Fu, Zhilin Peng, Yicheng Zhu, Qiuyan Lan, Chen Dong.
      CD4⁺ helper T (TH) cells consist of multiple functional subsets defined by specific effector cytokines and transcription factors. Recently, single-cell transcriptomic analyses have revealed possible existence of additional populations. Here we identify a unique CD4⁺ T cell subset in mouse and human colitis characterized by high levels of granzyme K (Gzmk) expression, designated as THK cells. These cells exhibit unique transcriptional signatures, with minimal expression of classical TH-defining factors but rather prominent Eomesodermin (Eomes) expression. Notably, THK cell differentiation is independent of TH1, TH2 and TH17 lineages in colitis. EOMES is both necessary and sufficient for THK cell induction, by directly driving the expression of Gzmk and associated effector molecules. Genetic ablation of Eomes ameliorates intestinal immunopathology in a T cell-induced colitis model. The THK transcriptional program seems to be conserved across species and in diverse disease contexts. Our findings establish THK cells as a distinct TH cell subtype, and the EOMES-THK axis may serve as a potential therapeutic target in inflammatory diseases.
    DOI:  https://doi.org/10.1038/s41590-026-02479-6
  41. Immunother Adv. 2026 ;6(1): ltaf038
    Chimeric CD3ζ chains containing CD28 signalling motifs enhance antigen-specific IL-2 production and expansion of human TCR-engineered T cells in vitro.
    Samuel J Burgess, Hans J Stauss, Emma C Morris.
      Gene-engineered T-cell products have been developed for immunotherapy to treat cancers, with great success observed in haematological malignancies but limited efficacy in treating solid cancers. TCR-engineered T cells utilize transferred TCRs targeting tumour-associated and cancer-specific peptides presented by MHC molecules. The CD3ζ chains are part of the TCR-CD3 complex expressed by T cells and mediate signal transduction when the TCR binds to MHC-presented peptides. In this study, we explored whether co-stimulation domains, that were effective in improving the function of T cells engineered with chimeric antigen receptors (CARs), can be exploited to improve the functionality of TCR-engineered T cells. We inserted the signalling domains of CD28 or 4-1BB at the membrane proximal or the membrane distal position of the intracellular tail of CD3ζ and engineered human T cells to express a specific TCR in combination with either modified CD3ζ or unmodified control. Antigen-specific in vitro stimulation assays revealed that T cells expressing CD3ζ constructs with CD28 signal domains displayed enhanced peptide-specific IL-2 production and, following repeated antigen stimulation, expanded to substantially greater numbers than T cells expressing unmodified CD3ζ. Importantly, greater expansion seen with the CD28-containing ζ did not result in any reduction of effector function as assessed by peptide-specific cytotoxicity and cytokine production. The data indicate that modification of the CD3ζ chain with a CD28 signal motif provides an opportunity to improve antigen-specific expansion and effector function of TCR-engineered T cells by combining signal 1 and co-stimulatory signal 2 in one molecular TCR-CD3 complex.
    Keywords:  CD28; CD3-zeta; T-cell function; T-cell receptor; TCR-T therapy
    DOI:  https://doi.org/10.1093/immadv/ltaf038
  42. Nat Commun. 2026 Mar 28.
    NEK8 kinase-mediated lactate increase impairs antitumor immunity decreasing radiotherapy sensitivity in colorectal cancer.
    Mingzhou Li, Yunfei Ni, Jieqiong Wu, Xin Zou, Yining Chen, Junfeng Qiu, Yifang Li, Huayu Cai, Li Wang, Feifei Wang, Hongxia Zhang, Fangyi Han, Jinghao Huang, Zilong Chen, Bingyu Xu, Li Liang.
      Radiotherapy effectively treats colorectal cancer (CRC), but local recurrence remains common and abscopal effects-regression of tumors distant from irradiated sites-are rarely observed even with immune checkpoint inhibitors. Here we show that the protein kinase NEK8, highly expressed in CRC, promotes radioresistance by suppressing anti-tumor immunity. In radiation-resistant tumors, NEK8 phosphorylates lactate dehydrogenase A (LDHA), driving lactate overproduction. This metabolite promotes histone modifications that silence antigen presentation machinery, while extracellular lactate directly impairs CD8+ T cell function, collectively excluding CD8+ T cell from the tumor microenvironment. Pharmacological inhibition of NEK8 using CX6258 restores CD8+ T cell infiltration and enhances both local and systemic tumor control following radiotherapy. These findings establish NEK8 as a promising therapeutic target for overcoming radioresistance and inducing abscopal responses in CRC.
    DOI:  https://doi.org/10.1038/s41467-026-70657-z
  43. Front Immunol. 2026 ;17 1706250
    Transdermal bicarbonate buffer therapy increases intratumoral pH and elicits antitumor responses in bladder cancer.
    Oluwaseyi Oluwatola, Sarah Bazargan, Pietro Irrera, Darwin Chang, Ashley Thomas, Jamie Blauvelt, Matthew Beatty, MacLean Hall, Christopher J Whelan, Veronica Estrella, Katarzyna A Rejniak, Michael Poch, Nathan Fitzsimmons, Ryan Beal, Arig Ibrahim-Hashim, Shari Pilon-Thomas.
       Introduction: Tumor acidosis is a hallmark of cancer that leads to abrogation of T cell function and cancer progression. Oral sodium bicarbonate therapy for alkalization of the extracellular tumor pH has shown moderate positive effects in tumor models. However, its applicability in the clinic is very limited due to the unreasonably high dosage required and gastrointestinal disturbances that arise. In this study, we assessed the functional effects of acidity on T cells.
    Methods: We show that acidity alters T cell proliferation, migration and effector functions as well as transcriptional programming using in vitro culture techniques and RNA sequencing. We then tested the potency of a proprietary transdermal formulation, DYV800, containing sodium bicarbonate to increase the extracellular tumor pH (pHe) and augment anti-tumor immune responses in a murine model of bladder cancer. The tumor pH was assessed using Chemical Exchange Saturation Transfer Magnetic Resonance Imaging (CEST-MRI) and antitumor immune responses via flow cytometry.
    Results: We found that transdermal DYV800 significantly reduced tumor burden and improved antigen-specific CD8+ T cell responses. Chemical Exchange Saturation Transfer Magnetic Resonance Imaging (CEST-MRI) of treated tumors showed an increase in intra-tumoral pH of bladder tumors, and this therapy also alkalizes the urine.
    Discussion/Conclusion: The transdermal delivery of DYV800 led to durable anti-tumor immune responses and is more clinically applicable to combat acidity in bladder cancer than oral bicarbonate. Targeting acidosis in the bladder tumor microenvironment has the potential to enhance T cell responses and improve anti-tumor immunity.
    Keywords:  DYV800; T cell; acidity; bladder cancer; pH; transdermal therapy; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1706250
  44. J Nanobiotechnology. 2026 Mar 30.
    Zinc-coordination-driven mitochondrial nanodisruptors to ablate cancer stemness for potentiating immunotherapy in colorectal malignancies.
    Yun Long, Wenting Cheng, Hailong Tian, Canhua Huang, Zhiqi Zhang, Yongfeng Jia, Shaojiang Zheng.
      Cancer stemness, sustained by mitochondrial metabolic plasticity, drives immunotherapy resistance in colorectal cancer (CRC). We reengineer zeolitic imidazolate framework-8 (ZIF-8), a zinc-coordination-driven metal-organic framework, from inert nanocarrier to a multifunctional mitochondrial synchronizer that disrupts stemness through tripartite bioenergetic targeting. A hyaluronic acid (HA)-modified nanoarchitecture (HA/ZGA) co-delivers glucose oxidase (GOx) and 5-aminolevulinic acid (5-ALA), leveraging ZIF-8's intrinsic Zn2+ release for dual metabolic blockade: Zn2+ inhibits glucose transporters and electron transport chain activity, while GOx depletes glucose to amplify energy stress. Concurrently, 5-ALA enables cristae-confined photodynamic ROS generation, collapsing oxidative phosphorylation and silencing pluripotency regulators. This metabolic triad coordinately eradicates stemness, reverses PD-L1/CD44 co-expression, and triggers cytotoxic T cell infiltration. In translational models, HA/ZGA achieves potent tumor regression, suppresses metastasis, and establishes immunological memory against rechallenge. Our work redefines ZIF-8 as a therapeutic chameleon that dismantles mitochondrial energetics, ablates stemness, and reignites antitumor immunity, exemplifying nanomaterial repurposing to bridge metabolic intervention with immune potentiation.
    Keywords:  Cell stemness; Chemo-immunotherapy; Colorectal cancer; Energy deprivation; Zeolitic imidazolate nano-frameworks
    DOI:  https://doi.org/10.1186/s12951-026-04184-w
  45. Immunity. 2026 Apr 01. pii: S1074-7613(26)00114-7. [Epub ahead of print]
    Distinct tissue niches contribute to prostate tissue-resident memory CD8+ T cell differentiation and heterogeneity.
    Kennidy K Takehara, Alexander Monell, Vida Luna, Baxter Melisso, Kianoosh M Mempel, Kitty P Cheung, Natalie Zane, Peter P Challita, Amir Ferry, Ethan C Xu, Violante Olivari, Nicole E Scharping, Giovanni Galletti, Sara Quon, Julien R Ishibashi, Nina Estep, John B Johanneson, Chinmayi Pandya, Stephanie D Anover-Sombke, Rana R McKay, Peter J Skene, Matthew E Pipkin, Maximilian Heeg, Miguel Reina-Campos, Ananda W Goldrath.
      The prostate is an important exocrine organ, a barrier tissue of the male reproductive system, and a common site of malignancy, yet CD8+ T cells in the prostate remain largely uncharacterized. Here, we show that a protective, heterogeneous pool of long-lived, tissue-resident memory CD8+ T (Trm) cells forms in the prostate following acute infection in mice. Characterization of prostate Trm cell differentiation over time, combined with functional interrogation of TGFβ, IL-7, and IL-15 signaling, revealed niche-dependent phenotypic and functional diversity arising from distinct prostate stromal and glandular epithelial niches in both mice and humans. For instance, the Trm-promoting cytokines IL-15 and TGFβ were highest in the prostate epithelium, where CD8+ T cells were most persistent, cytotoxic, and enriched for the Trm molecular program. In sum, we provide a spatial framework for prostate Trm cell differentiation, charting the discrete tissue regions that influence T cell fate through dynamic regulation of localized signals.
    Keywords:  CD8 T cell; memory T cell; prostate; spatial transcriptomics; tissue-resident memory T cells
    DOI:  https://doi.org/10.1016/j.immuni.2026.03.003
  46. Nucl Med Commun. 2026 Mar 31.
    Visualizing the metabolic battleground: the role of PET imaging in understanding immunometabolism and the tumor microenvironment.
    Raydel Briankwee Amalo, Hendra Budiawan, Budi Darmawan.
      PET has evolved beyond tumor glucose metabolism imaging to assess the immunometabolic landscape of the tumor microenvironment (TME) and systemic immune responses. Immunometabolism, encompassing glycolysis, oxidative phosphorylation, and fatty acid oxidation, governs immune cell activation, differentiation, and effector function, shaping antitumor immunity and immunotherapy outcomes. PET radiotracers, including fluorine 18-fluorodeoxyglucose, amino acid/nucleoside tracers (11C-methionine, 18F-F-AraG), cytokine/receptor-targeted tracers (64Cu-IFNγ, 68Ga-NOTA-Nb109), and macrophage-directed tracers (11C-PK11195, gallium-68-labeled NOTA-mannosylated serum albumin), enable noninvasive visualization of immune metabolism, proliferation, and polarization. Novel agents such as gallium-68-labeled fibroblast activation protein inhibitor and 68Ga-Pentixafor further capture stromal remodeling and immune cell recruitment. Clinically, immunometabolic PET guides oncology, immunotherapy, autoimmune, inflammatory, and infectious disease management by distinguishing immune activation from tumor progression, evaluating therapeutic response, and identifying active inflammation. This emerging imaging paradigm provides mechanistic insights into immune-tumor interactions and offers a precision tool for personalized treatment strategies.
    Keywords:  PET imaging; immune cell activation; immunometabolism; radiotracers; tumor microenvironment
    DOI:  https://doi.org/10.1097/MNM.0000000000002150
  47. FASEB J. 2026 Apr 15. 40(7): e71762
    Correction to "Type I Interferons Induce CD8+ T Cell Chemotaxis Through Regulating Melanocyte but Not Keratinocyte CXCL9/10/11 Secretion in the Initiation of Vitiligo".
      
    DOI:  https://doi.org/10.1096/fj.202601559
  48. Mol Ther. 2026 Mar 30. pii: S1525-0016(26)00217-0. [Epub ahead of print]
    Taming Autoimmunity: Alpha-1 Antitrypsin Overexpressing Mesenchymal Stem/Stromal Cells Promote Regulatory T Cell Crosstalk to Reverse Diabetes.
    Hua Wei, Wenyu Gou, Judong Kim, Suganya Subramanian, Tiffany Yeung, Paramita Chakraborty, Ahmed Lotfy, Shikhar Mehrotra, Stefano Berto, Charlie Strange, Hongjun Wang.
      Mesenchymal stem/stromal cell (MSC) therapy holds promise as a therapeutic option in diabetes treatment. The anti-inflammatory and immunomodulatory activities are enhanced when MSCs are engineered to overexpress alpha-1 antitrypsin (AAT-MSCs). Because a single infusion of AAT-MSCs reversed new-onset diabetes in over 50% of the female nonobese diabetic (NOD) mice, we used single-cell RNA sequencing, flow cytometry, and functional analyses to characterize how AAT-MSCs modulate CD4+ and CD8+ T cells in pancreatic lymph nodes (PLNs) and islets. AAT-MSC treatment increased T regulatory cells (Tregs) and more effectively suppressed T cell proliferation when stimulated with anti-CD3/CD28 antibodies. Treated mice exhibited reduced T helper 1 (Th1) cells and CD8+ cytotoxic T cells. In vitro studies confirmed the capacity of AAT-MSCs to promote Treg expansion in both mouse and human cells, drive CD8+ T cells toward an exhausted phenotype, and enhance mouse and human islet cell survival. Cellchat analysis showed that AAT-MSC therapy strengthens intercellular communication, especially signals originating from Tregs toward other PLN and islet cell populations. These findings clarify how AAT-MSCs modulate immune response and support their potential clinical application for type 1 diabetes and other autoimmune or inflammatory conditions.
    DOI:  https://doi.org/10.1016/j.ymthe.2026.03.032
  49. Aging Cell. 2026 Apr;25(4): e70452
    Targeting Mitochondrial Stress Responses: Terbinafine and Miglustat as Novel Lifespan and Healthspan Modulators.
    Amélia Lalou, Ioanna Daskalaki, Ilias Gkikas, Sandra Rodríguez-López, Jean-David Morel, Giorgia Benegiamo, Adrien Faure, Arwen W Gao, Joaquim Barmaz, Qi Wang, Terytty Yang Li, Feng Gao, Danaé Broustail, Kristina Schoonjans, Giovanni D'Angelo, Johan Auwerx.
      Mitochondria are central to cellular homeostasis and play a critical role in aging and age-related disorders, making them promising therapeutical targets. Here, we identify terbinafine and miglustat as novel mitochondrial stress inducers that extend lifespan and improve healthspan in Caenorhabditis elegans. Through a two-step screening, we found that both compounds activate the mitochondrial stress response (MSR) and exhibit distinct mechanisms of action. Terbinafine and miglustat robustly activated the mitochondrial unfolded protein response (UPRmt) mediator ATFS-1, upregulated MSR pathways, and modulated mitochondrial function across species, similarly to doxycycline. Interestingly, both compounds also engaged the insulin/IGF-1 signaling (IIS) pathway in C. elegans, revealing an integrated stress response involving coordinated action of ATFS-1 and the FOXO transcription factor DAF-16, distinct from canonical IIS activation. Experiments in human HEK293T cells confirmed the translational potential, with both compounds inducing mitochondrial stress and modulating mitochondrial function in mammalian systems. This study highlights the potential of harnessing the MSR to promote longevity and mitigate age-related functional decline. The identification of terbinafine and miglustat as mitochondrial stressors paves the way for novel anti-aging therapies.
    Keywords:   Caenorhabditis elegans ; aging; doxycycline; drug repositioning; longevity; miglustat; mitochondria; terbinafine
    DOI:  https://doi.org/10.1111/acel.70452
  50. Pharm Res. 2026 Apr 02.
    New Vistas for Withania somnifera in Signal Transduction of Inflammation and Aging.
    Eshita Sharma, Dilip Mehta, Prem Muthuraj, Sangita Panda, Saiprasad Ajgaonkar, Dishant Maniar, Aswathi Biju, Sujit Nair.
      Aging in humans is a multidimensional complexity featured by systematic chronic inflammation and further accompanied by organ dysfunction, gut dysbiosis, immune senescence, and age-related diseases. Chronic inflammation in cells relates to secretory factors like the senescence-associated secretory phenotype which induces senescence in normal cells. Simultaneously, immune senescence is promoted by chronic inflammation, resulting in an impaired immune system unable to clear out senescent cells and inflammatory factors. Long term accumulation of elevated inflammatory factors in cells causes organ damage and leads to other age-related disorders. Eliminating inflammation could be a viable anti-aging strategy since it has been identified as an endogenous component in aging. Lately, products of natural origin have been gaining attention in combating age-related diseases and chronic inflammation. Various in vitro, in vivo, and clinical studies have well documented the role of Withania somnifera (WS) in alleviating inflammation and aging in cells by mediating several cellular signaling pathways. This review discusses the features and mechanisms of inflammation and aging (inflammaging) and the modulation of key associated pathways by WS, examining its role as a promising candidate for future strategies against inflammaging.
    Keywords:   Withania somnifera ; age-related diseases; epigenetics; inflammaging; signal transduction
    DOI:  https://doi.org/10.1007/s11095-026-04060-0
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