bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2026–09–06
37 papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Decoding T cell exhaustion in the tumour microenvironment.
  2. Aging microenvironment induces CD8+ T cell exhaustion by suppressing hepatic β-hydroxybutyrylate synthesis.
  3. T cell senescence and exhaustion: molecular mechanisms and immune rejuvenation for cancer immunotherapy.
  4. Smad4 and Eomes converge on a shared transcriptional program associated with inflammatory CD8 T-cell differentiation.
  5. Uridine and pyruvate supplementation is associated with Th1 polarization during mitotoxic antibiotic therapy.
  6. Functional heterogeneity and plasticity in naïve CD8 T cells drive superior effector and memory responses.
  7. Post-Translational Modifications in Cancer-Associated CD8⁺ T-Cell Exhaustion: Mechanisms and Therapeutic Opportunities.
  8. CAR T Cell Therapy in Lung Cancer: Overcoming Tumor Microenvironment-Mediated Barriers.
  9. The Cancer Cell Metabolic Reprogramming Remodels the Tumor Microenvironment: Molecular Mechanisms and Therapeutic Strategies.
  10. HIF-1α regulates ADAM9 expression in Th17 cells during autoimmune disease.
  11. Physical Exercise in Immunotherapy.
  12. A modular γδ TCR-T platform combining KRAS pMHC targeting with re-dosable mRNA engager redirection.
  13. Single-cell transcriptomic signatures of T cells associated with rituximab responsiveness in idiopathic nephrotic syndrome.
  14. Inhibition of 3-mercaptopyruvate sulfurtransferase enhances CD8+ T-cell antitumor immunity.
  15. Priming of CD8+ T cells by peripheral dendritic cells exacerbates tau-mediated neurodegeneration.
  16. Mitochondrial Metabolic Reprogramming and Skin Immune Homeostasis: From Basic Mechanisms to Therapeutic Perspectives.
  17. Tumors steal a signal from T cells.
  18. Programmed cell death-1: from a T-cell immune checkpoint to a regulator of Natural Killer cell biology.
  19. Human CD4+ iNKT cells have highly oxidative metabolism and use glycogen reserves to sustain IFN-γ production in nutrient-limited environments.
  20. Macrophage reprogramming, not CD8 T cell dynamics, characterizes durable disease control following PD-1 blockade in smoldering myeloma.
  21. Akkermansia muciniphila and Its Bioactive Derivatives: Emerging Regulators of Healthy Aging.
  22. NAD+ precursor treatment prevents cardiomyopathy but disrupts erythroid maturation in mitochondrial progeria.
  23. Functional T Cell Responses Are Associated With Prolonged HIV Control After Treatment Interruption.
  24. Buying Time: T cells and Delayed HIV Rebound After Treatment Interruption.
  25. Editorial: Environmental toxicity in metabolism.
  26. Triple-costimulatory GD2-CAR T cells incorporating CD28, 4-1BB and CD27 mediate potent cytotoxicity and reduce exhaustion in solid tumour models.
  27. A CAR against rejection: dual-targeting allogeneic T cells.
  28. Tumor-derived antioxidants suppress immunity by depriving T cells of reactive oxygen species.
  29. Mitochondrial Complex I at the Crossroads of NK cell Dysfunction in Glioblastoma.
  30. Stress biology and metabolic ageing in older adults during prolonged crises: Ukraine as an example.
  31. Qualitative Superiority, Not Magnitude, of Lung-Resident CD8+ T Cells Determines Protective Efficacy of Influenza NP Versus PB1 Vaccines.
  32. Editorial: Chimeric antigen receptor T cell therapies and bispecific antibodies in hematologic malignancies.
  33. Targeting metabolic reprogramming in cancer: Past, present, and future.
  34. Psychological stress impairs hematopoietic stem cell function through a brain-gut-bone marrow axis.
  35. Bacillus subtilis exopolysaccharide enhances Lactobacillus johnsonii-kynurenic acid to restore intestinal T helper 17/regulatory T cell balance via aryl hydrocarbon receptor.
  36. Single-cell mapping of thymus-dependent naïve t-cell regeneration reveals CD61-associated states after hematopoietic stem cell transplantation.
  37. Cyclin E-CDK2 regulates cancer cell transcriptional program and response to immunotherapy through BRD4.
  1. Exp Mol Med. 2026 Aug;58(8): 2590-2602
    Decoding T cell exhaustion in the tumour microenvironment.
    Jin A Park, Jeyeon Im, Sung-Min Hwang.
      T cell exhaustion arises during chronic antigen stimulation and represents a major barrier to effective anti-tumour immunity. Rather than a uniform dysfunctional state, exhaustion is increasingly understood as a structured differentiation landscape that progresses from stem-like progenitor exhausted T cells to terminally exhausted T cells. Stem-like progenitor exhausted T cells retain self-renewal capacity and partial effector function, whereas terminally exhausted T cells exhibit epigenetically fixed dysfunction and limited cytokine production. Within the tumour microenvironment, persistent antigen stimulation, together with metabolic stressors such as hypoxia and nutrient deprivation, accelerates this differentiation trajectory, thereby constraining protective immunity. In this review, we conceptualize T cell exhaustion as a dynamic continuum shaped by both differentiation states and microenvironmental niches. We outline an integrative framework to define exhaustion by combining antigen experience, cellular phenotype, functional capacity, epigenetic fixation and spatial context. Viewing immunotherapies through this multidimensional framework highlights the notion that durable therapeutic responses depend on preserving stem-like progenitor exhausted T cells within supportive niches and preventing their terminal differentiation. Understanding how these cellular states are maintained or disrupted within the tumour microenvironment will provide new opportunities for designing therapies that sustain protective T cell immunity in cancer.
    DOI:  https://doi.org/10.1038/s12276-026-01809-w
  2. Cell Metab. 2026 Sep 03. pii: S1550-4131(26)00334-7. [Epub ahead of print]
    Aging microenvironment induces CD8+ T cell exhaustion by suppressing hepatic β-hydroxybutyrylate synthesis.
    Yifeng Xiao, Yanling Zhang, Zihao Zhao, Zijian Zhang, Xiaohui Zhang, Pengju Chen, Jin Gu, Haichuan Zhu, Peng Jiang, Jie Cheng.
      The metabolic mechanisms by which aging blunts CD8+ T cell antitumor and pathogen defense remain unknown. We demonstrate that the aged microenvironment induces CD8+ T cell exhaustion by reducing β-hydroxybutyrate (3HB) bioavailability. Aging represses hepatic BDH1-dependent 3HB synthesis, restricting SLC16A1-mediated 3HB uptake. Hepatic BDH1 ablation recapitulates age-associated CD8+ T cell dysfunction, compromising antiviral and antitumor immunity, whereas 3HB supplementation reverses these deficits via protein β-hydroxybutyrylation. Using a 3HB-derived chemical probe, 3Halk, together with functional screening, we identify PRKAR1B as a primary effector of 3HB signaling. PRKAR1B β-hydroxybutyrylation inhibits the transcription factor cyclic AMP (cAMP)-responsive element modulator (CREM), which activates T cell exhaustion-related gene expression. Age-associated 3HB depletion enhances CREM-dependent transcription, sustaining CD8+ T cell exhaustion. Consistently, the aged microenvironment compromises chimeric antigen receptor (CAR) T antitumor activity, which is substantially restored by 3HB treatment. Collectively, this study uncovers a hepatic metabolism-derived 3HB-CREM axis governing CD8+ T cell immunosenescence, highlighting 3HB as a viable immunorestorative strategy to improve immunotherapy outcomes in aged individuals.
    Keywords:  3HB; CD8(+) T cell exhaustion; aging; liver metabolism; β-hydroxybutyrylate
    DOI:  https://doi.org/10.1016/j.cmet.2026.08.009
  3. Signal Transduct Target Ther. 2026 Sep 03. pii: 362. [Epub ahead of print]11(1):
    T cell senescence and exhaustion: molecular mechanisms and immune rejuvenation for cancer immunotherapy.
    Lauren van den Broecke, Arne Van der Vreken, Fenja Watté, Fien Meeus, Kim De Veirman, Karine Breckpot, Elke De Bruyne, Eline Menu.
      T cell exhaustion and T cell senescence constitute distinct yet partially overlapping differentiation states that collectively constrain T cell functionality. T cell exhaustion arises under conditions of chronic antigen exposure and is characterised by a progressive, hierarchical loss of effector capacity, sustained expression of inhibitory receptors, and extensive transcriptional, epigenetic and metabolic reprogramming. By contrast, T cell senescence represents a more stable and terminal state, driven by replicative history, age-associated decline or stress-induced damage, and is defined by durable cell cycle arrest, altered differentiation, metabolic remodelling and acquisition of a pro-inflammatory secretory phenotype. In the context of cancer, dysfunctional T cells contribute to tumour progression, while also representing a major barrier to the success of T cell-based immune therapies, which strongly rely on the fitness, persistence and functional plasticity of T cells. Although substantial efforts have focused on overcoming exhaustion and optimising T cell manufacturing, senescence remains comparatively underexplored and presents unique therapeutic challenges due to its relative resistance to functional reprogramming. This review provides a comprehensive overview of T cell replenishment in homeostasis, followed by the molecular hallmarks and signalling pathways of T cell senescence and exhaustion. We discuss the current landscape of T cell-based immune therapies, including immune checkpoint blockade, T cell engagers and adoptive cell therapies, and explain how T cell dysfunction impacts their therapeutic outcomes. Finally, we highlight emerging strategies to prevent or overcome T cell dysfunction in adoptive cell therapy products.
    DOI:  https://doi.org/10.1038/s41392-026-02923-x
  4. Front Immunol. 2026 ;17 1858529
    Smad4 and Eomes converge on a shared transcriptional program associated with inflammatory CD8 T-cell differentiation.
    Karthik Chandiran, Nandu C Karingari, Srineeharika Sirigineedi, Linda S Cauley.
      The ability of CD8 T cells to mediate protective immunity while limiting immunopathology depends on critical transcription factors such as Smad4 and Eomes that regulate differentiation of activated CTLs. Disruption of transcriptional programs mediated by Eomes and Smad4 in activated CTLs has been implicated in viral infections, chronic inflammation and cancer. Smad4 and Eomes have been shown to be critical for differentiation of memory cells, particularly TRM cells. To understand the gene regulation programs mediated by Smad4 and Eomes, we have done an integrated RNAseq and ChIPseq analysis using CD8 T cells that are isolated from Smad4KO (S4KO), EomesKO, and Smad3/Smad4-DKO (S34-DKO) mice. We identified overlapping and distinct gene expression programs mediated by Smad4 and Eomes that are associated with shaping CD8 T cell identity and functional bias. They act as critical regulators of genes involved in T cell differentiation, metabolic programming and epigenetic control in CD8 T cells. Smad4 and Eomes regulate the genes involved in tissue residency and OXPHOS-linked mitochondrial bioenergetics. Finally, we showed that canonical TGF-beta signaling is active in the absence of Smad4 or Eomes and abrogated only when both Smad3 and Smad4 are deleted. Surprisingly, CD8 T cells lacking both Smad3 and Smad4 are more enriched for TRM signature genes compared to Smad4 or Eomes-deficient CD8 T cells.
    Keywords:  CD8 T cells; ChIPseq; Eomes: Eomesodermin; RNAseq; Smad3; Smad4; TGF-beta signaling
    DOI:  https://doi.org/10.3389/fimmu.2026.1858529
  5. iScience. 2026 Sep 18. 29(9): 117230
    Uridine and pyruvate supplementation is associated with Th1 polarization during mitotoxic antibiotic therapy.
    Stefania De Santis, Monica Rutigliano, Federica Simone, Letizia Larocca, Maria Laura Matrella, Martina Milella, Antonio Vavallo, Pasquale Ditonno, Nicola Marrano, Anna Mestice, Stefano Battaglia, Michele Battaglia, Antonio Moschetta, Peter Seibel, Elena Piccinin, Gaetano Villani.
      Antibiotics with off-target mitochondrial toxicity can impair host immunity, yet their impact on human adaptive immunity in vivo remains unclear. Because T cell activation and differentiation depend on mitochondrial metabolism, antibiotic-induced mitochondrial stress may alter T helper cell function. We investigated whether uridine and pyruvate (UP) supplementation modulates immune responses in patients receiving mitotoxic antibiotics. In a pilot observational study, 67 patients undergoing prophylactic antibiotic therapy received either antibiotics alone or antibiotics plus daily UP supplementation. Antibiotic exposure increased circulating growth differentiation factor-15 (GDF15), indicating mitochondrial stress, and altered T cell response. UP supplementation was associated with immune features consistent with preserved inflammatory competence, including a trend toward Th1 polarization. These findings suggest that mitotoxic antibiotics can influence human T cell programs and support the hypothesis that UP supplementation may preserve pro-inflammatory T cell responses during antibiotic therapy, representing a potential metabolic strategy to mitigate antibiotic-induced immunotoxicity.
    Keywords:  GDF15; OXPHOS; T cells; antibiotics; immunometabolism; mitochondria; pyruvate; uridine
    DOI:  https://doi.org/10.1016/j.isci.2026.117230
  6. J Exp Med. 2026 Oct 05. pii: e20252076. [Epub ahead of print]223(10):
    Functional heterogeneity and plasticity in naïve CD8 T cells drive superior effector and memory responses.
    Yamato Sajiki, Satomi Ando, Charles M Perkins, Yi-Chung Huang, Katie E Smith, Carolyn M Doerning, David A Hildeman, Koichi Araki.
      While significant progress has been made in defining subsets among antigen-experienced CD8 T cells, the heterogeneity of naïve CD8 T cells remains poorly understood. Here, we identify naïve CD8 T cell subsets with superior persistence and an enhanced capacity to generate effector and memory cells, leading to more effective protection. These functionally superior naïve CD8 T cells are marked by IL-18Rα, CD73, and CXCR3, and functionally less potent naïve CD8 T cells can convert into these superior subsets through tonic TCR signaling. Their enhanced response to infections is driven by better survival of the progeny effector cells during the T cell expansion phase. This improved survival is mediated by increased Ly6C expression on effector cells derived from these functionally superior naïve cells. Collectively, our findings reveal functional heterogeneity and plasticity among naïve CD8 T cells and uncover a mechanism by which functionally superior naïve subsets drive robust CD8 T cell responses, providing a previously unrecognized layer of immune regulation.
    DOI:  https://doi.org/10.1084/jem.20252076
  7. Int J Biol Sci. 2026 ;22(13): 7053-7081
    Post-Translational Modifications in Cancer-Associated CD8⁺ T-Cell Exhaustion: Mechanisms and Therapeutic Opportunities.
    Yongqi Lv, Qihang Shang, Yang Yu, Yahui Fu, Lijuan Liu, Changgang Sun.
      CD8⁺ T-cell exhaustion is a distinct differentiation state driven by persistent antigen stimulation, and its establishment and maintenance are major barriers to effective cancer immunotherapy. Although the transcriptional and epigenetic landscapes of exhausted CD8⁺ T cells have been extensively characterized, it remains unclear how sustained external stimulation is integrated at the level of protein function to produce stable dysfunction and altered cell fate. Post-translational modifications constitute a key regulatory layer of protein function. They form a dynamic network that links persistent antigenic stimulation and tumor microenvironmental stress to cell fate, and therefore provide a critical entry point for understanding how exhaustion is initiated and maintained. In this review, we focus on how post-translational modifications convert persistent antigen stimulation and tumor microenvironmental stress into protein-level dysregulation and ultimately lock CD8⁺ T cells into an exhausted fate. We summarize how multiple classes of post-translational modifications drive exhaustion through effects on signal transduction, protein homeostasis, metabolic stress responses, and epigenetic reprogramming. We then discuss potential intervention strategies centered on critical regulatory nodes that may preserve the plasticity of precursor exhausted CD8⁺ T cells, restrain stabilization of the terminally exhausted state in CD8⁺ T cells, and optimize rational combination therapies. Finally, we outline the translational challenges and future directions of targeting post-translational modifications, and emphasize that identifying actionable modification nodes will be important for patient stratification and combination design in cancer immunotherapy.
    Keywords:  CD8⁺ T-cell exhaustion; cancer immunotherapy; immune checkpoint blockade; post-translational modifications; tumor microenvironment
    DOI:  https://doi.org/10.7150/ijbs.138638
  8. Int J Biol Sci. 2026 ;22(13): 6985-7002
    CAR T Cell Therapy in Lung Cancer: Overcoming Tumor Microenvironment-Mediated Barriers.
    Lu Liu, Dandan Liang, Cui Wang, Jian Li, Jie Tang, Weimin Li, Xijie Yu.
      Chimeric antigen receptor (CAR) T cell therapy has achieved remarkable clinical success in hematological malignancies. However, its efficacy in solid tumors such as lung cancer remains constrained by the immunosuppressive tumor microenvironment (TME). Aberrant vascular architecture and dense stroma constitute major physical barriers that hinder CAR T cell infiltration. Additionally, an immunosuppressive cellular network, dominated by myeloid-derived suppressor cells and tumor-associated macrophages, further restricts CAR T cell expansion and function. Moreover, immune checkpoint signaling, inhibitory cytokines, dysregulated chemokine gradients, and metabolic reprogramming under hypoxia collectively create a hostile biochemical and metabolic milieu that drives CAR T cell dysfunction and exhaustion. This review systematically outlines these multifactorial barriers within the lung cancer TME and discusses emerging strategies, including combinatorial approaches, engineered CAR T designs, and microenvironment-modulating platforms, that aim to improve the therapeutic efficacy of CAR T cell therapy in lung cancer.
    Keywords:  CAR T cell therapy; immunotherapy; lung cancer; solid tumors; tumor microenvironment
    DOI:  https://doi.org/10.7150/ijbs.131261
  9. Adv Sci (Weinh). 2026 Aug 31. e77424
    The Cancer Cell Metabolic Reprogramming Remodels the Tumor Microenvironment: Molecular Mechanisms and Therapeutic Strategies.
    Guoqing Xiang, Zhicheng Zhou, Xue Jiang, Zhenguang Du, Yangyang Zhan, Xinli Liu.
      Metabolic reprogramming and immune evasion are two key mechanisms that facilitate tumor progression. Tumor cells achieve their energy requirements for rapid proliferation through metabolic reprogramming, such as glucose metabolism, lipid metabolism, and amino acid metabolism. Tumor cell metabolic reprogramming can influence immune cell function in the tumor microenvironment through various mechanisms, ultimately facilitating tumor immune escape. Targeting tumor cell metabolism and combining metabolic regulation with immunotherapy can enhance anti-tumor immune cells, inhibit the function of immunosuppressive cells, improve anti-tumor therapy, and overcome immune escape. This review elucidates the regulatory mechanisms by which glucose, lipids, amino acid metabolism, nucleotide metabolism, oxidative phosphorylation, lactate, and hypoxia modulate the proliferation, differentiation, and function of anti-tumor immune cells and immunosuppressive cells. Regulatory strategies to restore the anti-tumor function of immune cells in response to metabolic changes were discussed. These strategies are expected to improve the effect of immunotherapy and are used in combination with other treatments to provide new ideas for cancer management.
    Keywords:  cancer immune escape; cancer metabolic reprogramming; targeted therapeutic strategy; tumor microenvironment
    DOI:  https://doi.org/10.1002/advs.77424
  10. J Autoimmun. 2026 Sep 04. pii: S0896-8411(26)00099-5. [Epub ahead of print]164 103621
    HIF-1α regulates ADAM9 expression in Th17 cells during autoimmune disease.
    Kohei Karino, Seiya Oba, Rui Imai, Michihito Kono, Wenliang Pan, Maria G Tsokos, George C Tsokos.
      Hypoxia-inducible factor 1α (HIF-1α) promotes T helper 17 (Th17) differentiation, but whether it regulates ADAM9 expression in Th17 cells during autoimmune nephritis remains unclear. Hypoxia enhanced Th17 differentiation and increased ADAM9 expression in a HIF-1α-dependent manner. HIF-1α deficiency reduced ADAM9 expression and impaired Th17 differentiation in vitro. In anti-glomerular basement membrane nephritis and B6.lpr lupus-prone mice, T cell-specific HIF-1α deletion attenuated renal pathology and reduced kidney-infiltrating CD4+ and IL-17A-producing T cells. These findings identify ADAM9 as a HIF-1α-regulated target in Th17 cells that may contribute to autoimmune renal inflammation.
    Keywords:  ADAM9; Autoimmune disease; Hypoxia; Metalloproteinase; Th17
    DOI:  https://doi.org/10.1016/j.jaut.2026.103621
  11. Sports Med Open. 2026 Sep 03. pii: 130. [Epub ahead of print]12(1):
    Physical Exercise in Immunotherapy.
    Campbell M Johnston, Susan J Kim, Yiyu Zhang, Carolyn Tsung, Eric Kent, Allison May, Hongji Zhang.
       BACKGROUND: Accumulating evidence suggests that physical exercise can favorably modulate the tumor microenvironment (TME) and enhance the efficacy of cancer immunotherapies. MAIN: Exercise has been shown to modulate the immune environment to promote infiltration and function of cell types that confer anti-tumor effects. These effects counteract several mechanisms of immune evasion within the TME that limit the effectiveness of immune checkpoint blockade, particularly therapies targeting PD-1 and PD-L1. Preclinical models demonstrate that exercise not only enhances anti-tumor immune responses, but also sensitizes tumors to checkpoint inhibitors, resulting in improved tumor control. Mechanistically, these benefits appear to be mediated through enhanced cytokine signaling, metabolic reprogramming of immune cells, and alterations in chemokine gradients that facilitate immune cell trafficking.
    CONCLUSIONS: This review summarizes current insights into how exercise impacts tumor biology and immunity and discusses the emerging rationale for integrating structured physical activity into immunotherapeutic regimens. While clinical evidence remains limited, ongoing studies will be critical to determining the translational relevance of these findings across cancer types and patient populations.
    Keywords:  Cancer immunotherapy; Immune checkpoint inhibitors; Natural killer cells; Physical exercise; T cells; Tumor microenvironment; Tumor-associated macrophages
    DOI:  https://doi.org/10.1186/s40798-026-01101-1
  12. J Hematol Oncol. 2026 Jul 30. pii: 72. [Epub ahead of print]19(1):
    A modular γδ TCR-T platform combining KRAS pMHC targeting with re-dosable mRNA engager redirection.
    Ángel Ramírez-Fernández, Adham S Bear, Elahe Kamali, Robert Bartoszek, Matthew Ho, Gregory M Chen, Devin Dersh, Laura Córdoba-Espejo, Jiageng Liu, Mosha Deng, Miriam Velasco-Sidro, Ankita Jain, Julia Han Noll, Caitlin R Hopkins, Owen Koucky, Janna Minehart, Alexander J Dimitri, Erik Williams, Maya Lavorando, Alejandro Segura-Tudela, John Scholler, Julie Barber-Rotenberg, Julie K Jadlowsky, Daniel J Powell, Anne Chew, Vanessa E Gonzalez, Donald L Siegel, Bruce L Levine, Michael T Lotze, Carl H June, James L Riley, Robert H Vonderheide, Friederike Herbst, Joseph A Fraietta.
      Solid tumors often evade TCR-engineered αβ T cells when antigen expression varies or when the restricting Human Leukocyte Antigen (HLA) allele is lost. γδ T cells, in contrast, detect cellular dysregulation through non-peptide/Major Histocompatibility Complex (MHC) cues, including phosphoantigens and stress ligands, and can be developed as allogeneic therapies. Although intratumoral γδ T cell signatures are associated with improved outcome across cancers, γδ recognition itself is broad and still selected within the thymus just as αβ T cell receptors (TCRs) are. It does not, however, anchor specificity to a defined driver-mutation pMHC epitope. We therefore asked whether a high-affinity, co-receptor-independent αβ TCR could graft oncogenic-driver specificity onto γδ T cells while leaving the endogenous γδ TCR intact. We knocked the KRASG12V/HLA-A*11:01 TCR A11v into primary human γδ T cells. Engineered cells co-expressed the transgenic αβ TCR and the endogenous γδ TCR and lysed KRASG12V/HLA-A*11:01+ tumor cells in vitro and in vivo. To cover potential resistance through loss of HLA-A*11:01, we delivered an mRNA lipid nanoparticle (LNP) encoding a secreted mesothelin×CD3 (M5) bispecific T cell engager (TCE). LNP-M5 produced circulating TCE that redirected γδ A11v T cells and polyclonal bystander T cells to kill mesothelin+ targets, accompanied by development of higher γδ A11v T cell counts in vivo. In humanized mice bearing mixed HLA-A*11:01+ and HLA-A*11:01 - KRASG12V tumors, γδ A11v T cells produced transient control, whereas adding LNP-M5 yielded complete responses and prolonged survival. Thus, this two-part therapy couples invariant driver targeting to tunable redirection and addresses loss of the restricting HLA allele, a central escape route for TCR-based therapy. It provides an off-the-shelf reagent to enable KRAS-anchored treatment with the ability to redeliver the reagent.
    DOI:  https://doi.org/10.1186/s13045-026-01836-0
  13. iScience. 2026 Sep 18. 29(9): 117237
    Single-cell transcriptomic signatures of T cells associated with rituximab responsiveness in idiopathic nephrotic syndrome.
    Eri Koshi-Ito, Yu Watanabe, Chikao Onogi, Asuka Horinouchi, Koichi Ogami, Seiko Yoshino, Yohei Sugimoto, Shintaro Komatsu, Akihito Tanaka, Kazuhiro Furuhashi, Shoichi Maruyama, Hiroshi I Suzuki.
      Rituximab (RTX) is increasingly used in steroid-dependent minimal change disease, a leading cause of idiopathic nephrotic syndrome (INS), yet predictors of response remain unclear. Although RTX primarily targets B cells, T cells are also implicated in INS pathogenesis. We investigated RTX-induced T cell dynamics by single-cell RNA sequencing/T cell receptor profiling of peripheral T cells from three responders and three non-responders before and after RTX treatment. Responders exhibited RTX-driven broad transcriptomic remodeling, accompanied by reduced exhausted CD8+ T cells and clonal expansion of CD4+ cytotoxic T cells with enhanced oxidative phosphorylation (OXPHOS) signatures, whereas non-responders showed marginal changes. In a separate cohort, reactive oxygen species (ROS) levels tended to be higher in responders, and declined post-RTX, collectively associating enhanced mitochondrial activity with favorable response. Reanalysis of childhood INS data supported altered B-T cell crosstalk and T cell metabolism. Together, T cells may influence RTX responsiveness, warranting further biomarker studies.
    Keywords:  T cells; idiopathic nephrotic syndrome; oxidative phosphorylation; reactive oxygen species; rituximab; single-cell RNA sequencing
    DOI:  https://doi.org/10.1016/j.isci.2026.117237
  14. Redox Biol. 2026 Aug 28. pii: S2213-2317(26)00372-1. [Epub ahead of print]97 104373
    Inhibition of 3-mercaptopyruvate sulfurtransferase enhances CD8+ T-cell antitumor immunity.
    Muriel Urwyler, Marietta Margareta Korsos, Eloise Dupuychaffray, Nikita Markov, Kelly Ascenção, Maria Petrosino, Karim Zuhra, Darko Stojkov, Sara Barcos, Jérémie Tachet, Pragallabh Purwar, Montserrat Alvarez, Aurélien Pommier, Mohamed Z Gad, Reham M Abdel-Kader, Csaba Szabo, Carole Bourquin.
      Hydrogen sulfide (H2S) is a redox-active gasotransmitter implicated in tumor progression and immune regulation. The enzyme 3-mercaptopyruvate sulfurtransferase (3-MST) is a key contributor to endogenous H2S and polysulfide production, but its role in tumor-immune interactions remains poorly defined. Here, we show that 3-MST is the most abundantly expressed H2S-synthesizing enzyme in human renal cell carcinoma cells (RCC) and that high 3-MST expression correlates with reduced patient survival. Pharmacological inhibition of 3-MST lowered intracellular H2S levels in Renca renal carcinoma cells, suppressed proliferation, induced apoptosis, disrupted cellular metabolism, and increased expression of immune-related genes and proteins. In immune cells, partial inhibition of 3-MST promoted T cell activation, as evidenced by increased CD69 expression on CD3+, CD4+, and CD8+ T cells. In contrast, complete inhibition of 3-MST, achieved by high concentrations of the inhibitor, modestly reduced CD8+ T cell proliferation. Functionally, 3-MST inhibition potentiated antigen-specific CD8+ T cell-mediated killing of tumor cells, an effect further amplified by PD-L1 blockade. These results establish 3-MST as a redox-sensitive metabolic driver of tumor growth and immune evasion in RCC and demonstrate that its inhibition can boost antitumor immune responses, offering a potential avenue for combination immunotherapy.
    Keywords:  3-mercaptopyruvate sulfurtransferase (3-MST); Hydrogen sulfide (H(2)S); Immune checkpoint inhibition; Renal cell cancer; Tumor immunotherapy
    DOI:  https://doi.org/10.1016/j.redox.2026.104373
  15. Nat Neurosci. 2026 Sep 03.
    Priming of CD8+ T cells by peripheral dendritic cells exacerbates tau-mediated neurodegeneration.
    Hao Hu, Peter Bor-Chian Lin, Carisa Zeng, Yongyi Li, Megan E Bosch, Joshua T Emmerson, Prabal Sharma, Ray A Ohara, Wendy Dong, Tong Wu, Siling Du, Wenqing Gao, Hong Jiang, Liya Yuan, Xin Bao, Shasha Li, Anthony N Vomund, Petra Erdmann-Gilmore, Yichen Gu, Miwei Hu, Jonathan Nulman, Timothy M Miller, Wayne M Yokoyama, Cheryl F Lichti, Jeffrey Milbrandt, Richard J Perrin, Jonathan Kipnis, Maxim N Artyomov, Kenneth M Murphy, Jason D Ulrich, David M Holtzman.
      Alzheimer's disease and primary tauopathies are marked by changes in adaptive immunity, with increased brain CD8+ T cells correlating with tau pathology severity. However, how peripheral T cells get primed to enter the brain and contribute to tau-mediated neurodegeneration remains unclear. In different disease conditions, conventional type 1 dendritic cells (cDC1s) cross-present antigens to prime CD8+ T cells into effector cells. We show that tauopathy mice lacking cDC1s or antigen cross-presentation are protected from neurodegeneration, with reduced brain CD8+ T cell infiltration and glial activation. The remaining CD8+ T cells exhibit limited clonal expansion, consistent with impaired priming. We further demonstrate that brain-derived antigens are presented in secondary lymphoid tissues, suggesting a site of T cell activation. Together, these findings establish cDC1-dependent peripheral priming as a key driver of CD8+ T cell accumulation in the brain and tau-mediated neurodegeneration.
    DOI:  https://doi.org/10.1038/s41593-026-02427-5
  16. Immune Netw. 2026 Aug;26(4): e35
    Mitochondrial Metabolic Reprogramming and Skin Immune Homeostasis: From Basic Mechanisms to Therapeutic Perspectives.
    Nan Chen, Xiangping Xie, Shuangyan He, Lifen Liang.
      Mitochondria have long been viewed as the "powerhouses" of the cell, but research over the past decade has established that they play a far more complex role in skin immune homeostasis beyond ATP production. The metabolic preferences of immune cells and skin parenchymal cells-glycolysis, oxidative phosphorylation, or fatty acid oxidation-determine their fate choices during inflammatory responses. When mitochondrial function is impaired, the release of damage-associated molecular patterns (DAMPs) such as mitochondrial DNA and mitochondrial ROS can activate the cGAS-STING and NOD-like receptor family pyrin domain-containing 3 inflammasome pathways, driving inflammatory cycles in various skin diseases including psoriasis, atopic dermatitis, lupus erythematosus, and vitiligo. This review systematically examines the key mechanisms of mitochondrial metabolic reprogramming in skin immune disorders, focusing on 3 typical scenarios: the metabolic preferences of immune cells, mitochondrial DAMP-mediated autoinflammation, and the impact of mitochondrial dynamics imbalance on tissue-resident memory T cell function. Furthermore, we evaluate clinical evidence for repurposing old drugs such as metformin and thiazolidinediones, and discuss the translational prospects of emerging strategies including Nrf2 agonists, mitophagy inducers, and targeted nanocarriers. Understanding the "dual identity" of mitochondria in skin immunity-as both metabolic regulators and signaling sensors-will lay the foundation for developing precise metabolic immunomodulatory therapies.
    Keywords:  Atopic dermatitis; Metabolic reprogramming; Mitochondria; Psoriasis
    DOI:  https://doi.org/10.4110/in.2026.26.e35
  17. Science. 2026 Sep 03. 393(6815): 978-979
    Tumors steal a signal from T cells.
    Navdeep S Chandel.
      An antioxidant released by tumors dampens T cell immunity.
    DOI:  https://doi.org/10.1126/science.aek5854
  18. Front Cell Dev Biol. 2026 ;14 1924522
    Programmed cell death-1: from a T-cell immune checkpoint to a regulator of Natural Killer cell biology.
    Fabiana De Franco, Marco Greppi, Valentina Obino, Federico Rebaudi, Rayan Goda, Irene Caffa, Matteo Bozzo, Ombretta Melaiu, Enrico Munari, Valerio Gaetano Vellone, Camilla Jandus, Domenico Mavilio, Simona Candiani, Silvia Pesce, Emanuela Marcenaro.
      Programmed cell death protein 1 (PD-1, CD279) is a pivotal inhibitory immune checkpoint receptor that plays a central role in maintaining immune homeostasis and peripheral tolerance. Originally characterized as a negative regulator of T-cell activation, PD-1 limits excessive immune responses and prevents autoimmunity, while its sustained expression under conditions of chronic antigen stimulation contributes to T-cell dysfunction and exhaustion. The discovery that blockade of the PD-1 pathway can restore anti-tumor immunity has revolutionized cancer therapy and established immune checkpoint inhibition as a cornerstone of modern oncology. Although PD-1 has traditionally been viewed as a key regulator of adaptive immunity, accumulating evidence indicates that its biological functions extend beyond T cells. In recent years, PD-1 expression has been identified in several innate immune cell populations, particularly Natural Killer (NK) cells, where it has emerged as an important modulator of effector functions, cytokine production, metabolic fitness, and antitumor activity. These findings have challenged the classical view of PD-1 biology and revealed unexpected similarities between NK-cell dysfunction and the exhausted phenotype described in chronically stimulated T cells. In the tumor microenvironment, PD-1 expression on NK cells has been associated with impaired cytotoxicity and reduced immune surveillance, suggesting that NK cells may also represent relevant targets of PD-1-mediated immunosuppression. At the same time, the mechanisms regulating PD-1 expression and signaling in NK cells appear to differ, at least in part, from those operating in T lymphocytes, highlighting the complexity of this pathway across distinct immune cell subsets. In this review, we summarize the current knowledge of PD-1 biology, from its established role in T-cell regulation to its emerging functions in NK cells. We discuss the molecular mechanisms governing PD-1 expression and signaling, its contribution to immune dysfunction in cancer and chronic diseases, and the potential implications of targeting the PD-1 axis to enhance both adaptive and innate antitumor immunity.
    Keywords:  Natural Killer (NK) cells; Tumor Microenviroenment (TME); cancer immunotherapy; immune checkpoint; programmed cell death 1 (PD-1)
    DOI:  https://doi.org/10.3389/fcell.2026.1924522
  19. Front Immunol. 2026 ;17 1894113
    Human CD4+ iNKT cells have highly oxidative metabolism and use glycogen reserves to sustain IFN-γ production in nutrient-limited environments.
    Niharika M Patankar, Kelsey A Smith, Nidus Jacobsen, Nikhila S Bharadwaj, Jenny E Gumperz.
      Invariant natural killer T (iNKT) cells are promising candidates for allogeneic cellular immunotherapy, but the metabolic pathways that support their effector function in nutrient-limited tumor microenvironments remain poorly defined. Human iNKT cells segregate into CD4+ and CD4⁻CD8⁻ double-negative (DN) subsets with distinct functional profiles, yet whether they use divergent metabolic strategies to sustain IFN-γ production is unknown. Here we show that in vitro-expanded human CD4+ and DN iNKT cells employ distinct metabolic programs that differentially support IFN-γ secretion under nutrient stress. DN iNKT cells exhibit higher Glut1 expression and a more glycolytic phenotype, with IFN-γ production that is sensitive to extracellular glucose withdrawal and glycolytic inhibition. In contrast, CD4+ iNKT cells display high spare respiratory capacity, preferentially engage glutamine-supported mitochondrial respiration, and maintain IFN-γ production despite glucose deprivation or 2-DG inhibitor treatment. CD4+ iNKT cells generated excess ATP through oxidative metabolism, accumulated intracellular glycogen stores during expansion in vitro, and subsequently mobilized this glycogen to support IFN-γ production in tumor-exhausted media. Using a xenograft model of EBV-driven B cell lymphoma, we show that adoptively transferred human CD4+ iNKT cells infiltrate tumors in vivo and are associated with elevated intratumoral IFN-γ. These findings identify a distinctive combination of high mitochondrial oxidative capacity, glutamine utilization, and glycogen storage that endows human CD4+ iNKT cells with exceptional metabolic resilience, suggesting that CD4+ iNKT-based products may provide a particularly valuable platform for adoptive cellular immunotherapy.
    Keywords:  glucose independence; glycogen stores; interferon-gamma (IFN-g); invariant natural killer T (iNKT) cell; metabolic resilience; oxidative phosphorylation (OXPHOS); spare respiratory capacity (SRC)
    DOI:  https://doi.org/10.3389/fimmu.2026.1894113
  20. Leukemia. 2026 Sep 03.
    Macrophage reprogramming, not CD8 T cell dynamics, characterizes durable disease control following PD-1 blockade in smoldering myeloma.
    Noé Perron, Kane Foster, Tarek H Mouhieddine, Robert A Redd, Sophie Magidson, Jacqueline Perry, Ashlee Sturtevant, Christine Davie, Caroline Ricciardi, Frances Arters, Marjorie Marto, Amy Goguen, Yuxin Liu, Elizabeth K O'Donnell, Adam S Sperling, Jacob P Laubach, Paul G Richardson, Gad Getz, Romanos Sklavenitis-Pistofidis, Lorenzo Trippa, Yoshinobu Konishi, Omar Nadeem, Irene M Ghobrial.
      
    DOI:  https://doi.org/10.1038/s41375-026-03092-0
  21. Aging Cell. 2026 Sep;25(9): e70702
    Akkermansia muciniphila and Its Bioactive Derivatives: Emerging Regulators of Healthy Aging.
    Ting Zhang, Jinyuan Niu, Xiaoyu Hu, Zhiang Hu, Yuan Gao, Jialiang Liu, Ning Chen, Yaomin Hu.
      The global aging trend underscores the urgent need for innovative interventions against aging-related decline. Accumulating evidence identifies Akkermansia muciniphila (A. muciniphila) as a key gut microbiota regulator of aging, with its depletion associated with age-related diseases (ARDs), whereas its abundance is enriched in healthy centenarians. This review summarized current evidence linking A. muciniphila to aging, examining their causal relationship, the roles of its bioactive derivatives, underlying mechanisms in aging and ARDs, findings from human clinical trials, and challenges in therapeutic translation. Clinically, A. muciniphila depletion correlated with aging and various ARDs, while its supplementation effectively ameliorated neurodegenerative disorders, metabolic dysfunction, musculoskeletal decline, intestinal barrier dysfunction, and atherosclerosis. Mechanistically, A. muciniphila and its derivatives (Amuc_1100, Amuc_1409, extracellular vesicles, and metabolites such as SCFAs) exerted anti-aging effects by enhancing intestinal barrier function, maintaining metabolic homeostasis, suppressing chronic inflammation, and modulating immune function, ultimately improving glucolipid metabolism, insulin sensitivity, cognitive function, musculoskeletal health, and vascular health. Emerging clinical trials further demonstrated its translational potential in ameliorating age-related sarcopenia, metabolic dysfunction, and respiratory symptoms. Despite promising preclinical and clinical results, translational applications reserve challenges related to strain heterogeneity, antimicrobial resistance gene transfer risk, biosafety, production stability, and limited clinical validation in elderly populations. Future research should prioritize large-scale clinical trials to establish optimal dosage, safety, and long-term efficacy, while exploring combined microbiota-targeted therapies. Harnessing the diverse benefits of A. muciniphila may enable novel strategies for promoting healthy aging.
    Keywords:   Akkermansia muciniphila ; age‐related diseases; gut microbiota; healthy aging; microbiome therapeutics
    DOI:  https://doi.org/10.1111/acel.70702
  22. Cell Rep. 2026 Aug 29. pii: S2211-1247(26)00927-7. [Epub ahead of print]45(9): 117849
    NAD+ precursor treatment prevents cardiomyopathy but disrupts erythroid maturation in mitochondrial progeria.
    Nahid A Khan, Kati Ahlqvist, Swagat Pradhan, Juan Landoni, Christopher Jackson, Aleksandra Zhaivoron, Riikka Kivelä, Liliya Euro, Anu Suomalainen.
      Nicotinamide adenine dinucleotide (NAD+) plays a central role in energy metabolism, and its decline is linked to various degenerative diseases. While NAD+ restoration holds therapeutic promise, its long term, tissue-specific consequences remain poorly understood. We investigated effects of nicotinamide riboside (NR) supplementation for "mutator" mice manifesting mitochondrial progeria. Our results reveal strikingly divergent outcomes: in proliferative bone marrow, NR-treated mutators show reductive stress with accumulation of NADH/NADPH, altered amino acid, nucleotide, folate levels, and impaired heme biosynthesis. In blood, erythrocyte maturation defects are aggravated, exacerbating anemia. Conversely, in postmitotic cardiac tissue, NR enhanced contractility, reduces stress response markers and normalized metabolic profile. These findings indicate that while beneficial for heart, chronic NAD+ boosting can compromise erythrocyte maturation in the context of mitochondrial disease. The data emphasize importance of evaluating systemic effects of NAD+ boosting therapies beyond the primary affected tissues and development of tissue-specific metabolic interventions for degenerative diseases.
    Keywords:  CP: metabolism; NAD(+) metabolism; anemia; erythropoiesis; metabolism; mitochondria; post mitotic tissues; progeria
    DOI:  https://doi.org/10.1016/j.celrep.2026.117849
  23. J Infect Dis. 2026 Sep 02. pii: jiag448. [Epub ahead of print]
    Functional T Cell Responses Are Associated With Prolonged HIV Control After Treatment Interruption.
    Anders B Andersen, Anna K Juhl, Jesper D Gunst, Thomas A Rasmussen, Martin Tolstrup, Ole S Søgaard.
       BACKGROUND: CD8+ T cell responses are thought to be critical for spontaneous control of human immunodeficiency virus (HIV) but findings supporting their role in post-intervention control have been mixed. We hypothesized that HIV-specific T cell proliferation, interferon-γ (IFN-γ) and granzyme B response prior to analytical treatment interruption (ATI) were associated with time to viral rebound.
    METHODS: We pooled data from six different HIV cure trials including people living with HIV receiving antiretroviral therapy (ART) alone or combined with latency reversing agents, Toll-Like receptor 9 agonists or broadly neutralizing antibodies. Pre-ATI blood samples were analysed by IFN-γ ELISpot and lymphocyte proliferation assay (LPA).
    RESULTS: We included 91 participants (90% male, median age 45 years). Compared to participants without virologic control (two consecutive measurements >1000 copies of HIV RNA/mL or ART restart), participants with virologic control at day 28 post-ATI (n=49) had higher Gag-specific IFN-γ (210 vs. 50 SFC/106 PBMCs, p=0.03) and CD8+ T cell proliferation (0.48% vs. 0.16%, p=0.03) responses pre-ATI. The median duration of virologic control was 28 vs. 21 days in people with high vs low Gag-specific IFN-γ response (p<0.01) or CD8+ T cell proliferation (p=0.03). ELISpot and LPA responses were not associated with time to first plasma HIV RNA of >50 copies/mL.
    CONCLUSIONS: These findings indicate that high pre-ATI Gag-specific IFN-γ and CD8+ T cell proliferation responses were associated with an increase in the duration of virological control after stopping ART, supporting a role for CD8+ T cells in sustaining virological control.
    Keywords:  ELISpot; HIV; T cells; bNAbs; granzyme B; interferon gamma
    DOI:  https://doi.org/10.1093/infdis/jiag448
  24. J Infect Dis. 2026 Sep 03. pii: jiag449. [Epub ahead of print]
    Buying Time: T cells and Delayed HIV Rebound After Treatment Interruption.
    Charles R Crain, Gaurav D Gaiha, Rajesh T Gandhi.
      
    Keywords:  HIV; HIV control; T cells; immune responses; viral rebound
    DOI:  https://doi.org/10.1093/infdis/jiag449
  25. Front Toxicol. 2026 ;8 1925459
    Editorial: Environmental toxicity in metabolism.
    Tracey Woodlief.
      
    Keywords:  Per- and polyfluoroalkyl substances; endocrine disruption; environmental toxicology; lipid metabolism; metabolic reprogramming; mitochondrial dysfunction; oxidative stress; peroxisomal β-oxidation
    DOI:  https://doi.org/10.3389/ftox.2026.1925459
  26. Biomed Pharmacother. 2026 Sep 01. pii: S0753-3322(26)00933-9. [Epub ahead of print]203 119897
    Triple-costimulatory GD2-CAR T cells incorporating CD28, 4-1BB and CD27 mediate potent cytotoxicity and reduce exhaustion in solid tumour models.
    Jatuporn Sujjitjoon, Katesara Kongkla, Pornpimon Yuti, Nunghathai Sawasdee, Krissada Natungnuy, Naravat Poungvarin, Pa-Thai Yenchitsomanus.
      Disialoganglioside (GD2) is a validated tumour-associated antigen for chimeric antigen receptor (CAR) T-cell therapy; yet most GD2-CAR constructs carry limited costimulatory signaling, which may constrain efficacy and durability. We engineered humanised hu3F8-based GD2-CAR T cells bearing dual or triple costimulatory domains- GD2-28BBζ (CD28/4-1BB), GD2-28.27ζ (CD28/CD27) and GD2-28BB27ζ (CD28/4-1BB/CD27) - and compared their in-vitro function against GD2-positive neuroblastoma (SK-N-AS), lung adenocarcinoma (A549) and retinoblastoma (Y79 and WERI-Rb-1) cells. All three mediated antigen-specific cytotoxicity against GD2-positive lines while sparing GD2-negative targets. At the lowest effector-to-target ratio, GD2-28BB27ζ T cells retained significantly killing of SK-N-AS cells where the third-generation constructs did not, indicating potent cytotoxicity under limiting effector conditions, whereas GD2-28.27ζ T cells showed the greatest proliferation, reaching significance against WERI-Rb-1. On antigen engagement, GD2-28BB27ζ T cells sustained cytotoxicity while secreting less IL-2, IFN-γ and TNF-α than the other constructs, indicating an uncoupling of lytic function from effector-cytokine output. Under serial tumour rechallenge, GD2-28BB27ζ T cells maintained cytolytic function, acquired fewer activation and exhaustion markers (CD69, TIM-3 and, versus GD2-28BBζ, LAG-3; PD-1 unchanged), better preserved their CAR⁺ population, and retained a larger naïve-like (CD45RO⁻CD62L⁺) subset than the other constructs. Together, these in-vitro findings indicate that combining CD28, 4-1BB and CD27 within a single CAR confers potent cytotoxicity with low effector-to-target ratios, lower effector-cytokine output, reduced exhaustion-marker acquisition and greater phenotypic durability, identifying GD2-28BB27ζ as a promising configuration for GD2-positive tumours that warrants in vivo evaluation.
    Keywords:  CAR T cell; Chimeric antigen receptor; GD2; GD2-CAR T cell; Solid tumour
    DOI:  https://doi.org/10.1016/j.biopha.2026.119897
  27. Blood. 2026 Sep 03. 148(10): 1223-1224
    A CAR against rejection: dual-targeting allogeneic T cells.
    Philip Bucher, Josef Leibold.
      
    DOI:  https://doi.org/10.1182/blood.2026034919
  28. Science. 2026 Sep 03. 393(6815): 1036-1044
    Tumor-derived antioxidants suppress immunity by depriving T cells of reactive oxygen species.
    Alexander J Wesolowski, Ardon M Pillay, Panagiota Vardaka, Rabab Nasrallah, Randy Greaves, Housaiyin Li, Iliana Loffreda, Chelsea Jenkin, Andrew M James, Alica Nübling, Christopher J Ward, Teresa von Linde, Alberto G Conti, Sheue-Fen Tzeng, Layla Dahmani, Alexander C Evans, Sarah K Whiteside, Yumi Yamashita-Kanemaru, Charlotte J Imianowski, Jie Yang, Ignacio Moraga Gonzalez, Jack Chapman, Aws Al-Deka, Klaus Okkenhaug, Michael P Murphy, Bartlomiej Swiatczak, Geoffrey Guittard, Enrico Lugli, Lukas Flatz, Ping-Chih Ho, Robert L Eil, Rahul Roychoudhuri.
      Reactive oxygen species (ROS) promote genomic instability and fuel oncogenic signaling in cancer, but antioxidant therapies have so far failed to improve, or worsen, cancer outcomes. Emerging data suggest that T cells depend on ROS for signal transduction. In this study, we show that tumors exploit this dependency, releasing antioxidant enzymes into the tumor environment to suppress T cell-mediated antitumor immunity. The interstitial fluid of tumors possesses potent antioxidant activity, associated with enrichment of the antioxidant enzyme peroxiredoxin 1 (PRDX1). Extracellular PRDX1 deprives T cells of ROS, preventing oxidative inactivation of phosphatases required for T cell receptor-driven kinase signaling and effector function. Prdx1 is up-regulated upon cancer immunoediting, and loss of PRDX1 within tumors enhances antitumor immunity and immunotherapy responses. These findings define a redox-dependent mechanism of tumor immunosuppression that is potentially amenable to therapeutic intervention.
    DOI:  https://doi.org/10.1126/science.adz8203
  29. Cancer Discov. 2026 Sep 01. 16(9): 1727-1729
    Mitochondrial Complex I at the Crossroads of NK cell Dysfunction in Glioblastoma.
    Silvia Tiberti, Katayoun Rezvani, May Daher.
      Zhou and colleagues identify mitochondrial complex I activity, mediated through NDUFA9, as a critical determinant of natural killer (NK) cell metabolic fitness and antitumor function in glioblastoma. Their study links impaired oxidative phosphorylation to glutamine dependence, epigenetic repression of effector programs, and loss of NK cell activity, highlighting mitochondrial fitness as an actionable axis for improving cellular immunotherapy in solid tumors. See related article by Zhou et al., p. 1924.
    DOI:  https://doi.org/10.1158/2159-8290.CD-26-1267
  30. Biogerontology. 2026 Sep 03. pii: 158. [Epub ahead of print]27(5):
    Stress biology and metabolic ageing in older adults during prolonged crises: Ukraine as an example.
    Oleh Lushchak, Olha Strilbytska, Pavlo Petakh, Oleksandr Kamyshnyi.
      Prolonged crises expose older adults to chronic psychological and social stress, irregular nutrition, reduced physical activity, reduced access to health care, and interruptions in treatment of chronic disease. Together, these factors can compound age-related vulnerabilities and increase the risk of metabolic deterioration, multimorbidity and functional decline. This Perspective argues that prolonged crises should be viewed not only as social or psychological events, but also as conditions that may affect stress-related and ageing-related biological pathways. Severe or prolonged stress, however, can make these responses maladaptive and contribute to physiological dysregulation. Under prolonged crisis conditions, such maladaptive stress responses may be linked to abdominal obesity, sarcopenic obesity, physical frailty, and functional decline through chronic activation of the hypothalamic-pituitary-adrenal axis, altered glucocorticoid signalling, sleep disturbance, inflammation, cellular senescence and senescence-associated secretory phenotype, immunometabolic dysregulation, adipose tissue inflammation, insulin resistance, mitochondrial dysfunction and anabolic resistance in skeletal muscle. Ukraine is a timely example of this broader problem, as prolonged war, population ageing, non-communicable diseases, displacement, mental health needs, and new screening initiatives now intersect. Thus, a biologically informed framework for healthy ageing needs to incorporate mental health assessment, metabolic screening, nutritional assessment, muscle function and rehabilitation rather than address these in isolation. Functional ability reflects the combined effects of psychological stress, metabolic ageing, muscle loss, multimorbidity, and changes in the living environment. It should be considered a key indicator for older adults during and after prolonged crises.
    Keywords:  Functional ability; Inflammageing; Metabolic ageing; Older adults; Sarcopenic obesity; Stress biology
    DOI:  https://doi.org/10.1007/s10522-026-10502-4
  31. Immune Netw. 2026 Aug;26(4): e29
    Qualitative Superiority, Not Magnitude, of Lung-Resident CD8+ T Cells Determines Protective Efficacy of Influenza NP Versus PB1 Vaccines.
    Serin Lee, Eunju Jang, Jun Chang.
      T cell-based universal influenza vaccines aim to generate robust lung-resident memory CD8+ T cells (TRM), yet it remains unclear whether conserved Ags elicit equally protective TRM pools. We compared recombinant adenoviral vectors expressing the influenza A nucleoprotein (rAd/NP) or polymerase basic protein 1 (PB1). After intranasal immunization, both induced comparable magnitudes of respiratory Ag-specific CD8+ T cells, yet only rAd/NP provided 100% survival after lethal influenza challenge. This disparity reflected qualitative differences in the TRM pool; nucleoprotein (NP)-specific cells were predominantly CD103-CD49a+, a phenotype associated with superior cytotoxicity, whereas PB1-specific cells were mainly CD103+CD49a-. Furthermore, NP-specific CD8+ T cells showed 100-fold higher functional avidity and stronger lung-local CTL activity than PB1-specific cells. Our findings demonstrate that TRM quality-specifically phenotypic bias and functional avidity-rather than magnitude, are the primary determinants of vaccine-mediated protection. This study underscores the critical importance of Ag selection in optimizing T cell-based universal vaccine strategies.
    Keywords:  Adenoviral vector; Nucleoprotein; Tissue resident memory T cells; Universal influenza vaccine
    DOI:  https://doi.org/10.4110/in.2026.26.e29
  32. Front Oncol. 2026 ;16 1936446
    Editorial: Chimeric antigen receptor T cell therapies and bispecific antibodies in hematologic malignancies.
    Yangmin Zhu.
      
    Keywords:  bispecific antibodies; chimeric antigen receptor; hematologic malignancies; leukemia; lymphoma; myeloma
    DOI:  https://doi.org/10.3389/fonc.2026.1936446
  33. Pharmacol Ther. 2026 Aug 29. pii: S0163-7258(26)00136-1. [Epub ahead of print]288 109109
    Targeting metabolic reprogramming in cancer: Past, present, and future.
    Niti Kumari, Surendra K Shukla, Ravi Thakur.
      Cancer cells undergo profound metabolic reprogramming to sustain uncontrolled proliferation within a nutrient-limited and often hypoxic tumor microenvironment (TME). Metabolic rewiring is an active driver of oncogenesis, immune evasion, epigenetic remodeling, and therapy resistance. Over the past century, our understanding of tumor metabolism has grown from Warburg's seminal description of aerobic glycolysis to a comprehensive adaptive network. Cancer cells coordinate glucose catabolism, mitochondrial oxidative metabolism, fatty acid synthesis and oxidation, amino acid catabolism, nucleotide biosynthesis, and one‑carbon metabolism into an integrated metabolic framework. These pathways form a deeply interconnected web in which metabolic intermediates serve as biosynthetic building blocks, bioenergetic substrates, redox buffers, signaling molecules, and epigenetic cofactors. Within the TME, metabolic competition between tumor cells and immune cells, together with the accumulation of immunosuppressive metabolites such as lactate, kynurenine, and adenosine, creates a profoundly immune-hostile landscape. Recent work has further revealed that key post-translational modifications, directly driven by metabolic flux, reshape the chromatin and proteome of both cancer cells and tumor-infiltrating immune cells, linking metabolism to gene regulation in previously unanticipated ways. Therapeutically, the FDA approval of IDH1/IDH2 inhibitors for acute myeloid leukemia demonstrated that metabolic enzymes are tractable oncology drug targets. Yet the broader effort to translate metabolic insights into robust clinical benefit has encountered formidable obstacles, including metabolic plasticity, intratumoral heterogeneity, overlap with normal tissue function, and inadequate biomarkers. This review traces the evolution of our understanding of cancer metabolism from its origins to therapeutic targeting. It further examines how anabolic and catabolic pathways, energy production, redox balance, and metabolic crosstalk across intracellular, intercellular, and systemic domains shape tumor biology and therapeutic response. It also critically analyzes approved and investigational metabolic therapies and charts a course for the emerging era of precision metabolic oncology.
    Keywords:  Cancer metabolism; Epigenetics; Ferroptosis; Glycolysis; Immunometabolism; Metabolic reprogramming; Oncometabolites; Oxidative phosphorylation; Tumor microenvironment; Warburg effect
    DOI:  https://doi.org/10.1016/j.pharmthera.2026.109109
  34. Nat Cardiovasc Res. 2026 Aug 31.
    Psychological stress impairs hematopoietic stem cell function through a brain-gut-bone marrow axis.
    Andrea Tavosanis.
      
    DOI:  https://doi.org/10.1038/s44161-026-00879-3
  35. Carbohydr Polym. 2026 Oct 15. pii: S0144-8617(26)00885-4. [Epub ahead of print]390 125768
    Bacillus subtilis exopolysaccharide enhances Lactobacillus johnsonii-kynurenic acid to restore intestinal T helper 17/regulatory T cell balance via aryl hydrocarbon receptor.
    Ge Zhang, Li Cao, Gang Zhang, Rongrong Fu, Yujun Wu, Jinbiao Zhao, Zeyu Zhang.
      Weaning-induced intestinal dysfunction remains a significant challenge, characterized by microbial dysbiosis and immune suppression. However, the precise molecular mechanisms by which specific structural features of levan-fructans influence host homeostasis through microbial metabolic pathways are not fully understood. Here, a branched levan-type exopolysaccharide from Bacillus subtilis BS21 (BS21EPS), characterized by a β-(2 → 6)-D-fructofuranosyl backbone and β-(2 → 1) linkages, reduces colonic damage and systemic inflammation. Metagenomic sequencing shows that BS21EPS supplementation selectively increases Lactobacillus johnsonii 428 in the colon, which contains specialized GH32 enzymes for levan degradation. Integrative metabolomics identifies kynurenic acid (KYNA) as the primary microbial metabolite consistently increased both in vivo and in vitro, which mechanistically serves as a potent endogenous ligand for the aryl hydrocarbon receptor (AhR). In a mouse colitis model, supplementation with L. johnsonii 428 or KYNA enhances intestinal barrier function and reduces inflammation by influencing T-cell lineage decisions, especially by promoting Treg expansion while inhibiting Th17 differentiation. Notably, AhR antagonism with CH223191 abrogates these immunomodulatory effects, confirming the crucial role of the KYNA-AhR axis in maintaining immune balance. Collectively, these findings reveal a structural-functional link between dietary levans, providing a targeted nutritional strategy for managing weaning-related dysfunction and inflammatory bowel diseases.
    Keywords:  AhR-Th17/Treg axis; Bacillus subtilis BS21 exopolysaccharide; Intestinal barrier; Kynurenic acid; Lactobacillus johnsonii; Weaned piglets
    DOI:  https://doi.org/10.1016/j.carbpol.2026.125768
  36. Exp Hematol Oncol. 2026 Sep 02. pii: 87. [Epub ahead of print]15(1):
    Single-cell mapping of thymus-dependent naïve t-cell regeneration reveals CD61-associated states after hematopoietic stem cell transplantation.
    Fangqing Zhang, Xinya Jiang, Shuang Fan, Bixia Wang, Zhigui Wu, Jingrui Zhou, Qi Zhang, Zhiyu Zhang, Jianing Tang, Zheng-Li Xu, Yu Wang, Xiao-Jun Huang, Huidong Guo.
      Thymus-dependent de novo T-cell generation is essential for maintaining T-cell diversity and immune competence. Although thymic involution after puberty reduces thymic output, residual thymic function remains important for immune surveillance and immune reconstitution following hematopoietic stem cell transplantation (HSCT). However, the cellular features that distinguish thymus-derived naïve T cells from those maintained through peripheral homeostatic expansion remain poorly understood. Here, we employed a congenic GFP-labeled mouse transplantation model combined with longitudinal single-cell transcriptomic and T-cell receptor repertoire analyses to define the origin and dynamics of naïve T-cell regeneration after HSCT. By distinguishing thymus-derived de novo generated T cells from peripherally expanded T cells, we found that recent thymic emigrants and both CD4⁺ and CD8⁺ naïve T cells preferentially reconstitute through a thymus-dependent pathway. We further identified distinct naïve T-cell states enriched within the thymus-derived compartment, including CD61-associated and Ly6C-associated naïve T-cell states. These populations displayed dynamic changes during immune reconstitution and were associated with thymic functional status in transplantation and physiological thymic involution mouse models. In human datasets and primary peripheral blood samples, CD61-associated features correlated with age-related thymic activity, sjTREC levels, and preliminary measures of thymic recovery after allogeneic HSCT. Collectively, our study defines cellular features of thymus-dependent naïve T-cell regeneration after HSCT and identifies CD61-associated naïve T-cell states as candidate peripheral features linked to thymic recovery. These findings provide new insights into thymus-dependent immune reconstitution and establish a framework for evaluating peripheral signatures of thymic regeneration after HSCT.
    Keywords:  CD61; Hematopoietic stem cell transplantation; Ly6C; Recent thymic emigrants; Thymus-dependent naïve T cell reconstitution
    DOI:  https://doi.org/10.1186/s40164-026-00824-x
  37. Mol Cell. 2026 Sep 02. pii: S1097-2765(26)00554-X. [Epub ahead of print]
    Cyclin E-CDK2 regulates cancer cell transcriptional program and response to immunotherapy through BRD4.
    Chen Chu, Shanshan Zheng, Ning Mitchell, Zheqi Li, Xixi Zhang, Xiaowei Wu, Tian Zhang, Fabin Dang, Wojciech Michowski, Aleksandra Kolodziejczyk, Miranda L Xu, Krzysztof W Kotowski, Zhe Yang, Diego Martinez-Alonso, Joao Paulo, Jindan Sheng, Jane A Kirby, Finn Groezinger, Yubin Zhou, Miao He, Yoshinaga Ito, Anushree C Gulvady, Michael I Cole, Pierre Foidart, Jun Nishida, Xiaohan Ning, Samanta Sharma, Jan M Suski, Anne Fassl, Yu Zhou, Yan Geng, Wenyi Wei, Steven P Gygi, Kornelia Polyak, Kai W Wucherpfennig, Piotr Sicinski.
      The cyclin E-cyclin-dependent kinase 2 (CDK2) complex is a component of mammalian cell-cycle machinery that drives cell division. Hyperactivation of cyclin E-CDK2 is frequent in human cancers. Small-molecule CDK2 inhibitors are tested in clinical trials for cancer patients. Here, we report that cyclin E-CDK2 has a cell-cycle-independent function in regulating the global transcriptional program of cancer cells. CDK2 phosphorylates bromodomain-containing protein-4 (BRD4) and regulates its chromatin association. Overexpression of cyclin E and the resulting activation of CDK2 in cancer cells alter the cancer cell transcriptome, repress the expression of interferon-stimulated genes, and confer resistance to immunotherapy. Conversely, CDK2 inhibition has the opposite effect and augments the efficacy of immune checkpoint blockade. CDK2 inhibition also increases tumor infiltration by dendritic cells (DCs) and enhances antigen cross-presentation to CD8 T cells. These studies reveal an additional function of cyclin E-CDK2 in tumorigenesis and identify inhibition of CDK2 with clinically available compounds as a strategy for enhancing immune checkpoint blockade.
    Keywords:  BRD4; CDK2; antigen cross-presentation; cancer; cyclin E; dendritic cells; immune checkpoint blockade; immunotherapy resistance; interferon-stimulated genes; transcriptional regulation
    DOI:  https://doi.org/10.1016/j.molcel.2026.08.007
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