bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2026–06–07
forty-five papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. T cell exhaustion landscapes and therapeutic modulation in cancer immunity.
  2. Cristae Architecture as a Metabolic Checkpoint in Effector T Cells - Implications for Cancer Immunity.
  3. MicroRNA-29a enhances and preserves stem-like CD8 T cell differentiation by regulating master epigenetic circuits of exhaustion.
  4. Redox-metabolic circuits as a central regulator of T cell-based immunotherapy.
  5. The multifaceted landscape of T cell exhaustion in organ transplantation: From molecular mechanisms (epigenetics, transcription, metabolism) to induction strategies.
  6. T-cell exhaustion in tumor immunology: mechanisms, heterogeneity, and therapeutic strategies.
  7. Ezh2 Inhibits the Differentiation of Short-Lived Effector CD8+ T Cells and Promotes T Cell-Dependent Antitumor Immunity.
  8. Nicotinamide Riboside Enhances Adoptive T Cell Therapy by Promoting Memory Differentiation and Metabolic Fitness.
  9. Fed T cells.
  10. Aging of the adaptive immune system affects the gut microbiome and systemic levels of vitamin B6.
  11. Correction to "Sleep Deprivation Inhibits CD8+ T Cell Function by Elevating Galectin-9 Expression in Colorectal Cancer Cells".
  12. Targeting tumor-specific T cells with LAG3-directed interleukin-2 prevents T-cell exhaustion and reinvigorates antitumor immunity.
  13. Hiding in plain sight.
  14. T cell-specific loss of IRF1 results in defective CD8 T cell activation and antitumor immunity.
  15. The impact of aging on antitumor immunity and cancer immunotherapy.
  16. Distinct transcription factors control tissue adaptation and effector function in infant and adult memory T cells.
  17. Editorial: Immune cell metabolism beyond energy supply - an emerging era to showcase novel roles in immune effector functions.
  18. T cell dysregulation and remodeling in pediatric obesity and weight loss.
  19. Sphingosine kinase-2 inhibition promotes immunogenic differentiation of myeloid-derived suppressor cells through an Acetyl-CoA carboxylase-phosphatidylcholine axis.
  20. A "scan and stop" assay identifies CD40 and CD70 as selective regulators of T-cell arrest on APCs.
  21. Enforced BATF expression via clinically approved LNPs enhances adoptive T-cell therapies.
  22. Ciclopirox reprograms effector responses and modulates Notch1 activation in activated human T cells.
  23. [Immuno'logical (the scientific updates you would not dare to read anywhere else): Methionine deprivation, summer body and macrophages polarization].
  24. SLC25A51 mRNA-LNP Armors T Cells with Mitochondrial Fitness in Cancer Treatment.
  25. Enhancing antitumor immunity in triple-negative breast cancer through reversal of T-cell exhaustion using a CD8-targeted and membrane-camouflaged nanocarrier delivering small interfering RNA against sorting Nexin 9.
  26. Aging restricts maturation of CXCL13+ T follicular helper cells in human immunity.
  27. Lactate-Depleting Engineered Probiotics Remodel the Tumor Microenvironment and Enhance PD-1 Blockade.
  28. ATR kinase inhibitors induce mitochondrial fission in CD8 + T cells and impair immune memory in vivo.
  29. SOT201: cis-acting PD-1/IL-15 mutein-based immunocytokine under investigational study in solid tumors.
  30. A community machine learning challenge to predict the effects of gene perturbations on T cell differentiation for cancer immunotherapy.
  31. Insights into the therapeutic strategies for aging and aging-associated diseases.
  32. ArchVelo: archetypal velocity modeling for single-cell multi-omic trajectories.
  33. BLOC1S1 regulates autolysosomal and exosomal dynamics during CD4⁺ T cell differentiation.
  34. Targeting colorectal cancer and T‑cell metabolism for the treatment of colorectal cancer (Review).
  35. Targeted Supplementation and Nutritional Strategies for Healthy Aging: A Review of Physiological and Molecular Benefits.
  36. Mechanisms of NAD+ Homeostasis in Aging and Disease.
  37. Mitochondrial copper stabilizes lipoylated TCA cycle proteins to sustain metabolism and proliferation.
  38. Peroxisomal ABCD1 deficiency in mice drives Th1 bias through 25-HC-LXR signaling in CD4+ T cells.
  39. Aberrant IL-21/STAT3 signaling disrupts regulatory T cell function and CD4+ T cell homeostasis in children with type 1 diabetes.
  40. Exosomal circFXR1 drives immune evasion and tumor progression through dual regulation of PD-L1 and mTOR signaling in gastric cancer.
  41. miR-142-5p promotes TSCM differentiation and suppresses progressive T-cell maturation via targeting PRKCB.
  42. Bone Marrow Failure Model Mimics Aplastic Anemia Patients: Single-Cell Landscape of Immune Response Reveals Novel Mechanisms of Immune Imbalance in AA.
  43. Engagement of the TCR against an oncolytic virus generates a population of effector CAR T cells with potent antitumor activity.
  44. Oleoylethanolamide Enhances Regulatory T Cell Function to Accelerate Plaque Regression in Atherosclerosis via PPARα Activation.
  45. lncRNA-mRNA Co-expression Network Unveils Neutrophil Metabolic Reprogramming in Human Sepsis.
  1. Front Cell Dev Biol. 2026 ;14 1827716
    T cell exhaustion landscapes and therapeutic modulation in cancer immunity.
    Jhommara Bautista, Andrés López-Cortés.
      T cell exhaustion is a central framework for explaining why antitumor T cell responses often fail despite persistent antigen exposure and immune infiltration. Rather than a single dysfunctional endpoint, exhaustion is increasingly understood as a structured and dynamic continuum of antigen-experienced CD8+ T cell states that differ in proliferative capacity, effector potential, epigenetic constraint, metabolic fitness, and spatial distribution within tumors. This view has major therapeutic implications because clinically relevant interventions can remodel exhausted-state composition and function without fully restoring a non-exhausted identity. In this review, we examine the organization of exhausted T cell states from progenitor-like to terminal compartments and discuss how TOX-linked survival programs, epigenetic fixation, and tumor-imposed metabolic and spatial constraints stabilize exhausted fate under chronic stimulation. We highlight the role of progenitor exhausted T cells in sustaining therapeutic responsiveness, explain why reinvigoration after checkpoint blockade is often partial rather than transformative, and evaluate emerging strategies to modulate exhaustion dynamics, including combination immunotherapy and engineered control systems in CAR T cells. Together, these concepts support a shift from viewing exhaustion as a binary defect to understanding it as a constrained state system that can be measured, preserved, and selectively redirected. Defining which exhausted states remain productively controllable, and under what conditions, will be essential for developing more durable and mechanistically informed cancer immunotherapies.
    Keywords:  cancer immunotherapy; immune checkpoint blockade; progenitor exhausted T cells; tumor microenvironment; t cell exhaustion
    DOI:  https://doi.org/10.3389/fcell.2026.1827716
  2. J Cancer Immunol (Wilmington). 2026 ;8(1): 17-22
    Cristae Architecture as a Metabolic Checkpoint in Effector T Cells - Implications for Cancer Immunity.
    Prakash Jeysankar, Sonal Srikanth, Beibei Wu, Yousang Gwack.
      Effector T cells rely on tightly coordinated metabolic and epigenetic programs to sustain immune function. Emerging evidence highlights a central role for mitochondria in integrating these programs through nutrient utilization and regulation of metabolite flux. The electron transport chain (ETC), localized to the inner mitochondrial membrane, directs cellular metabolism toward oxidative phosphorylation. The efficiency of ETC activity is governed by the highly folded architecture of the inner mitochondrial membrane into cristae. Although mitochondrial metabolism is well recognized as a key determinant of cellular metabolic states, the regulatory roles of cristae-organizing structural proteins, particularly in T cells, remain poorly defined. Our recent study identifies the inner mitochondrial membrane protein TMEM11 as a critical structural determinant of cristae organization and demonstrates how cristae integrity governs effector T cell function by controlling oxidative phosphorylation and metabolite flux. TMEM11 deficiency disrupts cristae architecture in T cells without affecting mitochondrial biogenesis or cell viability. Mechanistically, loss of TMEM11 impairs ETC function, leading to elevated mitochondrial reactive oxygen species (mtROS), which diverts acetyl-CoA away from histone acetylation toward fatty acid synthesis, thereby suppressing cytokine production. Collectively, these findings reveal a structural-metabolic-epigenetic axis that is essential for effector T cell immunity and suggest potential relevance for T cell-mediated cancer therapy.
    Keywords:  Cristae; Effector T cells; Mitochondria; Reactive oxygen species
    DOI:  https://doi.org/10.33696/cancerimmunol.8.120
  3. bioRxiv. 2026 May 28. pii: 2026.05.25.727439. [Epub ahead of print]
    MicroRNA-29a enhances and preserves stem-like CD8 T cell differentiation by regulating master epigenetic circuits of exhaustion.
    Xuebing Leng, Lance A Buchness, Christine I Rafie, Panagiotis I Vlantis, Svetlana Ristin, Miguel A Gallardo, Supipi L Auwardt, Natasha K Khatwani, Yuan-De Tan, Yuguang Ban, Corneliu M Sologon, Benjamin B Currall, Sion L Williams, Kevin Van der Jeught, Jashodeep Datta, Alejandro Villarino, Aristeidis G Telonis, Erietta Stelekati.
      CD8 T cells mediate protective immune responses. However, persisting antigens such as chronic viruses or tumors redirect CD8 T cell differentiation to a sub-optimal, epigenetically defined state called exhaustion. Exhausted T cells (T EX ) lose their ability to persist long-term and to initiate functional memory responses. Checkpoint inhibitor blockade temporarily restores effector functions, but immune reinvigoration is not long-lasting, due to the epigenetic stability of T EX . Therefore, epigenetic reprogramming of T EX leading to durable T cell responses is essential to improve disease control. Here, we demonstrate that a single microRNA (miR), miR-29a, epigenetically re-directs T EX differentiation and preserves T EX into a stem-like state, leading to long-term persisting progenitor T EX . MiR-29a rewires epigenetic maintenance programs, including downregulation of key exhaustion-associated regulators (Dnmt1, Dnmt3a, and Dnmt3b), alongside increased expression of progenitor- and stemness-associated genes such as Tcf7 and Il7r. These reprogrammed CD8 T cells are more sensitive to PD-L1 checkpoint blockade. Ectopic expression of miR-29a combined with aPD-L1 treatments enhances effector responses, while preserving T cell stemness. Together, our findings suggest that miR-29a can be leveraged to overcome current barriers to immune checkpoint blockade.
    Highlights: MiR-29a rewires key exhaustion-associated epigenetic maintenance programs, while enhancing stemness-associated transcriptional circuits. MiR-29a drives extensive remodeling of accessible chromatin in T EX . MiR-29a preserves newly generated progenitor T EX in a durable, epigenetically defined stem-like state with increased effector function. MiR-29a synergizes with aPD-L1; while miR-29a preserves progenitor T EX state, addition of aPD-L1 enhances the cytotoxic potential of these progenitor T EX cells.
    DOI:  https://doi.org/10.64898/2026.05.25.727439
  4. Front Immunol. 2026 ;17 1807087
    Redox-metabolic circuits as a central regulator of T cell-based immunotherapy.
    Sarah McPhedran, Tian Zhao, Julian J Lum.
      T cell-based immunotherapies have transformed cancer treatment, yet their efficacy in solid tumors is constrained by the nutrient-poor and oxidative tumor microenvironment (TME). Accumulating evidence indicates that reactive oxygen species (ROS), methionine metabolism, and the amino acid stress sensor general control nonderepressible 2 (GCN2) are tightly interconnected regulators of T cell activation, differentiation, and effector function. In this review, we detail how these pathways form an integrated redox-metabolic circuit that dynamically tunes T cell responses to environmental stress. Physiological ROS are essential for T cell receptor signaling, glycolytic reprogramming, and cytotoxicity, whereas excessive or prolonged oxidative stress drives exhaustion and apoptosis. GCN2 links amino acid availability, particularly methionine and cysteine, to adaptive transcriptional and metabolic programs that regulate glutathione synthesis and redox homeostasis. We highlight how therapeutic manipulation of methionine availability, GCN2 signaling and ROS produces highly context-dependent outcomes across immune checkpoint blockade and adoptive cell therapy settings in solid tumors. Finally, we discuss emerging strategies to interrogate and modulate this circuit using integrated omics, CRISPR-based screening, and pharmacological approaches, emphasizing the need for context-aware and temporally controlled metabolic interventions to enhance T cell-based immunotherapies in solid tumors.
    Keywords:  GCN2; T cells; immunometabolism; immunotherapy; methionine; redox
    DOI:  https://doi.org/10.3389/fimmu.2026.1807087
  5. Genes Dis. 2026 Sep;13(5): 101965
    The multifaceted landscape of T cell exhaustion in organ transplantation: From molecular mechanisms (epigenetics, transcription, metabolism) to induction strategies.
    Yining Wang, You Wu, Yufei Shen, Yujia Chen, Yifan Zhao, Xiandong Zeng, Kang He.
      T cell exhaustion is a state of T cell dysfunction resulting from persistent antigenic stimulation, characterized primarily by the high expression of inhibitory receptors, metabolic reprogramming, and epigenetic remodeling. T cell exhaustion is closely associated with immune responses in chronic infections, tumor escape, and organ transplantation. In transplantation immunology, T cell exhaustion plays a dual role: moderate exhaustion can promote immune tolerance and reduce graft rejection, while excessive exhaustion may weaken the defensive capabilities of the immune system, increasing the risk of infection and tumorigenesis. Therefore, effective regulation of T-cell exhaustion has become a crucial issue in the field of immunotherapy. Epigenetic or metabolic interventions may offer novel insights for achieving graft-specific tolerance. Further studies can focus on precise modulation of T-cell exhaustion through metabolic reprogramming, epigenetic regulation, and immune checkpoint inhibition, ultimately enhancing the efficacy of transplantation immunology and immunotherapy. This review focuses on the molecular phenotype, metabolic patterns, and mechanisms of epigenetic changes in exhausted T cells. It also explores the research progress of T cell exhaustion in organ transplantation. Furthermore, the review introduces strategies to induce T cell exhaustion, discussing how these strategies can effectively reduce the side effects of immunosuppressive therapy and promote graft tolerance.
    Keywords:  Epigenetic remodeling; Immunotherapy; Metabolic reprogramming; T cell exhaustion; Transplantation
    DOI:  https://doi.org/10.1016/j.gendis.2025.101965
  6. Front Immunol. 2026 ;17 1841281
    T-cell exhaustion in tumor immunology: mechanisms, heterogeneity, and therapeutic strategies.
    Ruoxuan Wang, Yingjie Guo.
      T-cell exhaustion is a central mechanism limiting the durability of antitumor immunity and the long-term efficacy of cancer immunotherapy. Arising under persistent antigenic stimulation and sustained microenvironmental stress, exhausted CD8+ T cells undergo progressive functional impairment accompanied by stable transcriptional, epigenetic, and metabolic reprogramming. Importantly, exhaustion is now understood not as a uniform dysfunctional endpoint but as a hierarchically organized and context-dependent differentiation continuum comprising progenitor, intermediate, and terminally exhausted states with distinct degrees of plasticity and therapeutic responsiveness. This framework helps explain why immune checkpoint blockade and related therapies often produce incomplete and non-durable clinical responses, as they predominantly act on progenitor-like exhausted T cells while leaving terminally exhausted populations largely refractory to reprogramming. In this review, we integrate current knowledge of the developmental heterogeneity, molecular mechanisms, and tumor microenvironmental regulation underlying T-cell exhaustion, and examine how these features shape the efficacy of major immunotherapeutic strategies. We further suggest that future progress will depend on moving beyond attempts to globally reverse exhaustion and instead adopting state-oriented approaches that preserve progenitor-like T-cell pools, restrain terminal differentiation, and remodel the immunosuppressive tumor microenvironment.
    Keywords:  T-cell; immunology; mechanism analysis; therapeutic strategies; tumor
    DOI:  https://doi.org/10.3389/fimmu.2026.1841281
  7. Cancer Sci. 2026 Jun 02.
    Ezh2 Inhibits the Differentiation of Short-Lived Effector CD8+ T Cells and Promotes T Cell-Dependent Antitumor Immunity.
    Kenji Takagi, Junpei Suzuki, Yuko Matsuoka, Makoto Kuwahara, Taro Oshikiri, Masakatsu Yamashita.
      Appropriate regulation of the differentiation balance between effector CD8+ T cells and memory CD8+ T cells is crucial for an appropriate immune response. We previously reported that the tumor suppressor menin suppresses the differentiation of CD8+ T cells into short-lived effector T cells (SLECs) and positively regulates memory CD8+ T cell differentiation. In this study, we identified Ezh2, a histone H3K27 methyltransferase, as a factor responsible for regulating SLECs differentiation, located downstream of menin. In antigen-stimulated CD8+ T cells, the Ezh2 expression gradually decreased with proliferation, reaching the lowest levels in terminally differentiated CD8+ T cells. The decrease in the expression of Ezh2 was accelerated by menin deficiency. Reduced histone H3K27 acetylation at the Ezh2 locus was observed in Menin-deficient CD8+ T cells, indicating that menin is required for maintaining the expression of Ezh2. In vitro studies have demonstrated that Ezh2-deficient activated CD8+ T cells exhibit enhanced differentiation into SLECs, along with increased effector functions. In contrast, Ezh2-deficient effector CD8+ T cells showed a marked increase in apoptosis upon IL-2 removal. In studies using mouse tumor models, T cell-specific Ezh2 knockout mice exhibited increased tumor growth and reduced survival relative to wild-type mice, with a significant decrease in the number of tumor-infiltrating CD8+ T cells. RNA sequencing revealed that Ezh2-deficient effector CD8+ T cells exhibit the increased expression of terminal differentiation-related molecules and apoptosis-related genes. These results demonstrate that Ezh2 functions downstream of menin and is essential for the proper regulation of T cell-dependent antitumor immunity.
    Keywords:   Ezh2 ; CD8+ T cell; antitumor immunity; histone H3K27; short‐lived effector cells
    DOI:  https://doi.org/10.1111/cas.70439
  8. Mol Ther. 2026 Jun 02. pii: S1525-0016(26)00470-3. [Epub ahead of print]
    Nicotinamide Riboside Enhances Adoptive T Cell Therapy by Promoting Memory Differentiation and Metabolic Fitness.
    Nengzhi Pang, Jinping He, Lei Pei, Ying Xiao, Yingying Gu, Cheng Zhi, Xuye Lai, Mingtao Chen, Qiyao Xiao, Xueqian Wu, Zhenfeng Zhang, Lili Yang.
      Enhancing the efficacy of adoptively transferred T cells is essential for successful immunotherapy. The cytotoxic activity of these T cells is closely related to their mitochondrial function, which plays a critical role in T cell differentiation. This study explored the potential of nicotinamide riboside (NR), known to enhance mitochondrial function, to improve the efficacy of adoptively transferred CD8+ T cells against hepatocellular carcinoma (HCC). In subcutaneous and metastatic HCC tumor models, NR treatment significantly improved the effectiveness of adoptive T-cell therapy (ACT). NR promoted the differentiation of CD44hiCD62Lhi central memory T cells (TCM) and upregulated memory-associated genes (Tcf7, Ccr7, and Foxo1). Upon restimulation, NR-treated CD8+ T cells exhibited strong recall responses, as evidenced by metabolic reprogramming and increased cytokine production. Furthermore, RNA sequencing revealed an increased expression of Foxo1 and its target genes. Inhibition of Foxo1 partially reversed the beneficial effects of NR on mitochondrial fitness and cytotoxic function, suggesting a role for Foxo1-associated pathways in mediating these effects. In summary, NR improved mitochondrial fitness and promoted TCM differentiation, in part through a transcriptional program associated with Foxo1, thereby improving the efficacy of adoptive T-cell therapy. These findings identify NR as a promising and translatable metabolic adjuvant for HCC immunotherapy.
    DOI:  https://doi.org/10.1016/j.ymthe.2026.05.026
  9. Nat Immunol. 2026 Jun;27(6): 1085
    Fed T cells.
    Ioana Staicu.
      
    DOI:  https://doi.org/10.1038/s41590-026-02552-0
  10. Microbiome. 2026 Jun 05.
    Aging of the adaptive immune system affects the gut microbiome and systemic levels of vitamin B6.
    Selina Stahl, Hanna Widmaier, Vadim Sakk, Kodandaramireddy Nalapareddy, Ann-Kathrin Kissmann, Frank Rosenau, Medhanie A Mulaw, David B Haslam, Hartmut Geiger.
       BACKGROUND: Age-associated dysregulation of the gut microbiota is a hallmark of aging and has been linked to multiple age-related diseases, yet upstream host factors driving these changes remain incompletely defined. Extensive bidirectional crosstalk between gut microbiota and mucosal immunity has been described. Aging is accompanied by a progressive decline in immune function, collectively termed aging-associated immune remodeling (AAIR). AAIR encompasses widespread compositional and functional changes that impair an effective response to pathogens, vaccines, and tissue damage. We examined whether AAIR is an upstream host factor influencing the composition of the microbiome upon aging.
    RESULTS: Hallmarks of AAIR were also present in the ileal lamina propria, including reduced naïve CD4+ and CD8+ T cell populations and expansion of memory and regulatory T cell subsets. To test whether mucosal AAIR reflects intrinsic aging of the hematopoietic system, we used an HSC transplantation model where young RAG1-/- recipients develop an adaptive immune system derived exclusively from either young or aged donor HSC in an otherwise young host environment. Recipients of aged HSCs recapitulated key features of mucosal AAIR, particularly loss of naïve T cells, demonstrating that AAIR in the ileal LP is driven at least in part by aged HSCs. Shotgun metagenomic sequencing of fecal samples revealed that ileal AAIR is associated with alterations in gut microbiota. In detail, there was a reduced abundance of taxa associated with the vitamin B6 (VB6) biosynthesis and salvage pathways. Accordingly, VB6 levels in serum were reduced in mice with aged immune systems.
    CONCLUSION: Our findings link AAIR to reduced microbial VB6 pathway abundance and lower systemic VB6 availability, suggesting that immune aging shapes the functional output of the microbiome in ways that diminish its VB6 biosynthetic capacity. This postulates an immune-microbiome-VB6 association that warrants further investigations for therapeutic strategies to increase VB6 levels upon aging. Video Abstract.
    Keywords:  Age-associated gut dysbiosis; Aging; Immune system; Microbiota; Vitamin B6
    DOI:  https://doi.org/10.1186/s40168-026-02428-3
  11. J Biochem Mol Toxicol. 2026 Jun;40(6): e70951
    Correction to "Sleep Deprivation Inhibits CD8+ T Cell Function by Elevating Galectin-9 Expression in Colorectal Cancer Cells".
      
    DOI:  https://doi.org/10.1002/jbt.70951
  12. Signal Transduct Target Ther. 2026 Jun 02. pii: 207. [Epub ahead of print]11(1):
    Targeting tumor-specific T cells with LAG3-directed interleukin-2 prevents T-cell exhaustion and reinvigorates antitumor immunity.
    Xiaohong Yu, Huiping Liao, Jiaoyun Lv, Yu Sun, Ruiqi Zhang, Yiwei Chen, Yifan Lin, Lulu Liu, Shijie Li, Hui Tang, Panpan Jia, Bin Shao, Zaopeng Yang, Yang-Xin Fu, Zhenhua Ren.
      LAG3 is a critical inhibitory receptor that is highly enriched on exhausted T cells within the tumor microenvironment (TME), where it acts as a key driver of T-cell exhaustion-an archetypal barrier to robust antitumor immunity. In a colon cancer model, LAG3+CD8+ tumor-infiltrating lymphocytes (TILs) constitute the predominant type of tumor-specific T cells but exhibit defective IL2 signaling. To address whether exogenous IL2 replenishment unpins their dysfunction, we engineered LAG3-LaIL2 (low-affinity IL2), a fusion protein that selectively delivers IL2 to LAG3+CD8+ TILs. LAG3-LaIL2 expanded pre-exhausted tumor-specific CD8+ T cells, reprogrammed their exhaustion trajectory toward an intermediate effector state, and prevented terminal exhaustion, leading to tumor regression and prolonged survival in mice. Mechanistically, LAG3-LaIL2 restored IL2R-JAK3-STAT5 signaling by upregulating the high-affinity IL2 receptor subunit CD122, thereby restoring TIL functionality. Furthermore, LAG3-LaIL2 amplified tumor-specific effector and memory T cells in draining lymph nodes, enabling systemic antitumor immunity against distal tumors and preventing tumor recurrence. Collectively, our findings identify LAG3-LaIL2 as a precision immunotherapy that specifically targets exhausted TILs while restricting IL2 exposure to nontarget cells, thereby enhancing both the efficacy and safety of this approach. This approach provides a translatable strategy to overcome T-cell exhaustion in solid tumors and represents a promising avenue to improve clinical outcomes in cancer patients.
    DOI:  https://doi.org/10.1038/s41392-026-02667-8
  13. Sci Transl Med. 2026 Jun 03. 18(852): eaeh0704
    Hiding in plain sight.
    Robin Orozco.
      HIV-1-infected CD4+ T cells undergo lineage marker changes to become induced CD8+ T cells that harbor latent HIV-1 (Cai et al., this issue).
    DOI:  https://doi.org/10.1126/scitranslmed.aeh0704
  14. bioRxiv. 2026 May 18. pii: 2026.05.14.725206. [Epub ahead of print]
    T cell-specific loss of IRF1 results in defective CD8 T cell activation and antitumor immunity.
    Lulu Shao, Hridesh Bannerjee, Ecem Unal, Isha Mehta, Jishnu Das, A Rouf Banday, Larry Kane, Saumendra N Sarkar.
      Interferon regulatory factor 1 (IRF1) has long been recognized as a tumor suppressor; however, recent studies have revealed context-specific and sometimes opposing roles in cancer progression. Here, we describe a T cell-specific mechanism underlying the antitumor activity of IRF1. Unlike germline Irf1 -deficient mice, T cell-specific loss of IRF1 does not lead to a deficiency in cytotoxic CD8⁺ T cells. Nevertheless, tumor burden remains elevated in these mice, associated with reduced CD8⁺ T cell infiltration driven by impaired activation and proliferation in the absence of IRF1. Transcriptomic analysis of activated Irf1 -deficient T cells identified NFATc1 as a key gene significantly downregulated upon IRF1 loss. Analysis of human melanoma datasets further corroborated this finding, highlighting a previously unappreciated role for IRF1 in regulating T cell activation and antitumor immunity.
    DOI:  https://doi.org/10.64898/2026.05.14.725206
  15. Trends Cancer. 2026 Jun 02. pii: S2405-8033(26)00106-8. [Epub ahead of print]
    The impact of aging on antitumor immunity and cancer immunotherapy.
    Claudia Cifuentes Caballero, Ilaria Delle Fontane, Helen C Hope, Nicola Vannini.
      Aging is the first risk factor associated with cancer, predominantly due to cumulative somatic mutations and a profound decline in antitumor immunity. The aging process remodels immune function across hematopoietic, adaptive, and innate compartments through interconnected processes, including hematopoietic stem cell dysfunction, loss of metabolic fitness, altered B and T cell phenotypes, myeloid skewing, and a complex interplay between cellular senescence and inflammaging. These changes collectively establish an immunosuppressive landscape that weakens natural tumor surveillance and constrains responses to cancer immunotherapies. Given the shift toward an aging global population and the disproportionate cancer burden in older individuals, we emphasize the clinical relevance of patient-stratification strategies. We further discuss emerging approaches aimed at rejuvenating immune function to improve immunotherapy outcomes in older patients.
    Keywords:  aging; antitumor immunity; cancer immunotherapy; immunosenescence; inflammaging
    DOI:  https://doi.org/10.1016/j.trecan.2026.05.003
  16. Nat Immunol. 2026 Jun 02.
    Distinct transcription factors control tissue adaptation and effector function in infant and adult memory T cells.
    Peter A Szabo, Hanna M Levitin, Siddhi Nargund, Thomas J Connors, David Chen, Jenny Jin, Puspa Thapa, Rebecca Guyer, Daniel P Caron, Joshua I Gray, Rei Matsumoto, Masaru Kubota, Maigan Brusko, Todd M Brusko, Donna L Farber, Peter A Sims.
      Early life is essential for establishing memory T cells, which rapidly populate mucosal sites during infancy, although these nascent memory T cells are less protective than their adult counterparts. Here we used single-cell RNA sequencing of resting and CD3+CD28 antibody-stimulated T cells from lymphoid and mucosal tissues of infant (2-9 months) and adult (40-63 years) organ donors to investigate age-dependent mechanisms for functional regulation of human memory T cells. Infant CCL5+ effector memory T cells exhibited reduced effector function compared to adults. Transcription factor network analysis identified HELIOS and KLF6 as regulators of memory T cell states in infant and adult tissues, respectively. Using single-nucleus RNA sequencing, assay for transposase-accessible chromatin sequencing and CRISPR-Cas9 knockout, we defined HELIOS (IKZF2) as a critical regulator of the infant-specific transcriptional program in CCL5+ effector memory T cells and restricted effector function in SELL+CCR7+ naive and/or central memory T cells. Our findings reveal key mechanisms controlling T cell functional states in early life.
    DOI:  https://doi.org/10.1038/s41590-026-02535-1
  17. Front Immunol. 2026 ;17 1869468
    Editorial: Immune cell metabolism beyond energy supply - an emerging era to showcase novel roles in immune effector functions.
    Hao Wu, Henry Kurniawan, Bin Zheng, Wei He.
      
    Keywords:  T cell; cell metabolism; choline; fumarate; itaconate; macrophage; mesaconate; neutrophil
    DOI:  https://doi.org/10.3389/fimmu.2026.1869468
  18. bioRxiv. 2026 May 21. pii: 2026.05.19.722395. [Epub ahead of print]
    T cell dysregulation and remodeling in pediatric obesity and weight loss.
    Ceire A Hay, Samir U Sayed, Diego A Espinoza, Montana Knight, Eric D Abrams, Jose S Campos Duran, Maté Z Nagy, Molly A Nelson, Sydney A Sheetz, Pooja Gunnala, Elena N M Gonzalez, Jarad Beers, Colleen Tewksbury, Joy L Collins, Noel N Williams, Robert B Lindell, Melanie A Ruffner, Edward M Behrens, Kristoffel R Dumon, Elizabeth Parks Prout, Jorge Henao-Mejia, Sarah E Henrickson.
      Obesity is a chronic inflammatory disease associated with immune dysregulation. However, alterations in adaptive immune function remain unclear, particularly in the setting of childhood obesity and weight loss. We defined peripheral T cell dysregulation in a cross-sectional cohort of pediatric participants across weight categories and in a longitudinal cohort of adolescents with severe obesity undergoing bariatric surgery. We found increased expression of activation markers (including PD-1 and CD69) in non-naive CD8 + T cells whereas non-naive CD4 + T cells were skewed towards Tfh, Th17, and mixed Th2/Th17 populations. Consistent with a hyperactive state, T cells had enhanced capacity for inflammatory cytokine production (including IFN-γ and TNF-α), along with enrichment of gene sets associated with cytokine signaling, cell proliferation, and cell death. Notably, these phenotypic, functional, and transcriptional alterations were not fully resolved after bariatric surgery, despite clinically meaningful weight loss. Together, these findings demonstrate that pediatric obesity leads to dysregulation of adaptive immune function with incomplete normalization after weight loss.
    SUMMARY: The impact of pediatric obesity on immune cell function is not well understood. This study demonstrates that both CD4 + and CD8 + T cells are dysregulated in children living with obesity and further identifies that this dysregulated state persists following clinically significant weight loss.
    DOI:  https://doi.org/10.64898/2026.05.19.722395
  19. Nat Commun. 2026 Jun 02.
    Sphingosine kinase-2 inhibition promotes immunogenic differentiation of myeloid-derived suppressor cells through an Acetyl-CoA carboxylase-phosphatidylcholine axis.
    Paramita Chakraborty, Shilpak Chatterjee, Mohamed Faisal Kassir, Wyatt Wofford, Seungho Choi, Natalia Oleinik, Ozge Saatci, Odai Darawshi, Satyajit Das, Nathaniel Oberhoeltzer, Anupam Gautam, Stephanie Mills, Reid DeMass, Zacharia Hedley, Yueying Liu, Rasesh Y Parikh, Sandip Paul, Souvik Seal, Charles D Smith, Michael B Lilly, Vamsi K Gangaraju, Yuri Peterson, Meenal Mehrotra, Elizabeth Hill, Ozgur Sahin, Norbert Leitinger, Paulo C Rodriguez, Besim Ogretmen, Shikhar Mehrotra.
      Myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment (TME) limit the efficacy of adoptive T cell therapies, highlighting the need to overcome tumor-associated immunosuppression. Sphingosine-1-phosphate (S1P), is an abundant signaling lipid in the TME. Here, we show that inhibition of sphingosine kinase-2 (SphK2), the enzyme generating S1P in MDSCs, reduces the suppressive activity of monocytic MDSCs (M-MDSCs) while promoting their differentiation toward a mature, immunogenic phenotype characterized by enhanced antigen presentation. Pharmacological SphK2 inhibition enhances the response to anti-PD-1 therapy in preclinical models of checkpoint-resistant breast, bladder, and melanoma cancers by mitigating MDSC-mediated suppression and limiting tumor progression. Mechanistically, S1P directly binds acetyl-CoA carboxylase-1 (ACC1) to inhibit its activity, thereby rewiring fatty-acid metabolism. Lowering intracellular S1P restores ACC activity, promotes phosphatidylcholine synthesis, and reduces MDSC immunosuppression. These findings identify the SphK2-ACC-phospholipid axis as a metabolic checkpoint controlling the immunogenicity of MDSCs and a potential therapeutic target for enhancing cancer immunotherapy.
    DOI:  https://doi.org/10.1038/s41467-026-73827-1
  20. Life Sci Alliance. 2026 Aug;pii: e202503401. [Epub ahead of print]9(8):
    A "scan and stop" assay identifies CD40 and CD70 as selective regulators of T-cell arrest on APCs.
    Vincent Gloe, Richard Schregle, Christoph Ratswohl, Jérémie Rossy.
      T-cell activation requires firm arrest on APCs, a process essential for effective clonal expansion and differentiation. Although the role of co-inhibitory signals and integrin-mediated adhesion in modulating T-cell arrest is established, the contribution of co-stimulatory molecules to this process remains poorly understood. Here, we developed a quantitative "scan and stop" assay using engineered CHO cells as minimalistic APCs to systematically assess the influence of co-stimulatory proteins on T-cell arrest. These APCs express only selected peptide-MHC complexes and co-stimulatory ligands, allowing controlled investigation of their roles in both naïve and experienced CD4+ and CD8+ T cells. We found that CD40 selectively promotes the arrest of pre-activated CD4+ T cells, whereas CD70 enhances the arrest of CD8+ T cells, correlating with expression patterns of their respective receptors, CD40L and CD27. High-resolution imaging further revealed mechanical deformation of APCs during synapse formation, suggesting force generation by T cells. Altogether, our results identify CD40 and CD70 as subtype-specific regulators of T-cell arrest and reveal a novel dimension in co-stimulatory control of immune synapse formation.
    DOI:  https://doi.org/10.26508/lsa.202503401
  21. Blood Sci. 2026 Jun;8(2): e00291
    Enforced BATF expression via clinically approved LNPs enhances adoptive T-cell therapies.
    Hanchi Ge, Keyu Wang, Lianting Chen, Tong Yin, Fang Zhang, Haoxin Li, Jun Wei, Dan Ding, Wenting Zheng.
      Chimeric antigen receptor (CAR) T-cell therapy is highly effective in hematologic malignancies, yet its durability is limited by insufficient expansion, persistence, and T-cell exhaustion. Basic leucine zipper ATF-like transcription factor (BATF) promotes CD8+ T-cell effector differentiation but can drive exhaustion under chronic stimulation. Here, we developed a transient, non-viral strategy to modulate BATF expression in therapeutic T cells using clinically approved lipid nanoparticles (LNPs). Among 3 Food and Drug Administration (FDA)-approved ionizable lipids, SM-102-based LNPs achieved the highest mRNA delivery efficiency in primary T cells. Transient BATF overexpression enhanced T-cell cytotoxicity in vitro without inducing exhaustion. In vivo, BATF mRNA transfection enhanced T-cell expansion, reduced exhaustion, and improved anti-tumor activity for both OT-1 TCR-T cells in melanoma and CD19 CAR-T cells in acute lymphoblastic leukemia. These findings establish a safe and reversible platform for transient transcription factor modulation to optimize T-cell differentiation and function, thereby enhancing the efficacy of adoptive T-cell therapies and supporting clinical translation.
    Keywords:  BATF; CAR-T cell therapy; Lipid nanoparticles
    DOI:  https://doi.org/10.1097/BS9.0000000000000291
  22. iScience. 2026 Jun 19. 29(6): 116079
    Ciclopirox reprograms effector responses and modulates Notch1 activation in activated human T cells.
    Aprajita Tripathi, Debolina Dasgupta, Mehak Ahuja, Gabrielle Fisette, Emily Burt, Nadine Santana-Magal, Robyn Wood, John A Taylor, Stefan H Bossmann, Scott J Weir, Kalyani Pyaram.
      Ciclopirox (CPX) is an FDA approved, broad-spectrum antifungal agent. The prodrug of CPX, fosciclopirox, was evaluated for safety and preliminary efficacy in patients with advanced solid tumors, including bladder cancer, and was found to inhibit cell proliferation, the γ-secretase complex, and Notch signaling. However, the effects of CPX on human T cell function have remained undefined. In this study, we investigated the impact of CPX on primary human T cell activation and their effector responses. CPX enhanced early activation markers and IL-2 production; yet, suppressed activation-driven expansion, altered cell cycle progression, and reduced effector functions, including IFN-γ production and cytotoxic granule expression, in vitro. Mechanistically, CPX modulates Notch1 activation temporally and reprograms T cell metabolism by limiting glycolysis, both of which impact proliferative and effector responses in activated T cells. Together, these findings identify CPX as a modulator of T cell immunity, highlighting the broader immunologic implications for its therapeutic application.
    Keywords:  Biological sciences; Cancer; Cell biology; Immunology
    DOI:  https://doi.org/10.1016/j.isci.2026.116079
  23. Rev Med Interne. 2026 Jun 04. pii: S0248-8663(26)00568-0. [Epub ahead of print]
    [Immuno'logical (the scientific updates you would not dare to read anywhere else): Methionine deprivation, summer body and macrophages polarization].
    Valentin Lacombe.
      As summer approaches, methionine-restricted diets might appear to be just another "summer body" promise. Yet behind the loss of fat mass observed in mice lies a genuine metabolic reprogramming: methionine deprivation alters glucose utilization, reduces mitochondrial respiration, and promotes a more glycolytic metabolic profile. This energetic shift extends beyond muscle and adipose tissue, directly influencing immune cell behavior. We will explore how such restriction can skew macrophages toward a pro-inflammatory M1 phenotype, and limit the activation and proliferation of Th1 and Th17 lymphocytes, with effects that vary according to the pathological context - metabolic syndrome, cancer, or autoimmune diseases. Through this synthesis, Immuno'logique aims to make findings from fundamental science literature more digestible while highlighting their potential clinical implications. In short, let us be serious without taking ourselves too seriously, and discover how methionine deprivation can reshape metabolism and immunity.
    Keywords:  Cellular metabolism; Dietary restriction; Lymphocytes T; Macrophages; Methionine; Métabolisme cellulaire; Méthionine; Restriction alimentaire; T lymphocytes
    DOI:  https://doi.org/10.1016/j.revmed.2026.05.001
  24. ACS Appl Mater Interfaces. 2026 Jun 02.
    SLC25A51 mRNA-LNP Armors T Cells with Mitochondrial Fitness in Cancer Treatment.
    Xiaofeng Xu, Bin He, Jingbang Wu, Yeqian Yu.
      Pancreatic ductal adenocarcinoma remains largely refractory to adoptive T-cell therapies owing to a metabolically hostile tumor microenvironment that compromises mitochondrial functions. Here, we develop an ex vivo SLC25A51 mRNA-lipid nanoparticle (mRNA-LNP) engineering strategy to reinforce mitochondrial fitness in T cells and assess its therapeutic potential in pancreatic cancer xenografts. SLC25A51 mRNA-LNPs efficiently transfected primary T cells, resulting in sustained SLC25A51 expression and marked enhancement of mitochondrial membrane potential, oxidative respiration, and ATP production. These metabolic gains translated into increased T-cell proliferation, augmented effector cytokine secretion, and improved tumor-cell killing in vitro. In a subcutaneous Pan02 model, adoptive transfer of SLC25A51-engineered T cells significantly delayed tumor progression and extended survival, accompanied by enhanced intratumoral activation and enrichment of central-memory T-cell phenotypes. Therapeutic efficacy was further amplified by Galectin-9 blockade and conferred durable protection upon tumor rechallenge. Importantly, to assess clinical relevance, we extended this approach to a Capan-2-derived peritoneal metastasis model, in which SLC25A51-armored CAR T cells achieved robust control of disseminated tumor burden and prolonged survival. This study establishes SLC25A51 mRNA-LNP engineering as a practical and modular strategy to enhance mitochondrial fitness and restore T-cell antitumor activity.
    Keywords:  SLC25A51; T cell therapy; mRNA-LNP; mitochondria; pancreatic cancer
    DOI:  https://doi.org/10.1021/acsami.6c08070
  25. J Nanobiotechnology. 2026 Jun 04.
    Enhancing antitumor immunity in triple-negative breast cancer through reversal of T-cell exhaustion using a CD8-targeted and membrane-camouflaged nanocarrier delivering small interfering RNA against sorting Nexin 9.
    Wei Hu, Qishuai Chen, Yan Ma, Yang Liu, Shusheng Qiu, Xianing Dong, Zengjun Zhu, Xuanxuan Wu, Jianxin Du, Yanbin Xu, Maojin Tian, Peiqing Zhao.
      T cell exhaustion (Tex) severely limits the efficacy of tumor immunotherapy, yet strategies targeting its upstream regulatory mechanisms remain underexplored. In this study, a targeted nanodelivery system, CD8a-RM-MOF@siSNX9, was developed to preferentially enrich siRNA delivery in CD8+ T cells and evaluate its potential to reverse Tex in triple-negative breast cancer (TNBC). Using a 4T1-induced TNBC mouse model combined with RNA sequencing analysis, SNX9 was identified as a key regulator associated with Tex. Silencing SNX9 was accompanied by reduced NFATc2-NR4A1-TOX signaling, decreased exhaustion phenotypes, and enhanced cytokine secretion and cytotoxic activity of CD8+ T cells. The nanoplatform exhibited prolonged circulation in vivo (t₁/₂ ≈ 12.4 h) and efficient tumor-targeted accumulation (~ 8.5%ID/g). Importantly, the nanoparticles preferentially accumulated in CD8+ T cells within the tumor microenvironment, leading to SNX9 knockdown, attenuation of the NFATc2-NR4A1-TOX regulatory program, reversal of Tex, and significant suppression of TNBC tumor growth while maintaining favorable biosafety. Collectively, these findings demonstrate that CD8a-RM-MOF@siSNX9 represents a promising targeted siRNA delivery platform with preferential CD8+ T-cell enrichment for targeting Tex and enhancing antitumor immunity in TNBC.
    Keywords:  Metal–organic framework nanocarrier; Red blood cell membrane camouflage; Sorting Nexin 9; T-cell exhaustion; Triple-negative breast cancer; siRNA delivery
    DOI:  https://doi.org/10.1186/s12951-026-04623-8
  26. Cell Rep. 2026 Jun 04. pii: S2211-1247(26)00501-2. [Epub ahead of print]45(6): 117423
    Aging restricts maturation of CXCL13+ T follicular helper cells in human immunity.
    Nathan A Bracey, Casey Beppler, Tatjana Bilich, Adrienne H Long, Elsa Sola, Aviv Barak, Timothy J Few-Cooper, Azam Mohsin, Vishnu Shankar, Vamsee Mallajosyula, Lilit Kamalyan, Robson Capasso, Shai S Shen-Orr, Mark M Davis.
      A decline in specific antibody responses is a hallmark of human aging, yet the differential contributions of B and T lymphocytes remain unclear. CXCL13 is a chemokine that shapes germinal center (GC) organization, but the regulation of human-specific CXCL13+ T follicular helper (Tfh) cells during aging is not known. Using human tonsil organoids, single-cell RNA sequencing, and CRISPR perturbations, we mapped age-associated changes in Tfh cells, the cell type that provides help to B cells in GCs. Tonsil organoids from older donors generate weaker influenza-specific antibody responses, which we trace to Tfh cell defects rather than B cells. Single-cell profiling revealed a selective loss of mature CXCL13+ GC-Tfh cells accompanied by accumulation of precursor states. Trajectory analysis shows that aging arrests Tfh maturation at the early activated precursor transition, and CRISPR perturbations identify BACH2 and SOX4 as regulators of differentiation reduced with age. These findings reveal a human-specific mechanism of immune aging with implications for strategies to restore humoral immunity.
    Keywords:  CP: immunology; CXCL13; Tfh cells; aging; gene regulation; human immunology; maturation
    DOI:  https://doi.org/10.1016/j.celrep.2026.117423
  27. Adv Healthc Mater. 2026 Jun 01. e71316
    Lactate-Depleting Engineered Probiotics Remodel the Tumor Microenvironment and Enhance PD-1 Blockade.
    Jing Zhang, Qiushuang Zhang, Yuhan Liu, Yicong Dai, Xucong Teng, Jinghong Li.
      High lactate concentrations in the tumor microenvironment (TME) suppress antitumoral immunity. Although modulating intratumoral lactate is a promising strategy, tumor-targeted interventions remain limited. Here, we developed an engineered probiotic, Lac-EcN, capable of targeted lactate consumption within the TME. Lac-EcN reduces intratumoral lactate levels by over 60% and alleviates tumor acidosis, accompanied by reversal of aberrant NFAT1 nuclear translocation in Tregs and restoration of effector molecule production by cytotoxic T cells. In B16-F10 melanoma and MC-38 colorectal carcinoma models, Lac-EcN combined with anti-PD-1 improves tumor inhibition and extends survival. These results position engineered probiotics as a platform for targeted metabolic intervention in the TME, integrating metabolic reprogramming with immune checkpoint blockade.
    Keywords:  cancer immunotherapy; engineered probiotics; lactate metabolism, PD‐1 blockade; tumor microenvironment
    DOI:  https://doi.org/10.1002/adhm.71316
  28. bioRxiv. 2026 May 26. pii: 2026.05.25.727628. [Epub ahead of print]
    ATR kinase inhibitors induce mitochondrial fission in CD8 + T cells and impair immune memory in vivo.
    Frank P Vendetti, Carina R Sclafani, Yunqi Zhang, Pinakin Pandya, Yvonne M Mowery, Su Hyeong Kim, Rachel L Cumberland, Satishkumar R Ganakammal, Thomas P Conrads, Michael J Calderon, Simon C Watkins, Bennett Van Houten, Ava Clump, Robert L Ferris, Jan H Beumer, Greg M Delgoffe, Lawrence P Kane, Christopher J Bakkenist.
      The DNA damage response kinase ATR restrains CDK1 activity during S and G2 phases of the cell cycle, confining CDK1-driven processes to mitosis. ATR kinase inhibitors were originally developed to potentiate chemotherapy-induced DNA damage at stalled replication forks and to disrupt DNA damage-induced cell cycle checkpoints. Recent evidence, however, reveals that these inhibitors also disrupt cell cycle organization in cells that have not sustained any DNA damage. We show that ATR kinase inhibitors potently trigger unscheduled mitochondrial fission, causing loss of mitochondrial mass in actively dividing CD8 + T cells that persists in memory CD8 + T cells. Moreover, ATR inhibition during the peak of CD8 + T cell expansion in a mouse model of LCMV Armstrong infection impairs the formation of immune memory. These findings carry significant clinical implications. ATR kinase inhibitors are currently being evaluated in clinical trials in combination with chemotherapy, radiation, and immune checkpoint inhibitors in patients where anti-tumor immune responses are recognized as a determinant of durable response. Our results identify an unexpected consequence of ATR inhibition that disrupts cellular metabolism with broad implications for both preclinical research and clinical application.
    DOI:  https://doi.org/10.64898/2026.05.25.727628
  29. Expert Opin Investig Drugs. 2026 Jun 03. 1-8
    SOT201: cis-acting PD-1/IL-15 mutein-based immunocytokine under investigational study in solid tumors.
    Vladyslav Mazhara, Irfan Baki Kilic, Irena Adkins, Radek Spisek, Marek Kovar.
       INTRODUCTION: The systemic administration of cytokines is constrained by their pleiotropic activity, dose-dependent toxicities, and short serum half-life, limiting their therapeutic window in cancer treatment. To overcome these challenges, strategies that restrict cytokine signaling to defined immune cell subsets within the tumor microenvironment have been developed to enhance efficacy while minimizing off-target effects. Among these, antibody-cytokine fusion proteins represent a rational design platform that enables selective and localized cytokine delivery to specific immune populations.
    AREAS COVERED: This report outlines the design principles underlying tumor-associated antigen-targeted and cis-delivered IL-2- and IL-15-based immunocytokine platforms, with particular emphasis on the PD-1-directed cis-signaling strategy. Preclinical data on SOT201 are summarized, highlighting how its affinity optimized IL-15 mutein promote selective proliferation and enhanced effector function of PD-1+ CD8+ T cells.
    EXPERT OPINION: Cis-acting immunocytokines represent a promising class of advanced therapeutics that selectively direct cytokine payload to tumor infiltrating lymphocytes. This strategy has been shown to induce durable antitumor immunity and, in some cases, promote immune memory formation while limiting systemic toxicity. Ongoing clinical evaluation and rational combination approaches will ultimately define its therapeutic positioning in precision cancer immunotherapy.
    Keywords:  IL-15; PD-1; T cell; antitumor efficacy; immunocytokine
    DOI:  https://doi.org/10.1080/13543784.2026.2683841
  30. bioRxiv. 2026 May 22. pii: 2026.05.21.726863. [Epub ahead of print]
    A community machine learning challenge to predict the effects of gene perturbations on T cell differentiation for cancer immunotherapy.
    Jiaqi Zhang, Marc A Schwartz, Mohammed Mutaher, Oluwatomisin Olajide, Yuri Pritykin, Orr Ashenberg, Nir Hacohen, Caroline Uhler.
      Perturbations of genes with functional importance in T cells could be used to change the distribution of CD8 T cell states to enhance anti-tumor functions for cancer immunotherapies. We launched a world-wide computational challenge to predict the effects of gene perturbations and to devise objective functions for prioritizing gene perturbations that lead to desired T-cell state distributions. We supported the challenge by generating a single-cell Perturb-seq dataset profiling the effect of knocking out 73 individual expert-defined genes in T cells transferred into a mouse melanoma model. We compared the top algorithms developed by participants, and found that performance was primarily determined by the prior data used for gene feature representation, with perturbational data derived features, proving most effective. Experimental validation of the top 61 genes nominated by the algorithms revealed that perturbation of Ndufv2 and Dimt1 reached the defined objective and biased T cell differentiation toward desired states.
    DOI:  https://doi.org/10.64898/2026.05.21.726863
  31. Signal Transduct Target Ther. 2026 Jun 01. pii: 202. [Epub ahead of print]11(1):
    Insights into the therapeutic strategies for aging and aging-associated diseases.
    Ruifang Dong, Qiming Wu, Juntao Kan, Caili Fu, Vincenzo Sorrentino, Ashley Chow, Yanan Lei, Di Wu, Zhenzhen Xu, Jun Du, Dejian Huang.
      Aging is a complex biological process characterized by progressive functional decline, driving the incidence of age-related diseases such as neurodegeneration, metabolic disorders, and cardiovascular diseases. Therapeutic strategies targeting aging hallmarks can delay aging and mitigate disease risk. Emerging interventions focus on modulating core aging mechanisms, including cellular senescence, metabolic dysfunction, epigenetic alterations, and mitochondrial impairment, etc. Recent advances have focused on three strategies: senolytics (eliminating senescent cells, e.g., dasatinib + quercetin), senomorphics (inhibiting the senescence-associated secretory phenotype, e.g., rapamycin), and senoreversion (rejuvenating senescent cells via epigenetic reprogramming). Additionally, metabolic interventions such as caloric restriction mimetics (e.g., spermidine, α-ketoglutarate, ergothioneine) enhance mitochondrial function, activate autophagy, and reprogram energy metabolism, demonstrating lifespan extension and healthspan improvement in preclinical models. Collectively, these approaches hold promise for delaying aging and alleviating age-related pathologies, facilitating the transition to precision longevity medicine. Concurrently, artificial intelligence (AI) accelerates discovery by integrating multiomics data, predicting candidate compounds, identifying biomarkers, and enabling personalized interventions. Despite advancements, challenges remain in target specificity, off-target effects, and clinical translation. The convergence of AI, multitarget strategies, and precision medicine signals a transformative era in extending healthspan and combating aging-associated diseases. This review systematically summarizes current breakthroughs, clinical landscapes, and future directions in aging therapeutics, underscoring interdisciplinary strategies to redefine healthy aging.
    DOI:  https://doi.org/10.1038/s41392-026-02662-z
  32. Nat Commun. 2026 Jun 06.
    ArchVelo: archetypal velocity modeling for single-cell multi-omic trajectories.
    Maria Avdeeva, Sarah K Walker, Joris van der Veeken, Alexander Y Rudensky, Yuri Pritykin.
      Inferring cellular dynamics from static single-cell data remains a central challenge in genomics. We introduce ArchVelo, a computational framework for modeling gene regulation and inferring trajectories from paired single-cell chromatin accessibility (scATAC-seq) and transcriptomic (scRNA-seq) data. ArchVelo represents chromatin accessibility as archetypes-shared regulatory programs-to model their dynamic influence on transcription. It outperforms existing methods in trajectory inference accuracy and gene-level latent time alignment, enables trajectory decomposition into archetypal components, and identifies the underlying transcription factors. After benchmarking on mouse brain and human hematopoiesis datasets, we apply ArchVelo to CD8 T cells in viral infection and reveal distinct trajectories of differentiation and proliferation. Focusing on progenitor exhausted CD8 T cells, critical for sustained immunity and immunotherapy response, we identify differentiation from Ccr6- to Ccr6+ progenitors, shared between acute and chronic infections. ArchVelo provides a principled framework for modeling dynamic gene regulation and trajectory inference in multi-omic single-cell data across biological systems.
    DOI:  https://doi.org/10.1038/s41467-026-74000-4
  33. bioRxiv. 2026 May 18. pii: 2026.05.14.725149. [Epub ahead of print]
    BLOC1S1 regulates autolysosomal and exosomal dynamics during CD4⁺ T cell differentiation.
    Rahul Sharma, Zulfeqhar A Syed, Sandeep K Vishwakarma, Kaiyuan Wu, Kim Han, Anand K Gupta, Christian A Combs, Michael N Sack.
      Although the endolysosome system is central to intracellular recycling, signal transduction, and intercellular communication via exocytosis, its role in immunoregulation remains incompletely defined. We recently identified that CD4+ T cell-specific depletion of BLOC1S1, a component of multiprotein complexes regulating endolysosomal biology, predisposes toward type 2 (Th2) immunity. We therefore hypothesized that the study of BLOC1S1-deficient CD4+ T cells would expand our understanding of endolysosomal dynamics in Th2 function. Here, we demonstrate that CD4+ T cell BLOC1S1 deficiency resulted in aberrant lysosomal distribution, accumulation of endosomal vesicles, and increased exocytosis, which collectively correlated with enhanced Th2 immune responses. The phenotype was associated with upregulation of key components of the exocytosis machinery, including RAB11 and VAMP7. Functional inhibition of these vesicle trafficking proteins following siRNA knockdown of RAB11 and VAMP7 significantly attenuated Th2 cytokine secretion in BLOC1S1-deficient CD4+ T cells, highlighting their essential role in exosome-mediated cytokine export. Furthermore, exosomes derived from BLOC1S1-deficient CD4+ T cells promoted Th2 polarization in recipient cells, indicating a mechanism of intracellular amplification. Together, these findings identify BLOC1S1 as a critical regulator of lysosomal dynamics and exocytic vesicle fusion, thereby linking intracellular trafficking mechanisms to Th2 immune regulation.
    DOI:  https://doi.org/10.64898/2026.05.14.725149
  34. Oncol Rep. 2026 Aug;pii: 142. [Epub ahead of print]56(2):
    Targeting colorectal cancer and T‑cell metabolism for the treatment of colorectal cancer (Review).
    Qiangzong Yu, Pengbo Luan, Jingru Liang, Lixin Wang.
      Colorectal cancer (CRC) is a malignant tumor of the digestive tract that is highly prevalent worldwide, which is associated with a poor prognosis in advanced stages and for which current treatment plans have limited efficacy. T cells serve a crucial role in immune clearance and immune evasion within the tumor microenvironment. However, tumor cells directly impair the function of T cells through nutrient competition and the release of inhibitory metabolites. Notably, targeting 'metabolic checkpoints' has emerged as a crucial strategy to enhance T‑cell efficacy. The present literature review summarizes the role of reprogramming glycolysis, glutaminolysis and lipid metabolism in driving immune evasion in CRC, and discusses potential intervention strategies from two perspectives: Modulating tumor metabolism and optimizing the intrinsic metabolic functions of T cells. Finally, it is proposed that stratified precision therapy based on individual metabolic profiles represents a future direction for overcoming immune heterogeneity and drug resistance in CRC.
    Keywords:  T cell; colorectal cancer; metabolic checkpoints; metabolic reprogramming; tumor microenvironment
    DOI:  https://doi.org/10.3892/or.2026.9147
  35. Curr Nutr Rep. 2026 Jun 03. pii: 53. [Epub ahead of print]15(1):
    Targeted Supplementation and Nutritional Strategies for Healthy Aging: A Review of Physiological and Molecular Benefits.
    Jennifer A Kurtz, K Michelle Singleton, Ecaterina Vasenina, Ralf Jäger, Drew Gonzalez, Antonella Schwarz, Jonathan Howard, Jose Antonio.
       PURPOSE OF REVIEW: Aging is marked by progressive physiological decline driven by chronic inflammation, mitochondrial dysfunction, and impaired metabolic and musculoskeletal resilience. As the global population ages, dietary supplements have gained attention as potential tools to support healthy longevity. This review summarizes current evidence on nutritional compounds that target aging-related pathways, focusing on interventions that influence mitochondrial health, cognitive performance, immune function, metabolic regulation, and maintenance of muscle mass in older adults. Thirty-two human studies were identified through PubMed, Scopus, and Web of Science.
    RECENT FINDINGS: Evidence indicates that several targeted nutrients, including protein, probiotics, antioxidants, and emerging mitochondrial-support compounds, may contribute to healthy aging. Protein and collagen supplementation, particularly when paired with resistance training, consistently improve muscle mass and physical function. Antioxidants, glycine, N-acetylcysteine, and NAD⁺ precursors show potential benefits for mitochondrial efficiency, cellular stress responses, and cognitive performance; however, findings vary across populations and dosing strategies. Heterogeneity in study designs, supplement formulations, and biomarker endpoints underscores the need for individualized and context-specific application. A personalized, evidence-informed supplementation strategy integrated with exercise and balanced nutrition may help optimize physiological function in aging adults. Future research should refine dosing protocols, evaluate synergistic nutrient combinations, and clarify the roles of antioxidants and mitochondrial-targeted compounds across diverse older populations.
    Keywords:  Dietary supplementation; Healthy aging; Inflammation and oxidative stress; Longevity strategies; Mitochondrial function; Musculoskeletal and cognitive health
    DOI:  https://doi.org/10.1007/s13668-026-00776-y
  36. Annu Rev Nutr. 2026 Jun 02.
    Mechanisms of NAD+ Homeostasis in Aging and Disease.
    Melanie R McReynolds.
      Aging is the greatest risk factor for many of society's most prevalent diseases, including diabetes, cancer, cardiovascular disease, and neurodegenerative disorders. A common thread underlying these conditions is the disruption of cellular and metabolic homeostasis. All hallmarks of aging converge on mechanisms that disrupt how cells communicate, interact, and coordinate their functions. Emerging studies have implicated diminished NAD+ levels as a contributor to several hallmarks of aging, underscoring their regulatory role in age-dependent decline. While it remains unclear whether aging drives metabolic decline or if metabolic dysregulation accelerates aging-or both-a growing body of evidence suggests that NAD+ metabolism may be a key link between disrupted communication and metabolic dysfunction. This review integrates current insights into how NAD+ metabolism and signaling influence cellular and organismal aging, emphasizing the nutritional factors that modulate these processes. Together, these perspectives position NAD+ as a unifying framework linking nutrition, metabolic resilience, and the mechanisms of healthy aging and disease.
    DOI:  https://doi.org/10.1146/annurev-nutr-112525-013335
  37. bioRxiv. 2026 May 22. pii: 2026.05.20.726656. [Epub ahead of print]
    Mitochondrial copper stabilizes lipoylated TCA cycle proteins to sustain metabolism and proliferation.
    Santanu Ghosh, Andrew F Jarvis, Jordi C J Hintzen, Nate R McKnight, Pedro Costa-Pinheiro, Noelle H Noughton, Yumi Kim, Alison Jaccard, Scot C Leary, Paul A Cobine, Caroline R Bartman, Gina M DeNicola, Nathaniel W Snyder, Kathryn E Wellen, George M Burslem, Donita C Brady.
      Copper (Cu) is an essential cofactor for mitochondrial cytochrome c oxidase, yet whether it directly regulates mitochondrial metabolism beyond respiration remains unclear. Here we show that mitochondrial Cu, delivered by SLC25A3, is required to maintain the stability of lipoylated TCA cycle proteins. Loss of Slc25a3 or pharmacological Cu depletion selectively destabilized the lipoylated E2 subunits of mitochondrial dehydrogenases and the lipoylation enzymes LIPT1 and LIPT2, an effect not reproduced by acute electron transport chain inhibition. Mechanistically, we find that Cu directly engages the reduced lipoyl moiety using chemical probes and synthetic peptide approaches. Cu depletion impaired PDH and OGDH activity, rewired TCA cycle metabolism, and imposed a dependence on pyruvate carboxylase for anaplerosis. This metabolic defect depleted aspartate, suppressed mTORC1 signaling, and limited proliferation. Conversely, selective delivery of Cu to the mitochondria restored lipoylation, TCA cycle function, and cell growth. Together, these findings identify mitochondrial Cu as a structural regulator of the lipoylation machinery and reveal a direct link between Cu homeostasis and central carbon metabolism.
    DOI:  https://doi.org/10.64898/2026.05.20.726656
  38. Front Immunol. 2026 ;17 1722647
    Peroxisomal ABCD1 deficiency in mice drives Th1 bias through 25-HC-LXR signaling in CD4+ T cells.
    Reina Maeda, Mayu Oishi, Ryutaro Nagamori, Mari Hikosaka-Kuniishi, Shiro Watanabe, Jung-Bum Lee, Masashi Morita, Takanori So.
      X-linked adrenoleukodystrophy (X-ALD) is driven by ABCD1 dysfunction, causing very-long-chain fatty acid (VLCFA) accumulation and cerebral inflammation, yet the role of T cells in X-ALD remains unclear. Here, we show that Abcd1-deficient CD4+ T cells exhibit a strong Th1 bias, producing more IFN-γ and less IL-10 under antigen-specific immunization in vivo and Th1-polarizing conditions in vitro. Transcriptional profiling revealed early induction of Ifng and Tbx21 (T-bet) and late repression of Prdm1 (Blimp-1), indicating Blimp-1-dependent derepression of IFN-γ and reduced IL-10. Mechanistically, liver X receptor (LXR) signaling was markedly amplified, evidenced by upregulation of Abca1, Srebf1, and the oxysterol 25-hydroxycholesterol (25-HC), driven by increased Ch25h. Pharmacological modulation validated this axis: the LXR antagonist SR9238 restored Blimp-1 and IL-10 while reducing IFN-γ, whereas the LXR agonist T0901317 and exogenous 25-HC recapitulated the Abcd1-deficient phenotype. Thus, 25-HC-LXR signaling suppresses Blimp-1, enforcing Th1 polarization in Abcd1-deficient CD4+ T cells. These findings define an immunometabolic link between peroxisomal lipid metabolism and T cell differentiation and highlight the 25-HC-LXR-Blimp-1 axis as a mechanistic link regulating CD4+ T-cell polarization, with potential relevance to X-ALD-associated neuroinflammation.
    Keywords:  25-hydroxycholesterol; ABCD1; Blimp-1; CD4+ T cell; LXR; X-linked adrenoleukodystrophy; peroxisome
    DOI:  https://doi.org/10.3389/fimmu.2026.1722647
  39. Front Immunol. 2026 ;17 1791993
    Aberrant IL-21/STAT3 signaling disrupts regulatory T cell function and CD4+ T cell homeostasis in children with type 1 diabetes.
    Xiaofeng Sun, Jiou Zhao, Jin Liu, Wendi Zhou.
       Background: Type 1 diabetes (T1D) is an autoimmune disease characterized by profound dysregulation of CD4+ T cell subsets, particularly impaired regulatory T cell (Treg) function accompanied by excessive Th17 and T follicular helper (Tfh) cell responses. Interleukin-21 (IL-21) has been implicated in T cell-mediated autoimmunity; however, the immunoregulatory mechanisms linking IL-21 signaling to T cell imbalance in pediatric T1D remain incompletely understood.
    Methods: Single-cell RNA sequencing data from children with T1D were analyzed to characterize IL-21/STAT3 pathway activity across immune cell subsets. Functional assays were performed using primary human CD4+ T cells and Tregs treated with IL-21 and the STAT3 inhibitor Stattic. T cell differentiation, suppressive function, cytokine production, and STAT3 activation were assessed in vitro. The immunological and pathological effects of STAT3 inhibition were further evaluated in a non-obese diabetic (NOD) mouse model.
    Results: Single-cell transcriptomic analysis revealed enhanced IL-21/STAT3 signaling activity in CD4+ T cell populations from children with T1D. IL-21 stimulation induced STAT3 phosphorylation and nuclear translocation, leading to reduced FoxP3 expression, impaired Treg-associated suppressive function, and a shift in CD4+ T cell differentiation toward Th17 and Tfh phenotypes. Pharmacological inhibition of STAT3 effectively reversed IL-21-mediated Treg dysfunction and restored CD4+ T cell balance in vitro. In NOD mice, STAT3 inhibition ameliorated hyperglycemia, reduced pancreatic inflammation, preserved insulin-positive islets, and corrected systemic T cell subset imbalance.
    Conclusion: Aberrant activation of the IL-21/STAT3 signaling axis may contribute to impaired Treg function and CD4+ T cell imbalance in pediatric T1D. These findings suggest that IL-21-STAT3-dependent immune dysregulation represents an important mechanism involved in T cell imbalance and autoimmune pathology in T1D.
    Keywords:  CD4+ T cells; IL-21/STAT3 signaling; T cell homeostasis; autoimmune immunity; regulatory T cells; type 1 diabetes
    DOI:  https://doi.org/10.3389/fimmu.2026.1791993
  40. Cancer Lett. 2026 May 30. pii: S0304-3835(26)00388-5. [Epub ahead of print]655 218625
    Exosomal circFXR1 drives immune evasion and tumor progression through dual regulation of PD-L1 and mTOR signaling in gastric cancer.
    Hongwu Chu, Xin Liu, Xiaomei Zhuang, Fulin Wang, Ian M Evans, Yuntao Shi, Chen Wang, Junkui Guo, Huafu Li, Zhijun Zhou, Cuncan Deng, Changhua Zhang.
      Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide, largely due to aggressive tumor behavior, immune evasion, and limited responsiveness to immunotherapy. Circular RNAs (circRNAs) have emerged as important regulators of cancer progression; however, the roles of exosomal circRNAs in tumor-immune communication in GC remain poorly understood. Here, circRNA profiling of exosomes derived from GC tissues and matched adjacent normal tissues identified circFXR1 as an upregulated circRNA associated with poor survival and adverse clinicopathological features. Functional analyses using GC cell lines, patient-derived organoid, and multiple mouse models demonstrated that circFXR1 promotes tumor proliferation, migration, and growth both in vitro and in vivo. Mechanistically, circFXR1 interacts with miR-497-5p, thereby upregulating PD-L1 expression, which in turn impairs CD8+ T cell-mediated cytotoxicity. In parallel, circFXR1 activates tumor-intrinsic mTOR signaling in a miR-497-5p-dependent manner, further enhancing malignant phenotypes. Importantly, circFXR1 is enriched in tumor-derived exosomes and transferred to recipient tumor cells and CD8+ T cells, resulting in increased PD-L1 expression, impaired T cell effector function, and enhanced tumor progression. Clinically, circFXR1 expression was elevated in non-responders compared with responders to anti-PD-1 therapy. Consistently, in an NSG xenograft model with adoptive transfer of human CD8+ T cells, circFXR1 overexpression attenuated the therapeutic efficacy of anti-PD-1 treatment. Collectively, these findings identify exosomal circFXR1 as a regulator linking tumor-intrinsic signaling and CD8+ T cell-associated immune evasion in GC. CircFXR1 may be associated with anti-PD-1 treatment response in GC, although further validation in molecularly stratified, multi-center cohorts is required.
    Keywords:  Exosomes; Gastric cancer; PD-L1; circFXR1; mTOR signaling
    DOI:  https://doi.org/10.1016/j.canlet.2026.218625
  41. Front Immunol. 2026 ;17 1807053
    miR-142-5p promotes TSCM differentiation and suppresses progressive T-cell maturation via targeting PRKCB.
    Hongqiong Wang, Shengfang Xia, Jia Chen, Huishan Zhong, Xianpei Zeng, Zitao Lu, Wenfeng Zhang, Fenglin Wu.
       Introduction: Adoptive cellular immunotherapy (ACT) such as CAR‑T therapy holds promise for cancer treatment. However, genetically engineered T cells often undergo terminal differentiation during ex vivo expansion, which limits their persistence and antitumor efficacy in vivo. Early‑differentiated T‑cell subsets exhibit better survival and proliferative capacity after infusion. In our previous work, we isolated four T‑cell subsets at different differentiation stages: naïve T cells (TN), stem cell‑like memory T cells (TSCM), central memory T cells (TCM), and effector memory T cells (TEM), and obtained their miRNA expression profiles via high‑throughput sequencing. In the present study, we found that hsa‑miR‑142‑5p is highly expressed in TSCM cells and gradually decreases during T‑cell differentiation.
    Methods: Bioinformatics analysis suggested that miR‑142‑5p target genes are involved in transcription regulation. We identified four candidate targets through reverse enrichment analysis. Dual‑luciferase reporter assays were used to validate direct targets. Functional studies were then performed in T cells overexpressing miR‑142‑5p to assess expression of differentiation‑associated and effector‑related genes, surface markers (CCR7, CD62L, CD95), cell subset proportions (TN, TSCM, TEM/TEFF), proliferation, apoptosis, and cytokine secretion (TNF‑α, IFN‑γ).
    Results: Dual‑luciferase reporter assays confirmed PRKCB as a direct target of miR‑142‑5p, and miR‑142‑5p suppressed PRKCB expression in T cells. miR‑142‑5p overexpression upregulated early differentiation‑associated genes (LEF1, CD62L, CCR7) and the anti‑apoptotic gene BCL2, while downregulating late differentiation‑associated genes (KLRG1, EOMES, PDCD1) and effector function‑related genes (GZMB, PRF1). Consistently, it enhanced early differentiation markers (CCR7, CD62L) and reduced the late marker CD95. It also increased TN and TSCM proportions while decreasing TEM/TEFF cells. Additionally, miR‑142‑5p promoted T‑cell proliferation, reduced apoptosis, and suppressed TNF‑α and IFN‑γ secretion.
    Discussion: In summary, miR‑142‑5p inhibits progressive T‑cell differentiation by directly targeting PRKCB, helping maintain an early‑differentiated phenotype. This offers a potential strategy to improve the persistence and efficacy of adoptive T‑cell‑based immunotherapies.
    Keywords:  PRKCB; T cells; immunotherapies; miR-142-5p; progressive differentiation
    DOI:  https://doi.org/10.3389/fimmu.2026.1807053
  42. Cancer Med. 2026 Jun;15(6): e71978
    Bone Marrow Failure Model Mimics Aplastic Anemia Patients: Single-Cell Landscape of Immune Response Reveals Novel Mechanisms of Immune Imbalance in AA.
    Shuai Tan, Fang Fang, Jing Sun, Yumeng Li, Yaochi Chen, Wanling Sun.
       BACKGROUND: The pathogenesis of HSPCs impairment in aplastic anemia (AA) remains unclear. We focused on CD8+ T cells and investigated platelets, CD4+ T cells, macrophages, and mitochondrial energy metabolism, aiming to elucidate the cellular atlas changes associated with bone marrow failure (BMF).
    METHODS: We have successfully established a mouse model of bone marrow failure and analyzed the immune response at the single-cell level.
    RESULTS: Platelets regulate CD4+/CD8+ T cells and macrophages by releasing PF4. CXCR3/CXCR5 bind to PF4, activating mitochondrial signaling pathways. The decrease of Treg weakens immunosuppression. Additionally, there is a significant increase in CD8+ effector T cells. Increased energy metabolism was observed in CD8+ stress T cells. It should be noted that platelet reduction itself in AA weakens energy metabolism, subsequently impairing the hemostatic and thrombotic functions. However, platelets' regulatory function in immune cells remains significant. An imbalance in M1 and M2 macrophage polarization is observed. While a phenotype macrophage and CD8+ naive T cells are important cell phenotypes in marrow aging, they do not contribute to pathology failure.
    CONCLUSION: The possible mechanisms of BMF in AA: based on PF4, platelet-T cell/macrophage crosstalk leads to immune overactivation and the release of cytokines such as IFN-γ and TNF-α, which attack the marrow. Therefore, transforming imbalanced CD8+ effector T cells, stress T cells, Treg cells, and M1/M2 macrophages into CD8+ naive T cells and a phenotype of macrophages via inhibiting platelet immune regulatory function may provide a promising strategy to reverse BMF.
    Keywords:  aplastic anemia; bone marrow failure; immune cells; platelet; single‐cell sequencing
    DOI:  https://doi.org/10.1002/cam4.71978
  43. Sci Adv. 2026 Jun 05. 12(23): eaef5331
    Engagement of the TCR against an oncolytic virus generates a population of effector CAR T cells with potent antitumor activity.
    Olivia Liseth, Elizabeth Appleton, Benjamin Kendall, Jill Thompson, Thanich Sangsuwannukul, Jason Tonne, Rosa Maria Diaz, Laura Evgin, Anton Patrikeev, Nicolas Sarbia, Shane Foo, Kevin Harrington, Masahiro Ono, Alan Melcher, Richard Vile.
      Chimeric antigen receptor (CAR) T cell therapy faces many challenges against solid tumors including T cell exhaustion and poor CAR durability. Here, we show that engaging the CAR T cell endogenous T cell receptor (TCR) using an oncolytic virus enhances CAR T cell functionality, durability, and therapy. Upon combination therapy of solid tumors with CAR T cells and vesicular stomatitis virus (VSV), a subpopulation of antiviral, TCR-primed CAR T cells was generated with enhanced effector functions, altered activation states, and differential gene and protein expression when compared to non-TCR-primed CAR T cells. Single-cell RNA sequencing showed clonal expansion of anti-VSV CAR T cells and enhancement of effector-associated genes with VSV-mediated CAR T cell expansion. CD4 T cells played a pivotal role in the development of these TCR-primed CAR T cells. These results provide a strong rationale both for a novel use of systemic oncolytic virotherapy and for directly exploiting the CAR T cell TCR to fine tune the CAR T cell phenotype and function.
    DOI:  https://doi.org/10.1126/sciadv.aef5331
  44. J Biol Chem. 2026 Jun 04. pii: S0021-9258(26)02108-3. [Epub ahead of print] 113236
    Oleoylethanolamide Enhances Regulatory T Cell Function to Accelerate Plaque Regression in Atherosclerosis via PPARα Activation.
    Tong Ren, Yanchao Jiao, Le Zhang, Yijun Liu, Xilin Jiang, Lu Peng, Changsheng Yan, Jianbo Jia, Xin Jin.
      Regulatory T cells (Tregs) are essential for maintaining immune balance and limiting inflammatory damage within atherosclerotic plaques. Although the endogenous lipid mediator oleoylethanolamide (OEA) has reported anti-inflammatory and metabolic benefits, its effects on Treg differentiation and function during atherosclerosis are incompletely defined. Here, we tested OEA using in vitro naïve CD4+ T-cell polarization assays and in vivo atherosclerosis models. OEA increased CD25+Foxp3+ Treg differentiation in polarization cultures and shifted the Treg compartment in atherosclerotic mice toward a more functional phenotype. PPARα dependence was supported by pharmacologic inhibition with MK886 and by genetic loss of PPARα, both of which abrogated OEA-induced Treg differentiation and functional enhancement. Mechanistically, OEA engaged a PPARα-RORγt pathway consistent with suppression of RORγt-associated programs during Treg differentiation. In therapeutic studies, adoptive transfer of OEA-conditioned Tregs promoted regression of established atherosclerotic plaques. Together, these data identify OEA as a modulator of Treg differentiation and activity and support its potential as a PPARα-dependent strategy to promote plaque regression and immune homeostasis in atherosclerosis.
    Keywords:  OEA; PPARα; RORγt; atherosclerosis
    DOI:  https://doi.org/10.1016/j.jbc.2026.113236
  45. Inflammation. 2026 Jun 04.
    lncRNA-mRNA Co-expression Network Unveils Neutrophil Metabolic Reprogramming in Human Sepsis.
    Peng Zhang, Fupeng Wang, Kang Zhao, Zeqing Miao, Yang Yu, Aiqing Wen, Huang Wu.
      Sepsis is a life-threatening inflammatory syndrome driven by dysregulated immunity. Metabolic reprogramming and epigenetic regulation are now recognized as critical mechanisms underlying persistent immune cell alterations in sepsis. Neutrophils play a central role in sepsis by forming NETs, releasing inflammatory cytokines, and phagocytosing pathogens. During these processes, neutrophils undergo metabolic adaptation that supports their effector functions. Long non-coding RNAs (lncRNAs) have been implicated in multiple facets of sepsis progression, including the regulation of immune cell functions and organ injury. Recent studies further indicate that lncRNAs modulate metabolic reprogramming across various cell types during sepsis, highlighting extensive crosstalk between metabolic and epigenetic pathways. Nevertheless, the relationship between lncRNAs and metabolic reprogramming in neutrophils remains poorly understood. To better characterize the regulatory interplay between metabolic alterations and lncRNAs in neutrophils during sepsis, we performed RNA sequencing of neutrophils isolated from septic patients. We identified a set of hub differentially expressed genes enriched in amino acid metabolic processes and uncovered potential lncRNA networks that may regulate these genes. Our study delineates a broader landscape of neutrophil metabolic reprogramming in sepsis and provides a foundational co-expression network, offering new directions for investigating lncRNA-mediated amino acid metabolic alterations in neutrophils during sepsis.
    Keywords:  Metabolism; Neutrophil; Sepsis; lncRNAs
    DOI:  https://doi.org/10.1007/s10753-026-02532-4
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