bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2026–04–12
forty-six papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Epigenetic, epitranscriptomic, and metabolic control of T cell exhaustion.
  2. Pharmacologic DPP-4 inhibition promotes CD8⁺ T cell metabolic fitness to enhance anti-tumor activity.
  3. Haem from stressed mitochondria can drive T cell exhaustion.
  4. Targeting CB1 and TRPM8 receptors to counteract CD8+ T cell exhaustion.
  5. Asymmetry and redundancy of STAT5 paralogs across CD8+ T cell differentiation states.
  6. Proteostasis regulation in T cell dysfunction: dual regulation by KLHL6.
  7. Intratumoral virus-like particles containing a TLR9-agonist combined with systemic αPD-1 activate tumor-specific CD8+ T cells.
  8. Immune exhaustion in bacterial infections: mechanisms, consequences, and therapeutic implications.
  9. ATAD2 drives immunotherapy resistance by promoting lactic acid-mediated CD8+ T cell dysfunction in lung adenocarcinoma.
  10. Phenotypically and functionally unique CD86 expression CD8 T cell subset shapes immune regulation in the tumor microenvironment.
  11. ARID1A deficiency-driven reprogramming of polyamine metabolism promotes endometrial cancer malignancy and immune escape.
  12. Single-cell analysis of the human immune system reveals sex-specific dynamics of immunosenescence.
  13. Editorial: Regulation of inflammation: metabolic reprogramming and posttranslational modification.
  14. Aberrant immune regulation and enrichment of stem-like CD8 + T cells in the pancreatic lymph node during type 1 diabetes development.
  15. Dietary conjugated linoleic acid enhances resistance to Salmonella infection by promoting PPARγ-mediated metabolic reprogramming and effector function in CD8⁺ T cells.
  16. Inhibition of NR4A1 potentiates a CD8+ T cell response against active tuberculosis.
  17. Ponatinib inhibits LCK and PI3K signaling and promotes CD8+ T stem cell memory cell development.
  18. Correction: Anti-correlation of KLRG1 and PD-1 expression in human tumor CD8 T cells.
  19. Fat bursts T cells to drive joint inflammation.
  20. Arachidonic Acid Metabolism in PMN-MDSCs Suppresses Antitumor Capacity of T cells in KRAS-Mutant Cholangiocarcinoma.
  21. Non-necroptotic MLKL function damages mitochondria and promotes hematopoietic stem cell aging.
  22. Cytokine armored CAR T cells for cancer immunotherapy.
  23. Endothelial cell senescence and mitochondrial dysfunction in vascular ageing.
  24. SELL Marks an Effector-Deficient CD8+ T Cell Subset That Promotes Intracerebral Hemorrhage and Responds to Rutin Therapy.
  25. Translation factor eIF4G2 directs CD8+ T cell lineage commitment by selectively enabling the IL-7 receptor response.
  26. CD8+ TEMRA cells: A double-edged sword in immunity and disease-Mechanisms and therapeutic targets.
  27. Terminal T-cell exhaustion predicts tumor control independent of immunotherapy in ovarian cancer.
  28. Biological sex shapes divergent trajectories of immune aging.
  29. Single cell analysis of neonatal naïve CD8α + T cells reveals novel subsets bridging the innate-adaptive spectrum.
  30. Lipid metabolism reprogramming shapes the immune landscape in the tumor microenvironment.
  31. Peptide hydrogel boosts the cytotoxic and metabolic fitness of Vγ9Vδ2 T cells in melanoma immunotherapy.
  32. Declining nitric oxide bioavailability in cardiovascular aging: mechanistic insights and emerging interventions.
  33. Efficient Generation of Functional TCRαβ + Cytotoxic T Cells from hiPSCs via Small-Molecule Modulation.
  34. CD8+ T cell responses recognizing immunodominant Chlamydia antigens fail to protect against infection.
  35. Metabolic reprogramming by caloric restriction enhances acute phase virological control and reduces chronic inflammation in SIV-infected rhesus macaques.
  36. Multi-Omics Analysis in Autoimmunity: Identification of MicroRNA Regulatory Networks and Cell-Type-Specific Dysregulations in Multiple Sclerosis and Type 1 Diabetes.
  37. Extracellular vesicles derived from senescent hepatocytes drive pan-cancer metastasis in aging.
  38. Lysosomal Control of Aging through Transcriptional and Epigenetic Regulation.
  39. Double-Pronged NAD Preservation: Delaying Cellular Senescence and Initiating Musculoskeletal Regeneration.
  40. Mitochondrial ACSS1 Links Acetate Metabolism to Pyrimidine Biosynthesis in Nutrient-Stressed B-Cell Lymphomas.
  41. Cardiomyocyte-intrinsic SLC25A1 regulates cardiac differentiation and mitochondrial function.
  42. When Binding Is Not Blockade: Interpreting IgG4+ T Cells After PD-1 Therapy.
  43. Increased Granzyme K+ CD8+ T cells and senescent subset in Behçet's disease.
  44. The emerging role of T cells in depression.
  45. Glial Dynamics in Brain Aging: Cellular Heterogeneity and Regional Vulnerability.
  46. Clonotype-Resolved Single-Cell Multi-Omics Unlocks the Profile of Tumor-Infiltrating CD39⁺CD8⁺ T Cells and Enables Adoptive Cell Therapy for Solid Tumor.
  1. Trends Cancer. 2026 Apr 09. pii: S2405-8033(26)00057-9. [Epub ahead of print]
    Epigenetic, epitranscriptomic, and metabolic control of T cell exhaustion.
    Chloe Slater, Albane Simon, Marguerite Laprie-Sentenac, Laurie Menger.
      T cell exhaustion is an adaptive dysfunctional state driven by chronic antigen exposure and an immunosuppressive tumor microenvironment, which significantly impedes effective antitumor immunity and T cell therapies. This progressive loss of effector function and memory potential is governed by the complex and coordinated interplay of epigenetic, transcriptional, epitranscriptomic, and metabolic networks, which collectively establish stable exhaustion-associated programs. Emerging evidence demonstrates that modulating these layers, whether permanently or transiently, can reverse exhaustion and reinvigorate T cell function. Furthermore, core metabolites serve as shared cofactors, directly linking cellular metabolism to these epigenetic and epitranscriptomic changes. Characterizing these multilayered regulatory mechanisms is critical for developing novel strategies to reprogram exhausted T cells and improve therapeutic efficacy against cancer.
    Keywords:  CAR T cells; T cell exhaustion; T cell therapy; epigenetics; epitranscriptomics; metabolism
    DOI:  https://doi.org/10.1016/j.trecan.2026.03.002
  2. bioRxiv. 2026 Apr 03. pii: 2026.03.31.715681. [Epub ahead of print]
    Pharmacologic DPP-4 inhibition promotes CD8⁺ T cell metabolic fitness to enhance anti-tumor activity.
    Oriana Y Teran Pumar, Elton L VanNoy, Abigail Haffey, Durga Prasad Gannamedi, Christine Isabelle Rafie, Dylan Scott Lykke Harwood, Julia R Benedetti, Christine Ann Pittman Ballard, Erika Ciervo, Pedro Henrique Assenza Tavares Coroa, Payal Grover, Brandon Emanuel León, Jonathan Mitchell, Asmita Pathak, Bruno Colon, Lyenne El Ghorayeb, Laura O'Sullivan, Venu Venkatarame Gowda Saralamma, Clara Lopez Ruiz, Natasha Khatwani, Surinder Kumar, Priyamvada Rai, Jonathan Schatz, Ashish Shah, Zev A Binder, Michele Ceccarelli, Quinn T Ostrom, Bjarne Winther Kristensen, Erietta Stelekati, Dionysios C Watson, David B Lombard, Dalia Haydar, Defne Bayik.
      Metabolic dysfunction is a hallmark of CD8 + T cell exhaustion in the tumor microenvironment. Thus, there is growing interest in developing strategies that enhance anti-tumor functions of CD8 + T cells via metabolic reprogramming. Here, we identify dipeptidyl peptidase 4 (DPP-4) as a previously unknown regulator of CD8 + T cell function and metabolism. We discovered that DPP-4 is upregulated in exhausted CD8 + T cells. Pharmacological inhibition of DPP-4 with the FDA-approved anti-diabetic drug sitagliptin transcriptionally and metabolically reprogrammed CD8 + T cells, increasing spare mitochondrial respiratory capacity, proliferation, cytotoxic mediator production, and antigen-specific cancer cell killing capability. The functional effects of sitagliptin were dependent on upregulation of glutamate decarboxylase 1 (GAD1), an enzyme that feeds glutamate into the tricarboxylic acid (TCA) cycle, highlighting a new role for GAD1 in CD8 + T cell respiration and proliferation. We found that systemic inhibition of DPP-4 in preclinical mouse glioblastoma (GBM) models prolongs survival in a CD8 + T cell-dependent manner, and retrospective clinical cohort analysis revealed better outcomes in GBM patients using DPP-4 inhibitors. Importantly, preconditioning of Chimeric Antigen Receptor (CAR) T-cells with DPP-4 inhibition enhanced their cytotoxicity, persistence, and therapeutic efficacy in pediatric GBM. Together, our findings provide mechanistic and biological rationale for repurposing readily accessible DPP-4 inhibitors to enhance anti-tumor CD8 + T cell responses.
    DOI:  https://doi.org/10.64898/2026.03.31.715681
  3. Nat Rev Immunol. 2026 Apr 07.
    Haem from stressed mitochondria can drive T cell exhaustion.
    Yvonne Bordon.
      
    DOI:  https://doi.org/10.1038/s41577-026-01301-6
  4. Sci Rep. 2026 Apr 10.
    Targeting CB1 and TRPM8 receptors to counteract CD8+ T cell exhaustion.
    Adel Mohammadzadeh, Sahand Moazzendizzaji, Aliasghar Tabatabaei Mohammadi, Afsaneh Ahmadi, Rahim Mahmodlou, Ali Akbar Pourfathollah.
      The prolonged interaction between the immune system and tumor antigens can result in T cell exhaustion. Extensive research has been conducted on strategies to reactivate exhausted T cells within the tumor microenvironment. However the exact contribution of the endocannabinoid system (ECS) and nociceptors in regulating CD8+ T cells within the framework of cancer-related inflammation has not been thoroughly studied. This study investigated the use of a TRPM8 antagonist (RQ-00203078), a selective cannabinoid receptor 1 (CB1) antagonist (AM251), and alpelisib (BYL-719) to control CD8+ T cell exhaustion. Our findings showed that administration of the CB1 antagonist AM251, either alone or in combination with alpelisib, significantly reduced the expression of PD-1 and Lag-3 on CD8+ T cells. Interestingly, treatment with the TRPM8 antagonist led to a notable increase in PD-1 expression on CD8+ T cells. These findings suggest that the decreased expression of inhibitory receptors on CD8+ T cells after treatment with the CB1 antagonist whether alone or with alpelisib and TRPM8 highlights the potential of ECS as a promising therapeutic target in cancer treatment.
    Keywords:  Alpelisib; CB1 and TRPM8 antagonists; CD8+ T cell exhaustion; Neuro-immune interaction; Nociceptors; PD-1 and Lag-3
    DOI:  https://doi.org/10.1038/s41598-026-46794-2
  5. Commun Biol. 2026 Apr 04.
    Asymmetry and redundancy of STAT5 paralogs across CD8+ T cell differentiation states.
    Svetlana Ristin, Molly Dalzell, Christopher Armstrong, Nisa Ilsin, Antonio M Fontanella, Luis Nivelo, Lothar Hennighausen, John J O'Shea, Alejandro V Villarino.
      Fostering STAT5 signaling is key to immunotherapies that leverage CD8+ T cell biology. Using mouse models, we demonstrate that the two mammalian STAT5 paralogs, STAT5A and STAT5B, are at once redundant and functionally distinct in CD8+ T cells. Thus, they are asymmetric paralogs, exhibiting both widespread homology at molecular level and functional asymmetry at cellular level, with STAT5B emerging as dominant. For mechanisms, we determined that STAT5B is twice as abundant, accounting for two-thirds of the total STAT5 pool, and present evidence that it also has distinct, paralog-specific properties. We also defined cytokine- and cell state-restricted STAT5B functions and devised a core signature that spotlights key downstream properties and serves as bioinformatic probe. Together, these studies affirm the centrality of STAT5 in CD8+ T cells, reveal common and circumscribed activities for STAT5A and STAT5B, and present a unifying model that foregrounds both redundancy and asymmetry.
    DOI:  https://doi.org/10.1038/s42003-026-09999-9
  6. Trends Cell Biol. 2026 Apr 08. pii: S0962-8924(26)00043-7. [Epub ahead of print]
    Proteostasis regulation in T cell dysfunction: dual regulation by KLHL6.
    Yang Yu, Jing Zhuang, Changgang Sun.
      T cell exhaustion represents a major barrier to the efficacy of cancer immunotherapy, driven by complex transcriptional reprogramming, epigenetic remodeling, and metabolic imbalance. Cheng et al. report in Nature that the E3 ubiquitin ligase Kelch-like protein 6 (KLHL6) dually suppresses T cell exhaustion and mitochondrial dysfunction via proteostasis control, establishing a new therapeutic target.
    Keywords:  KLHL6; T cell exhaustion; mitochondrial dynamics; proteostasis; ubiquitination
    DOI:  https://doi.org/10.1016/j.tcb.2026.03.012
  7. Cancer Res Commun. 2026 Apr 09.
    Intratumoral virus-like particles containing a TLR9-agonist combined with systemic αPD-1 activate tumor-specific CD8+ T cells.
    Travis D Fischer, Caitlin D Lemke-Miltner, George J Weiner.
      One strategy for enhancing the anti-cancer immune response is to inject tumors with immunostimulatory agents that modify the tumor microenvironment (TME) to induce a stronger anti-tumor T cell response. In situ immunization with Vidutolimod, a virus-like particle containing a CpG-A TLR9 agonist, has demonstrated anti-tumor activity in pre-clinical and early phase clinical studies, however its effect on tumor-specific CD8⁺ T cells remain poorly defined. Using the OT-1 model, we assessed how Vidu impacts activation, cytotoxicity, and anti-tumor activity of tumor-specific CD8⁺ T cells in vitro and in vivo. In vitro, Vidu reduced proliferation but increased expression of both activation and exhaustion markers. In vivo, repeated intratumoral Vidu injections induced a transient increase in the frequency of intratumoral tumor-specific CD8+ T cells and enhanced anti-tumor activity. The addition of αPD-1 to Vidu led to a persistent increase in intratumoral tumor-specific CD8+ T cells and sustained tumor control. Vidu treatment increased expression of markers associated with terminal exhaustion on intratumoral tumor-specific CD8⁺ T cells. Such treatment also increased the number of circulating tumor-specific CD8⁺ T cells that expressed high PD-1 but lacked co-expression of other exhaustion markers. Together, these findings demonstrate Vidu treatment expands the number of intratumoral and circulating tumor-specific CD8⁺ T cells, and that the number of tumor specific CD8+ T cells and the anti-tumor response is sustained by the addition of αPD-1. These results support continued evaluation of Vidu as a cancer immunotherapeutic agent, including in combination with immune checkpoint blockade.
    DOI:  https://doi.org/10.1158/2767-9764.CRC-26-0175
  8. Braz J Infect Dis. 2026 Apr 03. pii: S1413-8670(26)01199-2. [Epub ahead of print]30(3): 105809
    Immune exhaustion in bacterial infections: mechanisms, consequences, and therapeutic implications.
    Saeed Hemati, Zeinab Mohsenipour.
      T-cell exhaustion, a well-characterized phenomenon, has historically been studied in the context of viral and oncological diseases. However, its relevance to chronic bacterial infections has only recently garnered attention. This review summarizes emerging evidence suggesting that bacterial pathogens can induce immune exhaustion through a variety of mechanisms. Additionally, we explore how bacterial biofilms, immune-privileged niches, and regulatory T-cell expansion contribute to persistent immune dysfunction. The article further examines the consequences of immune exhaustion, including secondary infections, antibiotic resistance, and microbiome dysbiosis, which are often underappreciated aspects of chronic immune impairment. Therapeutic strategies targeting these exhaustion pathways, such as immune checkpoint blockade, metabolic reprogramming, and microbiome modulation, are also discussed. We emphasize the need to consider chronic bacterial infections not as static conditions but as dynamic processes that interact with and suppress the immune system. Thus, understanding the mechanisms behind immune exhaustion highlights the importance of developing therapies that restore immune function, rather than solely relying on traditional antimicrobial treatments.
    Keywords:  Bacterial infections; Immune response; Immunotherapy; Regulatory T-cells; T-cell exhaustion
    DOI:  https://doi.org/10.1016/j.bjid.2026.105809
  9. Front Immunol. 2026 ;17 1800533
    ATAD2 drives immunotherapy resistance by promoting lactic acid-mediated CD8+ T cell dysfunction in lung adenocarcinoma.
    Wanfeng Gao, Jialei Xu, Yue Li, Jingchang Zhang, Chenghao Ma, Junfeng Chen, Jiajing Chen.
       Background: T cell-based immunotherapies have improved outcomes in lung adenocarcinoma (LUAD), yet many patients develop primary or acquired resistance. Tumor-intrinsic mechanisms that suppress CD8+ T cell function remain incompletely understood.
    Methods: Public LUAD transcriptomic datasets were analyzed to assess the association of ATPase family AAA domain-containing protein 2 (ATAD2) with prognosis and immune infiltration. Atad2-deficient LUAD cell lines were generated using CRISPR/Cas9 and co-cultured with activated CD8+ T cells to evaluate cytotoxicity, cytokine production, PD-1 expression and survival. The mediating role of lactic acid (LA) was confirmed using conditioned medium exposure, exogenous LA supplementation, and LDHA overexpression rescue experiments. ATAD2-mediated transcriptional regulation of LDHA was investigated by ChIP-qPCR and c-Myc overexpression. Subcutaneous tumor models were used to determine the effects of Atad2 deletion on LA accumulation, CD8+ T cell infiltration, tumor growth, and response to anti-PD-1 therapy.
    Results: ATAD2 was significantly upregulated in LUAD and correlated with poor survival and decreased CD8+ T cell infiltration. Atad2 deletion enhanced CD8+ T cell function and survival, effects reversed by exogenous LA. Mechanistically, ATAD2 enhanced c-Myc-dependent LDHA transcription, leading to increased lactic acid production and an immunosuppressive microenvironment. LDHA overexpression restored LA levels and reversed the immune-activating effects of Atad2 loss. In vivo, Atad2 deficiency reduced intratumoral LA, remodeled the immunosuppressive microenvironment, increased CD8+ T cell infiltration, inhibited tumor growth, and improved sensitivity to anti-PD-1 therapy.
    Conclusions: ATAD2 drives immunotherapy resistance in LUAD by activating an ATAD2-LDHA-LA axis that impairs CD8+ T cell function. Targeting ATAD2 may broadly restore antitumor immunity and enhance the efficacy of T cell-based immunotherapies.
    Keywords:  ATAD2; LDHA; T cell therapy resistance; lactic acid; lung adenocarcinoma
    DOI:  https://doi.org/10.3389/fimmu.2026.1800533
  10. J Adv Res. 2026 Apr 05. pii: S2090-1232(26)00285-7. [Epub ahead of print]
    Phenotypically and functionally unique CD86 expression CD8 T cell subset shapes immune regulation in the tumor microenvironment.
    Xin Hu, Yifang Shui, Yixian Fan, Shuji Takada, Miho Terao, Miyuki Shindo, Weitao Que, Masayuki Fujino, Wen-Zhi Guo, Xiao-Kang Li.
       INTRODUCTION: The tumor microenvironment (TME) promotes immune evasion by fostering regulatory immune programs. Although CD8+ regulatory T cells have been described, their identity, upstream drivers and impact in tumors remain incompletely defined.
    OBJECTIVES: To define the phenotype, regulation determinants, and functional of CD86high CD8+ T cells in tumor immunity.
    METHODS: Murine tumor models were used to isolate tumor-infiltrating lymphocytes (TILs) for flow cytometry (FCM), functional co-cultures, and RNA-seq. Upstream cues were probed through cytokine stimulation and transcription factor analyses. Dendritic cells (DCs) conditioning was tested with bone marrow derived DCs and OT-I/OT-II antigen-specific systems. The in vivo function of CD86 on CD8+ T cells was evaluated using conditional Cd86 knockout in CD8+ T cells mouse model.
    RESULTS: CD86 was markedly upregulated on tumor-infiltrating CD8+ T cells, defining a CD86high subset that accumulated in tumors. Transcriptomic profiling revealed enrichment of immunoregulatory and terminal-exhaustion programs while preserving effector modules. CD86high cells upregulated Il12rb1 and IRF5; exogenous IL-12 increased the frequency and intensity of CD86 expression showing dose and time dependent effects, whereas IRF5 inhibition curtailed this induction, establishing an IL-12-IRF5 axis controlling CD86. Functionally, CD86high CD8+ T cells selectively suppressed antigen-specific OT-I/OT-II responses, reducing IFN-γ, IL-2, and Ki-67, and reprogrammed DCs toward a regulatory phenotype characterized by increased IDO, IL-10, CTLA-4, and CD39. Genetic ablation of Cd86 in CD8+ T cells reduced tumor growth, diminished CD39 and PD-1 on TILs, enhanced IFN-γ and granzyme B, and remodeled the myeloid compartment toward immunostimulatory DCs with elevated CD40/CD80/CD86 and reduced IDO/IL-10/CTLA-4/CD39.
    CONCLUSIONS: CD86high CD8+ T cells constitute a distinct immunoregulatory subset in cancer. Their differentiation is driven by an IL-12-IRF5 program, and their crosstalk with DCs via CD86/CTLA-4 engagement promotes tolerogenic remodeling of the TME. Targeting CD86 on CD8+ T cells may disrupt this suppressive circuit and potentiate antitumor immunity.
    Keywords:  CD8(+) T cells; CD86; Immunoregulation; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.jare.2026.04.006
  11. Cell Death Dis. 2026 Apr 08.
    ARID1A deficiency-driven reprogramming of polyamine metabolism promotes endometrial cancer malignancy and immune escape.
    Han Tao, Xiaojun Wang, Zhiyi Hu, Yiran Li, Mengwen Kong, Yeli Sun, Kun Gao, Xiaoping Wan.
      Metabolic reprogramming is crucial in developing endometrial cancer (EC); however, the mechanisms through which tumor suppressors control metabolites that drive cell proliferation and tumor growth remain unclear. ARID1A, an SWI/SNF chromatin remodeling complex subunit, is frequently mutated in endometrium-related malignancies. Here, EC tumors with ARID1A deleted exhibit increased polyamine production, which enhances malignant proliferative capacity while inhibiting the efficacy of functional CD8+ T cells. Mechanistically, ARID1A depletion in tumor cells interrupts the competitive binding of ARID1A to YAP, causing excessive YAP activation and transcriptionally increasing the expression of polyamine metabolic enzymes, thereby enhancing polyamine synthesis. Increased spermidine production from polyamines can directly hypusinate eukaryotic translation initiation factor 5A (eIF5A) at lysine residues, resulting in efficient histone demethylase LSD1 protein translation. Moreover, polyamine accumulation suppresses the recruitment of CD8+ T cells and hampers antitumor immune responses in vivo. Notably, polyamine depletion induced by eflornithine (DFMO) significantly reduces EC cell proliferative capacity and enhances CD8+ T-cell efficacy. Together, these findings highlight the role of ARID1A in regulating polyamine metabolism and suggest that elevated polyamine levels in tumors enhance malignant cellular behaviors and contribute to immune evasion by inhibiting CD8+ T cell-mediated cytotoxic responses. Therefore, targeting polyamine biosynthesis could be an important therapeutic strategy for ARID1A-inactivated EC.
    DOI:  https://doi.org/10.1038/s41419-026-08722-0
  12. Nat Aging. 2026 Apr 10.
    Single-cell analysis of the human immune system reveals sex-specific dynamics of immunosenescence.
    Maria Sopena-Rios, Aida Ripoll-Cladellas, Fatemeh Omidi, Sara Ballouz, Jose Alquicira-Hernandez, Roy Oelen, Alex W Hewitt, Lude Franke, Monique G P van der Wijst, Joseph E Powell, Marta Melé.
      Immunosenescence, the progressive aging of the immune system, is characterized by changes in immune cell composition and function that increase susceptibility to disease. However, how biological sex shapes immune aging at the cellular level remains poorly understood. Here, we analyze single-cell RNA sequencing data from the peripheral blood mononuclear cells of 982 female and male donors across adulthood. We find that aging drives sexually dimorphic compositional and transcriptional changes, with female individuals exhibiting stronger immune remodeling. Female-specific changes include the expansion of cytotoxic CD8⁺ effector memory T cell subsets and inflammatory monocytes, and age-related shifts in the CD4⁺ central memory T cell populations involved in autoimmunity. In contrast, a subset of male participants shows an age-associated expansion of a B cell population linked to an asymptomatic precursor state of chronic lymphocytic leukemia. Together, these findings reveal sex-specific hallmarks of immunosenescence and highlight the importance of incorporating biological sex into strategies aimed at promoting healthy immune aging.
    DOI:  https://doi.org/10.1038/s43587-026-01099-x
  13. Front Immunol. 2026 ;17 1823350
    Editorial: Regulation of inflammation: metabolic reprogramming and posttranslational modification.
    Zhengyu Jiang, Tianliang Li, Jinjun Bian, Wanwan Huai.
      
    Keywords:  O-GlcNAcylation; ferroptosis; immunometabolism; inflammation; metabolic reprogramming; posttranslational modification
    DOI:  https://doi.org/10.3389/fimmu.2026.1823350
  14. bioRxiv. 2026 Apr 01. pii: 2025.05.23.655848. [Epub ahead of print]
    Aberrant immune regulation and enrichment of stem-like CD8 + T cells in the pancreatic lymph node during type 1 diabetes development.
    Leeana D Peters, Howard R Seay, Justin Smith, Amanda L Posgai, Reed Berkowitz, Clive H Wasserfall, Mark A Atkinson, Rhonda Bacher, Maigan A Brusko, Todd M Brusko.
      Effector CD8 + T cells are key cellular drivers of type 1 diabetes (T1D) pathogenesis, yet questions remain regarding the molecular defects leading to altered cytotoxicity, their signature in peripheral tissues, and their receptor specificity. Thus, we analyzed human pancreatic lymph nodes (pLN) using mass cytometry and single cell RNA sequencing (scRNAseq) with combined proteomic and T cell receptor (TCR) profiling. Cytometric analysis revealed an enriched population of T stem-cell memory (TSCM)-like cells (CD8 + CD45RA + CD27 + CD28 + CCR7 + CXCR3 + T cells) in T1D pLNs. scRNAseq profiling indicated an elevated inflammatory cytokine gene signature ( IFITM3 , LTB ) along with regulators of terminal differentiation ( BCL6 , BCL3 ), coupled with reduced expression of exhaustion-associated genes ( DUSP2 , NR4A2 , TSC22D3 ) in CD8 + T cells in T1D pLN. Additionally, effector CD8 + T cells expressed features of progenitor exhausted cells ( BCL2 ) in T1D pLN. Immune Response Enrichment Analysis (IREA) indicated IL-15 signaling as a significant driver of these phenotypes. Integrated TCR and transcriptomic analysis revealed a cluster of diverse naïve-like CD8 + T cell clones in T1D pLN. When comparing pLN and pancreatic slice cellular isolates, we observed sharing of effector CD8 + T cells, with upregulation of terminal effector signatures detected within the pancreas relative to paired pLN samples. Multiplex imaging revealed differential localization of TCF1 and TOX expressing T cells in the pancreas, with TCF1 + TOX + cells located in closer proximity to the islets and displaying a mixture of activation and exhaustion-associated phenotypes. Thus, we provide multimodal cellular profiles enriched in T1D tissues for consideration in therapeutic targeting.
    DOI:  https://doi.org/10.1101/2025.05.23.655848
  15. Gut Microbes. 2026 Dec 31. 18(1): 2657625
    Dietary conjugated linoleic acid enhances resistance to Salmonella infection by promoting PPARγ-mediated metabolic reprogramming and effector function in CD8⁺ T cells.
    Lei Deng, Xinyu Wang, Dinku Yigezaw Mebratie, Yiting Tang, Jiangang Hu, Jingjing Qi, Mingxing Tian, Yanqing Bao, Lihui Zhu, Shaohui Wang.
      Conjugated linoleic acid (CLA) is a dietary lipid that modulates host-microbiota-immune interactions, yet its mechanistic impact on mucosal defense remains unclear. Here, we show that oral CLA supplementation enhances resistance to Salmonella Typhimurium infection and is associated with coordinated changes in gut microbial composition and mucosal immune responses. CLA-enriched commensals, including Dubosiella and Lactobacillus, were associated with increased production of CLA-derived oxylipins and activation of immune surveillance genes. Functionally, CLA pretreatment reduced Salmonella colonization, preserved epithelial integrity, and decreased neutrophilic inflammation without direct antibacterial effects. Single-cell RNA sequencing of ileal intraepithelial lymphocytes revealed that CLA predominantly reprogrammed intestinal CD8⁺ T cells toward an oxidative phenotype and enhanced effector activity. ATAC-seq revealed increased chromatin accessibility at loci associated with metabolic regulation, consistent with transcriptional reprogramming toward oxidative fitness. Mechanistically, CLA directly activated PPARγ signaling to promote mitochondrial biogenesis, oxidative phosphorylation, and the production of IFN-γ and granzyme B in CD8⁺ T cells; pharmacologic inhibition of PPARγ attenuated these effects both in vitro and in vivo. Notably, depletion of CD8⁺ T cells eliminated CLA-mediated protection and abolished early restriction of bacterial dissemination at Peyer's patches and mesenteric lymph nodes. Although CLA enhanced CD8⁺ T-cell effector programs, antibiotic depletion and fecal microbiota transplantation experiments demonstrated that an intact gut microbiota is necessary for effective protection in vivo. Together, these findings identify CLA as a dietary modulator that strengthens mucosal resistance to Salmonella by promoting PPARγ-mediated metabolic reprogramming and enhanced effector fitness in intestinal CD8⁺ T cells.
    Keywords:  CD8+ T cells; Conjugated linoleic acid; PPARγ; Salmonella Typhimurium; mucosal immunity
    DOI:  https://doi.org/10.1080/19490976.2026.2657625
  16. Nat Rev Immunol. 2026 Apr 07.
    Inhibition of NR4A1 potentiates a CD8+ T cell response against active tuberculosis.
    Guillaume J Trusz, Christopher Sundling.
      
    DOI:  https://doi.org/10.1038/s41577-026-01299-x
  17. Nat Commun. 2026 Apr 07.
    Ponatinib inhibits LCK and PI3K signaling and promotes CD8+ T stem cell memory cell development.
    Yuki Okuhiro, Sachiko Ito, Keisuke Watanabe, Yue Yan, Kazuhiro Kumagai, Takahiko Sato, Yasuhiro Kojima, Yuki Fujioka, Naoto Takahashi, Hitoshi Kiyoi, Yuka Maeda, Takuma Kato, Hiroyoshi Nishikawa.
      CD8+ T stem cell memory (TSCM) cells show clinical promise for cancer immunotherapy, but TSCM cell generation in clinical settings requires further optimization. Ponatinib is a tyrosine kinase inhibitor primarily targeting BCR-ABL1 and used for the treatment of chronic myeloid leukemia. Here, we investigate the effect of ponatinib on T cell activation and differentiation. Acting off-target, ponatinib inhibits LCK and PI3K signaling to enhance the transcriptional functions of TCF7 and FOXO1, thereby promoting CD8+ TSCM cell differentiation. Mechanistically, stable and sustained, but not intermittent, inhibition of the LCK and PI3K pathways is essential for CD8+ TSCM cell induction. In mouse tumor models, ponatinib treatment exhibits antitumor efficacy alone and in combination with PD-1 blockade. Furthermore, ponatinib increases chimeric antigen receptor (CAR) TSCM cells by reducing CAR T cell exhaustion, resulting in durable antitumor efficacy. Our results thus implicate ponatinib as therapeutic immunomodulator, inducing TSCM cells for improved antitumor T cell activity.
    DOI:  https://doi.org/10.1038/s41467-026-71375-2
  18. Oncotarget. 2026 01 06. 17(1): 57-58
    Correction: Anti-correlation of KLRG1 and PD-1 expression in human tumor CD8 T cells.
    Steven A Greenberg.
      
    DOI:  https://doi.org/10.18632/oncotarget.28846
  19. Cell Metab. 2026 Apr 07. pii: S1550-4131(26)00050-1. [Epub ahead of print]38(4): 641-642
    Fat bursts T cells to drive joint inflammation.
    Wei Li, George C Tsokos.
      Chronic autoimmune inflammation is increasingly understood to be shaped by the tissue metabolic environment. Weyand and colleagues show that lipid-rich tissues trigger lipid droplet-dependent, gasdermin D-mediated pyroptosis in metabolically exhausted CD4+ T cells, thereby sustaining inflammatory pathology.
    DOI:  https://doi.org/10.1016/j.cmet.2026.02.007
  20. Cancer Discov. 2026 Apr 08.
    Arachidonic Acid Metabolism in PMN-MDSCs Suppresses Antitumor Capacity of T cells in KRAS-Mutant Cholangiocarcinoma.
    Jian Lin, Chen Sang, Bin Xiang, Xia Shen, Junmei Zhao, Shengshi Xu, Jiaomeng Pan, Youpei Lin, Liangqing Dong, Qianqian Chu, Guoming Shi, Jian Zhou, Jia Fan, Mao Zhang, Qiang Gao.
      Metabolic reprogramming within the tumor microenvironment impairs antitumor immunity and compromises the efficacy of immunotherapy. Through multi-omics-based metabolic subtyping in intrahepatic cholangiocarcinoma (iCCA), we identified a subgroup with the worst prognosis that demonstrates significant enrichment in both Cyclooxygenase/Arachidonic acid (COX/AA) metabolism and KRAS mutations. Mechanistically, KRAS mutation-mediated NF-κB pathway activation upregulates CXCL5 expression, thereby recruiting CXCR2+ polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) into the tumor microenvironment. Concurrently, KRAS mutation drives prostaglandin E2 (PGE2) production in tumor cells, and PGE2 in turn enhances arachidonic acid uptake and COX-2 expression in PMN-MDSCs, establishing an amplifying loop between tumor cells and PMN-MDSCs that exacerbates PGE2 production. PGE2 accumulation potently suppresses the antitumor activity of CD8+ T cells via prostaglandin E receptor 4 (EP4). Therapeutic targeting of the COX-2-PGE2-EP4 axis, combined with anti-PD-1 immunotherapy, demonstrates profound synergistic efficacy in both KRAS-mutant murine models and patient-derived tumor fragments harboring KRAS mutations.
    DOI:  https://doi.org/10.1158/2159-8290.CD-25-1844
  21. Nat Commun. 2026 Apr 06. pii: 2798. [Epub ahead of print]17(1):
    Non-necroptotic MLKL function damages mitochondria and promotes hematopoietic stem cell aging.
    Yuta Yamada, Jinjing Yang, Akiho Saiki-Tsuchiya, Yuji Watanabe, Shuhei Koide, Shin Murai, Yuriko Sorimachi, Yu Fukuda, Kenta Sumiyama, Hiroshi Sagara, Hiroyasu Nakano, Keiyo Takubo, Atsushi Iwama, Masayuki Yamashita.
      Hematopoietic stem cells (HSCs) survive many types of cellular stress but often lose their regenerative and lymphopoietic capacities as a result. Such functional decline also occurs with age, and dysfunctional HSCs with impaired mitochondria accumulate during aging. However, the molecular link between HSC stress response and age-related functional decline remains poorly understood. Here we show that multiple stress responses converge on the RIPK3-MLKL axis to induce age-related changes in HSCs. The necroptosis effector MLKL is readily activated by inflammation and replication stress and accumulates in HSC mitochondria. Consequently, activated MLKL does not cause cell death but impairs HSC self-renewal and lymphoid differentiation. Such MLKL-mediated functional decline also occurs in HSCs during organismal aging, with activated MLKL primarily mediating age-related mitochondrial damage and reduced glycolytic flux. Collectively, our results establish the RIPK3-MLKL axis as a key mediator of HSC aging and identify a necroptosis-independent role of MLKL in mitochondrial damage.
    DOI:  https://doi.org/10.1038/s41467-026-71060-4
  22. Immunol Cell Biol. 2026 Apr 05.
    Cytokine armored CAR T cells for cancer immunotherapy.
    Kevin Sek, Kah Min Yap, Woon Xuan Hong, Phillip K Darcy.
      Cytokine armoring of CAR T cells for enhancing the immunotherapy of cancer. Reprogramming of CAR T-cell phenotypes through (a) IL-158 or (b) IL-9Rα9 engineering. Reprogramming of the tumor microenvironment and recruitment of host antitumor immunity through (c) IL-36γ10 or (d) IL-1211,12 engineering. (e) Tumor-inducible cytokine expression utilizing synthetic NFAT or endogenous NR4A2 promoter systems to restrict systemic expression of potent cytokines for improved safety.
    Keywords:  CAR T cells; cytokine armoring; tumor microenvironment
    DOI:  https://doi.org/10.1111/imcb.70112
  23. Ageing Res Rev. 2026 Apr 02. pii: S1568-1637(26)00111-X. [Epub ahead of print]118 103119
    Endothelial cell senescence and mitochondrial dysfunction in vascular ageing.
    Iga Walczak, Maria Tarnawska, Klaudia Stawarska, Alicja Braczko, Aleksandra Paterek, Filip Rolski, Przemysław Leszek, Dorota Smolarek, Małgorzata Kapusta, Magdalena Narajczyk, Jean-Luc Cracowski, Beata Schlichtholz, Marcin Hellmann, Michał Mączewski, Barbara Kutryb-Zając.
      The vascular endothelium performs numerous regulatory functions that impact inflammatory responses, thrombosis, vascular tone and angiogenesis. Endothelial dysfunction is a key contributor to the pathogenesis of various human diseases, either as a primary trigger or as a consequence of organ damage. This review examines how ageing reshapes endothelial cell metabolism and mitochondrial function, progressively undermining endothelial homeostasis and resilience. Age-related endothelial alterations, including reduced nitric oxide bioavailability, heightened oxidative stress, impaired vasodilatory capacity and pro-inflammatory activation, arise from coordinated shifts in energy production, substrate utilization and redox signaling. In this context, cellular senescence, a stable arrest of the cell cycle accompanied by distinct metabolic, secretory and inflammatory changes, appears to be an important response to cumulative metabolic and mitochondrial stress. Senescent endothelial cells not only reflect this stress burden but also actively propagate dysfunction through sustained pro-inflammatory and pro-oxidant signalling, thereby accelerating vascular ageing. We highlight the central role of mitochondria in these events. Age-associated mitochondrial dysfunction disrupts bioenergetics, enhances reactive oxygen species generation and fuels chronic low-grade inflammation, amplifying endothelial decline. By bringing together current evidence-based knowledge on endothelial cell bioenergetics, mitochondrial impairment and metabolic reprogramming, this review identifies mitochondria-driven metabolic deterioration as a key mechanism underlying endothelial ageing and underscores mitochondrial metabolism as a promising, yet underexploited, therapeutic target in age-related vascular dysfunction.
    Keywords:  Bioenergetics; Endothelium; Metabolism; Mitochondria; Senescence; Vascular ageing
    DOI:  https://doi.org/10.1016/j.arr.2026.103119
  24. Hum Mutat. 2026 ;2026 4033506
    SELL Marks an Effector-Deficient CD8+ T Cell Subset That Promotes Intracerebral Hemorrhage and Responds to Rutin Therapy.
    Yan Huang, Haochen Xu, Congxia Bai, Jing Liu, Yingying Sun, Jingzhou Chen.
       Background: Intracerebral hemorrhage (ICH) is a devastating stroke subtype with high mortality and limited therapeutic options. While neuroinflammation contributes to secondary brain injury, the role of peripheral CD8+ T cell dysfunction in ICH pathogenesis remains poorly characterized. This study is aimed at identifying disease-associated CD8+ T cell subpopulations and potential therapeutic targets through integrative multiomics analysis.
    Methods: We performed bulk RNA sequencing on peripheral blood from 130 patients (66 ICH and 64 hypertension controls) across two independent cohorts, combined with single-cell RNA sequencing of 13 patients. The scPAS algorithm integrated bulk and single-cell data to identify phenotype-associated cells. Five machine learning algorithms (LASSO, random forest, XGBoost, SVM, and Boruta) were employed for biomarker discovery. The therapeutic efficacy of rutin was evaluated in murine hypertensive ICH models.
    Results: We identified a distinct SELL-high CD8+ T cell subpopulation (scPAS+ cells) exhibiting comprehensive effector dysfunction, characterized by downregulation of cytotoxicity genes (GZMA, GZMB, GNLY, NKG7, and CCL5). Pseudotime trajectory analysis revealed progressive differentiation toward this dysfunctional phenotype. SELL emerged as a consensus diagnostic biomarker across all five algorithms, demonstrating excellent discriminative performance (AUC: 0.876-0.936). In vivo, rutin treatment reduced SELL expression, restored CD8+ T cell cytotoxicity, decreased hemorrhage incidence, and attenuated neuroinflammation and oxidative stress.
    Conclusions: This study identifies SELL-marked effector-deficient CD8+ T cells as a hallmark of ICH and establishes SELL as a robust diagnostic biomarker. Rutin represents a promising therapeutic candidate targeting peripheral immune dysfunction in hypertensive ICH.
    Keywords:  SELL/CD62L; T cells; biomarker; intracerebral hemorrhage; machine learning; rutin; single-cell RNA sequencing
    DOI:  https://doi.org/10.1155/humu/4033506
  25. iScience. 2026 Apr 17. 29(4): 115313
    Translation factor eIF4G2 directs CD8+ T cell lineage commitment by selectively enabling the IL-7 receptor response.
    Jialong Cui, Xinhui Zhang, Yang Yang, Lidong Shan, Yang Li, Long Jiang, Wei Xie, Tengchuan Jin, Xueting Lang.
      CD8+ T cell lineage commitment in the thymus requires interleukin-7 receptor (IL-7R) signaling, but the mechanisms enabling its cytokine responsiveness are unclear. Here, we identify the translation factor eIF4G2 as an essential, selective regulator of this process. eIF4G2 expression is upregulated in double-positive thymocytes and its T cell specific deletion causes a severe post-selection blockade, specifically abolishing CD8+ single positive thymocyte lineage commitment while sparing CD4+ lineage choice and TCR signaling. Mechanistically, eIF4G2 deficiency ablates IL-7 responsiveness by failing to sustain the receptor γc subunit via an untranslated region dependent manner, with a concomitant impairment of IL-7Rα mRNA level. Our findings establish eIF4G2 as a pivotal translational checkpoint that licenses IL-7R signaling to enforce faithful CD8+ T cell fate determination.
    Keywords:  Cell biology; Immunology
    DOI:  https://doi.org/10.1016/j.isci.2026.115313
  26. Int Immunopharmacol. 2026 Apr 06. pii: S1567-5769(26)00459-5. [Epub ahead of print]179 116614
    CD8+ TEMRA cells: A double-edged sword in immunity and disease-Mechanisms and therapeutic targets.
    Jiajin Ma, Yue Wu, Lujun Chen, Xiao Zheng.
      The generation of long-lived immune memory is a hallmark of adaptive immunity, ensuring rapid recall responses upon antigen re-exposure. Within the memory CD8+ T cell compartment, TEMRA cells (CD45RA+CCR7-) represent a unique, terminally differentiated population defined by potent cytotoxicity and distinct migratory properties. Historically viewed as a state of replicative senescence and dysfunction, recent evidence has shifted this paradigm, portraying TEMRA cells as hyper-functional effectors with a Senescence-Associated Secretory Phenotype (SASP). This review comprehensively synthesizes the biological complexity of CD8+ TEMRA cells, dissecting the transcriptional (e.g., ZEB2, T-bet) and metabolic reprogramming (e.g., glycolytic reliance) that governs their fate. We critically examine their dichotomous roles in health and disease: while serving as indispensable sentinels in antiviral and anti-tumor immunity, their dysregulation contributes to tissue pathology in autoimmune disorders and chronic infections. Furthermore, we address the "tumor immunity paradox" by discussing the confounding role of bystander virus-specific cells and the predictive value of specific subsets (e.g., CX3CR1+ TEMRA). Finally, we highlight the potential of targeting metabolic checkpoints and senescence pathways as novel therapeutic strategies to modulate TEMRA function in clinical settings.
    Keywords:  Autoimmunity; Bystander effect; CD8(+) T(EMRA); Immunosenescence; Metabolic reprogramming; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.intimp.2026.116614
  27. NPJ Precis Oncol. 2026 Apr 10.
    Terminal T-cell exhaustion predicts tumor control independent of immunotherapy in ovarian cancer.
    Anna Salvioni, Marie Michelas, Mathilde Del, Pierre Vuattoux, Bertille Segier, Clara-Maria Scarlata, Noémie Thébault, Giulia C Leonardi, Nathalie Van Acker, François-Xavier Frenois, Virginie Feliu, Myriam Maixent, Lise Scandella, Sylvie Giuriato, Claire Illac, Sarah Betrian, Charlotte Chollet, Bastien Cabarrou, Carlos Martinez-Gomez, Christel Devaud, Ayman Al Saati, Christine Toulas, Thomas Filleron, Guillaume Bataillon, Jean-Pierre Delord, Maha Ayyoub, Alejandra Martinez.
      T-cell exhaustion is typically studied in the context of immune checkpoint blockade, where proliferation and reinvigoration of exhausted cells drives therapeutic responses. However, terminal exhaustion may also represent a marker of chronic tumor-specific activation, raising the possibility that exhausted T cells reflect ongoing endogenous tumor control. Here, we sought to evaluate T-cell exhaustion as a prognostic marker using high-grade serous ovarian cancer (HGSC), an immunotherapy-resistant malignancy, as a model. In a cohort of 80 patients with stage III/IV HGSC, we assessed T-cell infiltration and exhaustion according to homologous recombination (HR) deficiency status. While overall immune infiltration was comparable between HR-deficient and proficient tumors, terminally exhausted CD8 and conventional CD4 T cells were enriched in HR-deficient tumors, where their presence correlated with improved progression-free survival. These findings suggest that exhausted T cells may indicate protective immunity even outside the context of immunotherapy and underscore their prognostic relevance in solid tumors.
    DOI:  https://doi.org/10.1038/s41698-026-01412-2
  28. Nat Aging. 2026 Apr 10.
    Biological sex shapes divergent trajectories of immune aging.
      
    DOI:  https://doi.org/10.1038/s43587-026-01110-5
  29. bioRxiv. 2026 Mar 09. pii: 2026.03.05.706693. [Epub ahead of print]
    Single cell analysis of neonatal naïve CD8α + T cells reveals novel subsets bridging the innate-adaptive spectrum.
    Adam Geber, Brandon Groff, Jordan McMurry, Nathan Laniewski, Adam Tyrlik, Connor Kean, Ruoqiao Wang, Darline Castro-Melendez, Janiret Narvaez-Miranda, Natalie Vance, Gloria Pryhuber, Timothy Mosmann, Brian D Rudd, Juilee Thakar, David J Topham, Andrew Grimson, Kristin Scheible.
      There is growing evidence that neonates harbor innate-like CD8a + T cell subsets that contribute to both protection and hyper-inflammatory states. It remains unclear, however, where these innate-like features are found among the many conventional and unconventional T cell populations that can upregulate the CD8 receptor. Further delineation of these unique populations and functions, with a focus on CD8ab co-expression, will enable studies that seek to understand the unique immune features in conventional T cell populations that are present during fetal and early postnatal life. We used cord blood from infants across the full viable gestational age range to examine phenotypic and transcriptional heterogeneity, with a particular focus on the naïve T cell pool. We report a set of fetally-derived and innate-like naïve CD8αβ + T cells ('FITs') that are marked by their KLRG1 + CD161 + phenotype, unique transcriptomic features and which are sparsely detected in adult peripheral blood. Additionally, using T cell receptor repertoire profiling, we can distinguish FITs from well-described and semi-invariant unconventional T cell populations such as mucosa-associated invariant T cells. Our delineation of FITs' unique features will enable future investigation into their ontogeny and tissue distribution, and ultimately their role in immune-related outcomes in preterm infants.
    DOI:  https://doi.org/10.64898/2026.03.05.706693
  30. Cell Mol Immunol. 2026 Apr 07.
    Lipid metabolism reprogramming shapes the immune landscape in the tumor microenvironment.
    Yun-Wei Du, Ze-Rong Cai, Xiao-Tong Duan, Xin-Yu Li, Tong Yue, Tian Tian, Jian-Jun Li, Huai-Qiang Ju.
      Given the fundamental biological importance of lipids not only as structural components and energy substrates but also as potent bioactive molecules that govern immune and oncogenic signaling, lipid metabolism reprogramming has emerged as a central driver of tumor progression. Rather than merely fueling tumor growth, this extensive metabolic rewiring profoundly reshapes the tumor microenvironment (TME), establishing complex metabolic crosstalk that actively drives immune evasion. This review examines the current understanding of lipid metabolism reprogramming across different cellular compartments within the TME and its far-reaching implications for cancer immunotherapy. We first delineate how altered lipid metabolism directly fuels tumor cell proliferation, survival, and metastatic potential. We then examine the distinct lipid metabolic patterns in different immune cells, detailing how this reprogramming drives dysfunction in antitumor subsets such as CD8+ T cells and natural killer cells and how it promotes immunosuppressive populations such as tumor-associated macrophages and myeloid-derived suppressor cells. In addition to these immune alterations, we address the metabolic rewiring of stromal cells, particularly cancer-associated fibroblasts. Furthermore, by exploring intricate intercellular crosstalk, we highlight how tumor lipid metabolism promotes immune escape and how lipids from reprogrammed immune and stromal cells, in turn, support tumor growth, thereby reinforcing an immunosuppressive niche. Finally, we highlight emerging therapeutic strategies targeting these pathways and discuss how leveraging multiomics advances can translate lipid insights into cancer immunotherapy.
    Keywords:  Lipid metabolism reprogramming; antitumor immunity; immune evasion; tumor microenvironment
    DOI:  https://doi.org/10.1038/s41423-026-01411-0
  31. Front Immunol. 2026 ;17 1793631
    Peptide hydrogel boosts the cytotoxic and metabolic fitness of Vγ9Vδ2 T cells in melanoma immunotherapy.
    Hongjie Liu, Man Li, Ying Jiao, Lilumeng Huang, Qi Liu, Shuang Xiao, Mingjie Zhan, Xianfeng Zha, Li Shi, Zhinan Yin, Zheng Xiang, Chengbiao Yang, Yan Xu.
       Background: Adoptive cell therapy with Vγ9Vδ2 T cells represents a promising approach for melanoma treatment. However, its efficacy is often limited by poor persistence, inadequate tumor infiltration, and functional suppression within the tumor microenvironment. Peptide-based hydrogel as a vehicle has exhibited great potential for delivery of biologics and enhancement of their function, but their ability to directly modulate the metabolic and cytotoxic fitness of Vγ9Vδ2 T cells remains largely unexplored.
    Methods: We developed a peptide hydrogel (Self-assembly material based on peptide Nap-GFFF, named as SAM.1) and assessed its ability to activate Vγ9Vδ2 T-cell and amplify their cytotoxicity to A375 melanoma cells in vitro, and to enhance antitumor efficacy in a melanoma xenograft model. Mechanistic studies focused on integrin signaling, PI3K/AKT/mTOR activation, and metabolic reprogramming.
    Results: SAM.1 significantly enhanced the cytotoxic activity of Vγ9Vδ2 T cells against A375 melanoma cells in vitro. It promoted Vγ9Vδ2-T cell activation, evidenced by increased CD25 and CD69 expression, and boosted the secretion of key cytotoxic effector molecules such as IFN-γ, TNF-α and perforin. Mechanistically, SAM.1 engaged integrin signaling (upregulating CD11c and CD103), leading to activation of the PI3K/AKT/mTOR pathway. This signaling cascade drove a beneficial metabolic reprogramming, shifting T cell energy production from glycolysis towards oxidative phosphorylation, thereby enhancing their bioenergetic capacity. Beyond that, peritumoral delivery of Vγ9Vδ2 T cells increased intratumoral T cell infiltration. As a result, melanoma growth was inhibited after administration of SAM.1 encapsulating Vγ9Vδ2 T cells.
    Conclusion: SAM.1 hydrogel acted as a two-in-one scaffold, controlled release and an immunomodulatory agent, to enhance the persistence and antitumor function of Vγ9Vδ2 T cells. This strategy provided a new paradigm for γδ T-cell-based immunotherapy in melanoma.
    Keywords:  Vγ9Vδ2 T cells; immunotherapy; integrin signaling; melanoma; metabolic reprogramming; peptide hydrogel
    DOI:  https://doi.org/10.3389/fimmu.2026.1793631
  32. J Cardiovasc Aging. 2025 ;pii: 20. [Epub ahead of print]5(4):
    Declining nitric oxide bioavailability in cardiovascular aging: mechanistic insights and emerging interventions.
    Hriju Adhikari, Priyanka Patel, Namratha Javvaji, Mark J Crabtree, Jillian N Simon.
      Nitric oxide (NO) is essential for maintaining normal cardiovascular function, and accumulating evidence suggests that its diminished bioavailability contributes to endothelial dysfunction, vascular stiffening, and impaired cardiac performance - hallmarks of cardiovascular aging. This review posits that reduced NO bioavailability with age stems from impaired endothelial and neuronal NO synthase activity, increased oxidative stress, and metabolic shifts that drive cardiovascular decline. We further discuss emerging research which highlights potential interventions, including dietary nitrate supplementation, caloric restriction, and exercise, that may restore NO signaling and counteract age-related cardiovascular dysfunction. These findings underscore the growing recognition of NO as a key regulator of cardiovascular aging and a promising therapeutic target. Addressing NO-related deficits could open new avenues for preventing and treating age-associated cardiovascular diseases, reshaping strategies for promoting healthy aging and longevity.
    Keywords:  Nitric oxide; Sirtuin 1 (SIRT1); cardiovascular aging; lifestyle interventions; myocardial remodeling; oxidative stress; vascular dysfunction
    DOI:  https://doi.org/10.20517/jca.2025.14
  33. bioRxiv. 2026 Apr 01. pii: 2026.03.31.715684. [Epub ahead of print]
    Efficient Generation of Functional TCRαβ + Cytotoxic T Cells from hiPSCs via Small-Molecule Modulation.
    Caroline Kubaczka, Netra Kambli, Roland Windisch, Kelly Yu, Yunliang Zhao, Sharon Wu, Katie Frenis, Morgan T Walcheck, Marcelo Falchetti, Mohamad Najia, Zachary C LeBlanc, Trista E North, R Grant Rowe, George Q Daley, Thorsten M Schlaeger.
      Genetically engineered human induced pluripotent stem cells (hiPSCs) represent a promising platform for regenerative medicine and next-generation immunotherapies. While recent advances enable stroma-free differentiation of hiPSCs into mature CD3⁺TCRαβ⁺ cytotoxic T lymphocytes (CTLs), overall efficiency remains limited. Here, we identify small-molecule modulators that enhance T cell output, particularly at the ProT cell stage. Targeted and stage-specific inhibition of AHR, DOT1L, or GSK3 drives robust maturation from ProT to CD4⁺ immature single-positive (ISP) cells, markedly increasing CD4⁺CD8⁺ populations and augmenting CTL production of up to 2000 fold. hiPSC-derived T (iT) cells matured under these conditions display superior activity in cytotoxicity assays using AMG-701 (BCMAxCD3) or Blinatumomab (CD19xCD3). These effects were reproducible across independent hiPSC lines, diverse hematopoietic progenitor generation methods, and multiple stroma-free differentiation platforms, and were further validated in cord blood CD34⁺ cells. Notably, AHR inhibition enhanced T cell development and promoted B lymphopoiesis, revealing shared regulatory pathways in lymphoid lineage specification. We also demonstrate that the Oct4-activating compound OAC1 functions as a weak AHR inhibitor, partially recapitulating the effects of canonical AHR blockers in both cellular and zebrafish AHR reporter systems. Collectively, our findings define key molecular circuits governing human lymphoid differentiation and establish practical strategies to optimize the yield and function of hiPSC-derived cytotoxic T cells. This work advances the development of both universal and autologous hiPSC-derived T cell therapies, offering a path forward even for patient-specific hiPSC lines with suboptimal T cell differentiation potential.
    DOI:  https://doi.org/10.64898/2026.03.31.715684
  34. iScience. 2026 Apr 17. 29(4): 115242
    CD8+ T cell responses recognizing immunodominant Chlamydia antigens fail to protect against infection.
    Safia Guleed, Nina Dieu Nhien Tran Nguyen, Sharmila Subratheepam, Kristoffer Mazanti Melchiors, Anja Weinreich Olsen, Matias Ciancaglini, Anna Lena Kastner, Emanuele Nolfi, Daniel Pinschewer, Frank Follmann, Jan Pravsgaard Christensen, Alice Sijts, Jes Dietrich.
      Chlamydia trachomatis (C.t.) causes the most common bacterial sexually transmitted infection, yet no licensed vaccine exists. CD4+ T cells are known to protect, while the role of CD8+ T cells is unclear. This study examined whether CD8+ T cells targeting five immunodominant C.t. proteins could protect against infection. Using an in silico approach, we identified six novel CD8+ T cell epitopes from ArtJ, GroES, IncA, OmpH, and major outer membrane protein (MOMP). These epitopes elicited C.t.-specific CD8+ T cells when delivered with the cationic adjuvant formulation 09b (CAF09b) liposomal adjuvant or a lymphocytic choriomeningitis virus (LCMV) vector expressing the MOMP-based CTH522 protein. After C.t. challenge, vaccine-induced CD8+ T cells rapidly accumulated in the genital tract, became resident after bacterial clearance, produced effector cytokines, and showed strong cytotoxicity. However, neither single nor combined CD8+ T cell responses conferred protection, whereas a CD4+ T cell-inducing CTH522-based vaccine did. This implies that vaccine-induced CD8+ T cells play a minor or no role in protection against C.t.
    Keywords:  Biological sciences; Immunology
    DOI:  https://doi.org/10.1016/j.isci.2026.115242
  35. bioRxiv. 2026 Mar 12. pii: 2026.03.11.711076. [Epub ahead of print]
    Metabolic reprogramming by caloric restriction enhances acute phase virological control and reduces chronic inflammation in SIV-infected rhesus macaques.
    Naveen Suresh Babu, Chrysostomos Perdios, Maggie Hallmets, Anna T Brown, Celeste Coleman, Christine M Fennessey, Carolina Allers, Matilda J Moström, Pratik Khare, Cissy Zhang, Brandon T Smith, Nadia A Golden, Adam Myers, Lara Doyle-Meyers, Alexandra Blaney, Robert V Blair, Ahmad A Saied, Ricki Colman, Brandon F Keele, Anne Le, Clovis S Palmer, Joseph C Mudd.
      Nutrient metabolism influences HIV-1 replication, antiviral immunity, and chronic inflammation, yet is difficult to leverage for therapeutic gain. We sought to modulate metabolism in the non-human primate model of HIV-1 by caloric restriction (CR), a modality canonically known for its antiaging benefits. Four months of 30% CR was safe and resulted in broad and systemic metabolic reprogramming in healthy adult male and female rhesus macaques. Relative to that of ad libitum- fed animals, CR lowered the frequencies of target CCR5+ CD4 T cells in the gut mucosa. Upon infection with SIV, CR reduced acute phase viremia, dampened type I interferon signaling, and overall permitted a more vigorous cycling of CD8+ T cells in lymphoid tissues. CR-induced protection from SIV was associated with a robust up-regulation of glycolysis, which supported an early reduction in viremia that ultimately waned over time. During virologic suppression with antiretroviral therapy (ART), CR significantly limited gastrointestinal (GI) immune activation, improved tricarboxylic acid cycle flux, and lowered concentrations of soluble CD14 and several TNF-related molecules in plasma. Blood SIV DNA levels however were unchanged by CR, suggesting that residual GI dysfunction and inflammation can be decoupled from viral persistence. Our findings highlight that a dietary modality can limit pathology in a primate lentiviral infection. They also reveal the robust but temporally constrained nature of glycolysis in supporting an acute antiviral response.
    SIGNIFICANCE: Caloric restriction (CR) is a safe dietary intervention known to confer anti-aging and health benefits across diverse animal models. However, its application in the context of infectious diseases has yielded mixed outcomes and has largely been limited to murine systems. In this study, we therefore employed CR to examine the impact of dietary modulation on SIV infection outcomes. Our findings demonstrate that CR reduced acute-phase viremia and attenuated markers of chronic inflammation following ART, effects that were associated with distinct metabolic signatures. Collectively, these findings underscore the importance of diet and nutrition in shaping chronic viral infection outcomes, such as SIV, within a clinically relevant non-human primate model.
    DOI:  https://doi.org/10.64898/2026.03.11.711076
  36. MedComm (2020). 2026 Apr;7(4): e70647
    Multi-Omics Analysis in Autoimmunity: Identification of MicroRNA Regulatory Networks and Cell-Type-Specific Dysregulations in Multiple Sclerosis and Type 1 Diabetes.
    Jacopo Ronchi, Roberta Rigolio, Davide Maria Trevisan, Angela Papagna, Angela Stabilini, Martina Gallinaro, Maria Letizia Fusco, Martina Gaia Cogo, Guido Cavaletti, Giovanni Malerba, Manuela Battaglia, Maria Foti.
      Autoimmune diseases (AIDs) arise from complex immune dysregulations involving multiple immune cell types, cytokines, and molecular mediators. Among these, microRNAs (miRNAs) have recently emerged as key regulators of leukocyte processes and are frequently dysregulated in AIDs. However, their role in disease pathophysiology remains poorly understood. In this study, we performed a comprehensive analysis of miRNA expression in three immune populations, namely, CD14+ monocytes, neutrophils, and CD8+ T cells, in multiple sclerosis (MS) and type 1 diabetes (T1D), two prototypical AIDs. Our results reveal distinct patterns of miRNA dysregulation in each cell type, with monocytes from T1D patients showing enhanced M1 polarization and supporting inflammatory vascular damage. On the other hand, CD8+ T cells from MS patients show profound alterations related to CD8+ T cell-fate commitment, apoptosis regulation, and migratory capacity. Notably, we identified miRNAs that regulate key transcription factors such as FOXP3, IRF4, and RORγt, potentially shaping T cell differentiation programs. Our results suggest that miRNA networks play a central role in orchestrating disease-specific dysregulation in AIDs. By elucidating these intricate regulatory mechanisms, our study provides a foundation for future therapeutic strategies targeting miRNAs in autoimmunity.
    Keywords:  Type 1 diabetes; autoimmunity; data integration; microRNAs; multiple sclerosis; multi‐omics
    DOI:  https://doi.org/10.1002/mco2.70647
  37. Nat Aging. 2026 Apr 06.
    Extracellular vesicles derived from senescent hepatocytes drive pan-cancer metastasis in aging.
    Huilong Li, Ruzhou Zhao, Luming Wan, Yang Yuan, Enhao Ma, Yingang Li, Zhuangzhuang Chen, Binbin Liu, Yurong Song, Ziwei Cao, Xinxin Jiao, Yue Wang, Peng Wu, Hao Jin, Jiatong Li, Xiaopan Yang, Linfei Huang, Yanhong Zhang, Ke Yang, Jiang Huo, Haoran Jin, Hui Zhong, Min Min, Shaohua Zhang, Yuan Cao, Wenlong Li, Rui Zhang, Congwen Wei.
      Malignant tumors are the leading cause of death in individuals over 65 years old, with metastasis as the primary driver. Emerging evidence suggests that age-related metabolic changes and secreted factors increase the risk of metastasis, but the underlying mechanisms remain unclear. Here we demonstrate in mice that extracellular vesicles (EVs) from senescent hepatocytes promote metastasis across tumor types. We show that aged liver tissue exhibits elevated expression of P2X purinoceptor 7 (P2RX7), which is associated with increased EV biogenesis. We identify EV-encapsulated miRNAs (miR-25, miR-92a, miR-30c and miR-30d) that reach primary tumors through the circulation and enhance tumor invasiveness and metastatic potential. Similarly, clinical samples from older patients show reduced expression of the miRNA target genes PTEN and LATS2, as well as enhanced epithelial-mesenchymal transition in metastatic tumors. Therapeutically, targeting senescence with dasatinib and quercetin (D + Q), inhibiting P2RX7, or silencing EV-associated miRNAs considerably reduces metastasis in aged mice. Together, our study uncovers a mechanism by which senescent hepatocyte-derived EVs drive tumor metastasis during aging and highlights potential strategies to mitigate this process.
    DOI:  https://doi.org/10.1038/s43587-026-01102-5
  38. Ageing Res Rev. 2026 Apr 08. pii: S1568-1637(26)00126-1. [Epub ahead of print] 103134
    Lysosomal Control of Aging through Transcriptional and Epigenetic Regulation.
    Yikai Bai, Yu Luo, Yuyuan Wang, Jiayi Qiu, Dan Li.
      Despite the well-known role as degradative organelles, lysosomes have been identified as a central signaling hub in maintaining cellular homeostasis. Lysosomal dysfunction is a well-established driver of cellular senescence and age-related pathologies. However, the precise molecular mechanisms through which lysosomes actively regulate aging remain unclear. Excitingly, latest studies show that lysosomes are not merely passive in aging but may actively govern longevity. In this review we summarize two significant discoveries about lysosome and senescence. Li et al. discovered the lysosomal surveillance response (LySR) and Zhang et al. uncovered transgenerational lysosomal signaling. These pathways substantially contribute to enhanced organismal longevity. We further discuss the transcription factor EB (TFEB) as a central regulator linking lysosomal activity to senescence and tissue homeostasis. Together, these findings reposition lysosomes as dynamic regulators that integrate stress and metabolic cues to modulate aging programs. Therefore, targeting lysosomal signaling emerges as a promising strategy for extending healthspan and mitigating age-related disorders.
    Keywords:  Aging; Lysosome; Senescence; Transcription, TFEB
    DOI:  https://doi.org/10.1016/j.arr.2026.103134
  39. Aging Cell. 2026 Apr;25(4): e70468
    Double-Pronged NAD Preservation: Delaying Cellular Senescence and Initiating Musculoskeletal Regeneration.
    Jianfeng Yu, Mingzhuang Hou, Yaoge Deng, Chenqi Yu, Yang Liu, Kang Kang, Xiaowei Xia, Xiaoping Li, Huilin Yang, Dinghua Jiang, Wu Xu, Yijian Zhang, Xuesong Zhu.
      In the context of population aging, musculoskeletal fitness has emerged as a cornerstone of overall well-being and injury prevention, relying on the coordinated function of cartilage, bone, and muscle. Drawing on the principle of "increasing income and reducing expenditure," we propose a combinatorial formulation consisting of the nicotinamide adenine dinucleotide (NAD) precursor nicotinamide mononucleotide (NMN) and the NAD+-consuming enzyme inhibitor apigenin (API), hereafter referred to as the "N + A" regimen, to enhance NAD+ reserves. Our results revealed that the N + A formulation alleviated cellular senescence, thereby promoting the differentiation of skeletal precursor cells into chondrocytes, osteoblasts, and myocytes for the reconstruction of the musculoskeletal system. Oral administration of the N + A formulation alleviated cartilage degeneration, bone loss, and muscle atrophy; additionally, it enhanced exercise capacity in aged mice. Mechanistically, the N + A strategy preserves NAD+ levels, which are subsequently utilized by mitochondrial sirtuin 3 (SIRT3) to promote deacetylation modifications and alleviate the senescent phenotype. Moreover, oral administration of N + A indirectly enhanced the synthesis of the metabolite phytosphingosine (PHS) by the intestinal microbiota members Coriobacteriaceae_UCG-002 and Ruminococcus, thereby alleviating age-related degeneration. In summary, our findings demonstrate that enhancing the NAD+ reservoir represents a promising strategy for promoting musculoskeletal regeneration, and we developed a rational combinatorial regimen with potential for clinical translation.
    Keywords:  apigenin; cellular senescence; musculoskeletal disorders; nicotinamide adenine dinucleotide; nicotinamide mononucleotide; phytosphingosine
    DOI:  https://doi.org/10.1111/acel.70468
  40. Cancer Lett. 2026 Apr 07. pii: S0304-3835(26)00251-X. [Epub ahead of print] 218488
    Mitochondrial ACSS1 Links Acetate Metabolism to Pyrimidine Biosynthesis in Nutrient-Stressed B-Cell Lymphomas.
    Johnvesly Basappa, Aaron R Goldman, Cosimo Lobello, Shengchun Wang, David Rushmore, Olga Melnikov, Neil V Sen, Vinay S Mallikarjuna, Priyanka Jain, Masoud Edalati, David S Nelson, Kathy Q Cai, Pin Lu, Reza Nejati, Hossein Borghaei, Pradeep K Gupta, Kavindra Nath, Kathryn E Wellen, Mariusz A Wasik.
      Acetate serves as an alternative carbon source in nutrient-limited tumors, yet its role in supporting nucleotide biosynthesis remains poorly understood. Here, we identify the mitochondrial enzyme ACSS1 as a key metabolic driver in mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia (CLL). ACSS1 is frequently overexpressed and catalyzes the conversion of acetate to mitochondrial acetyl-CoA, sustaining oxidative metabolism and biosynthesis under nutrient stress. Genetic silencing of ACSS1 impairs mitochondrial respiration and disrupts acetate incorporation into acetyl-CoA, TCA cycle intermediates, glutamate, and aspartate, while markedly reducing 13C-acetate labeling of dihydroorotate and orotate, intermediates in de novo pyrimidine synthesis. Untargeted metabolomics reveal enrichment of pyrimidine biosynthesis pathways in ACSS1-high cells. Notably, acetate or uridine supplementation rescues the growth of ACSS1-deficient cells, confirming a functional link between acetate metabolism and nucleotide synthesis. Importantly, in vivo studies using two different MCL xenografts demonstrate that ACSS1 knockdown profoundly suppresses tumor growth, indicating that ACSS1 is required not only for metabolic adaptation of lymphoma cells in vitro but also in vivo. Collectively, our results uncover an ACSS1-dependent mitochondrial acetate-pyrimidine axis that sustains lymphoma growth and represents a previously unrecognized therapeutic vulnerability.
    Keywords:  ACLY; ACSS1; ACSS2; CAD; DHODH; acetate metabolism; cancer metabolism; oncometabolite
    DOI:  https://doi.org/10.1016/j.canlet.2026.218488
  41. bioRxiv. 2026 Mar 11. pii: 2026.03.06.710200. [Epub ahead of print]
    Cardiomyocyte-intrinsic SLC25A1 regulates cardiac differentiation and mitochondrial function.
    Chiemela Ohanele, Nahum F Arefeayne, Nasab Ghazal, Ethan H Liu, Nina C Turcanu, Matthew J Horchar, Biplab Dasgupta, Adriana Harbuzariu, Chunhui Xu, Victor Faundez, Jennifer Q Kwong.
      Cardiac morphogenesis is an intricate process that requires a precise coordination between metabolic and structural maturation, but how these processes are linked remain unclear. In previous work, we identified one candidate underlying this connection: the mitochondrial citrate carrier (SLC25A1), a critical regulator of embryonic heart development. Here, using systemic and cardiomyocyte-specific Slc25a1 deletion in mice together with SLC25A1 knockout (KO) human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), we demonstrate that SLC25A1 functions cell-autonomously within cardiomyocytes to regulate differentiation, mitochondrial maturation, and ventricular morphogenesis. Transcriptomic analysis of SLC25A1-deficient hearts revealed dysregulation of gene programs regulating cardiomyocyte differentiation and mitochondrial function. Consistent with these changes, loss of SLC25A1 in developing cardiomyocytes impaired mitochondrial function and resulted in defective ventricular wall compaction in vivo. Likewise, SLC25A1 KO hiPSC-CMs exhibited defective cardiomyocyte differentiation, disorganized myofibrils, and immature mitochondrial organization and function in vitro. Together, our findings position SLC25A1 as a cardiomyocyte-intrinsic, cell-autonomous regulator that links mitochondrial citrate export to developmental gene programs, revealing a mitochondrial regulatory axis for cardiomyocyte maturation and cardiac morphogenesis that contributes to congenital heart disease.
    DOI:  https://doi.org/10.64898/2026.03.06.710200
  42. Cancer Sci. 2026 Apr 09.
    When Binding Is Not Blockade: Interpreting IgG4+ T Cells After PD-1 Therapy.
    Man Sun, Dan Zang, Jun Chen.
      IgG4 positivity on circulating T cells after PD-1 therapy may indicate residual antibody binding rather than sustained functional PD-1 blockade. During sequential ramucirumab plus docetaxel plus G-CSF treatment, peripheral IgG4+ T-cell dynamics may also be influenced by redistribution and treatment-related confounders, limiting direct inference about effective intratumoral antitumor immunity.
    Keywords:  IgG4‐positive T cells; PD‐1 blockade; antiangiogenic therapy; biomarker interpretation; immunotherapy sequencing
    DOI:  https://doi.org/10.1111/cas.70379
  43. Immunobiology. 2026 Mar 29. pii: S0171-2985(26)00022-7. [Epub ahead of print]231(3): 153176
    Increased Granzyme K+ CD8+ T cells and senescent subset in Behçet's disease.
    Heera Lee, Soo-Jin Lee, Young Joon Park, Han Seul Kim, Eun-So Lee, Sun Park.
       OBJECTIVES: Behçet's disease (BD) is a chronic inflammatory condition with immune system dysregulation. Recent evidence suggests proinflammatory roles of extracellular granzyme K (GzmK), particularly in aged immune cells. This study investigated GzmK-expressing CD8+ T cells and their senescent subset in BD pathology.
    METHODS: We analysed lymphocyte subsets in blood samples from 19 active BD (aBD), 19 inactive BD (iaBD), and 19 healthy controls (HC) using flow cytometry and granzymes, as well as IL-6 using enzyme-linked immunosorbent assay.
    RESULTS: Active BD patients showed significantly higher serum GzmK levels and GzmK+CD8+ T cells with advanced differentiation markers. GzmK+CD8+ T cells positively correlated with TNF-α+ and IFN-γ+ lymphocytes. The senescent subset (GzmK+CD27-CD28-CD57+CD8+) specifically correlated with TNF-α+ lymphocytes, indicating involvement in TNF-α-centered inflammatory pathways.
    CONCLUSION: GzmK+CD8+ T cells and their senescent counterparts are not merely biomarkers of disease activity but may function as extracellular proinflammatory effectors that amplify the TNF-α-mediated inflammatory loop in BD. Targeting the GzmK-senescence axis represents a promising therapeutic strategy for managing chronic inflammation in BD.
    Keywords:  Behçet's disease; CD8(+) T cells; Granzyme K; Immunosenescence; Interferon-gamma (IFN-γ); Tumor necrosis factor-alpha (TNF-α)
    DOI:  https://doi.org/10.1016/j.imbio.2026.153176
  44. Front Psychiatry. 2026 ;17 1780383
    The emerging role of T cells in depression.
    Huaibing Wang, Hongxia Tao, Minlan Yuan, Wei Zhang.
      Depression is increasingly recognized as a disorder involving immune brain interactions beyond classical monoaminergic dysfunction. Among immune components, T cells have emerged as key regulators linking peripheral immune dysregulation to central neuroinflammation and impaired neuroplasticity. Accumulating clinical and preclinical evidence indicates that alterations in T cell subsets, including regulatory T cells, Th1 cells, and Th17 cells, contribute to depressive pathophysiology through coordinated effects on blood-brain barrier permeability, glial activation, cytokine signaling, and neurotrophic support. This review synthesizes current evidence on the mechanisms by which T cells migrate into the central nervous system and modulate depressive behaviors. Particular emphasis is placed on the T cell regulation of brain derived neurotrophic factor signaling, and a role for T cell derived extracellular vesicles as modulators of immune neural communication and neuroplasticity. Finally, we discuss the therapeutic implications of targeting T cells in depression, including modulation of T cell subset balance, cytokine-based interventions, microbiota immune regulation, and inhibition of pathogenic T cell trafficking into the brain. Together, these findings position T cells as central orchestrators of immune neural crosstalk and promising targets for mechanism informed immunotherapies in depression.
    Keywords:  T cells; depression; immunotherapy; neuroinflammation; neuroplasticity
    DOI:  https://doi.org/10.3389/fpsyt.2026.1780383
  45. Prog Neurobiol. 2026 Apr 07. pii: S0301-0082(26)00041-9. [Epub ahead of print] 102915
    Glial Dynamics in Brain Aging: Cellular Heterogeneity and Regional Vulnerability.
    Kyoungho Suk.
      Brain aging involves progressive structural, functional, and molecular changes that impair cognition and increase vulnerability to neurodegenerative diseases. While neurons have traditionally received primary research focus, recent advances in single-cell transcriptomics, spatial genomics, and functional imaging reveal that glial cells-microglia, astrocytes, and oligodendrocytes-undergo profound, heterogeneous alterations during aging that actively drive brain dysfunction. These changes include microglial transition from homeostatic surveillance to inflammatory, dystrophic states; astrocyte shift from metabolic support to atypical reactive phenotypes with impaired neurovascular coupling; and oligodendrocyte dysfunction causing progressive myelin degeneration. Critically, glial aging exhibits marked regional heterogeneity, with hippocampus and prefrontal cortex showing heightened vulnerability while cerebellum remains relatively preserved, patterns mirroring cognitive decline topography. At the molecular level, glial senescence involves interconnected mechanisms including cellular senescence with senescence-associated secretory phenotype (SASP), oxidative stress and mitochondrial dysfunction, impaired proteostasis and autophagy, epigenetic alterations favoring inflammatory gene expression, and dysregulated inflammatory signaling pathways. These changes propagate through complex glial-glial and neuron-glia interaction networks, amplifying dysfunction beyond individual cellular deficits. Importantly, glia retain plasticity enabling therapeutic intervention through diverse strategies: senolytic elimination of senescent cells, microglial phenotype modulation, remyelination enhancement, metabolic interventions, and lifestyle modifications including exercise and dietary approaches. This review synthesizes current understanding of glial heterogeneity, regional vulnerability patterns, underlying molecular mechanisms, and emerging therapeutic opportunities, providing an integrated framework for targeting glial dysfunction to promote healthy brain aging and prevent cognitive decline.
    Keywords:  Brain aging; Cellular senescence; Glia; Neuroinflammation; Regional vulnerability; Therapeutic interventions
    DOI:  https://doi.org/10.1016/j.pneurobio.2026.102915
  46. Int J Biol Sci. 2026 ;22(6): 2869-2884
    Clonotype-Resolved Single-Cell Multi-Omics Unlocks the Profile of Tumor-Infiltrating CD39⁺CD8⁺ T Cells and Enables Adoptive Cell Therapy for Solid Tumor.
    Zihan Zhao, Xiangyu Wu, Qingyang Jin, Xin Yang, Wenjie Zhu, Ning Jiang, Tianyao Liu, Tianhang Li, Feng Fang, Hongqian Guo, Rong Yang.
      Tumor-reactive T cells are central to cancer immunotherapy, and immune checkpoint inhibitors (ICIs) have revolutionized treatment by relieving immune suppression on tumor-reactive T cells, yet response rates remain suboptimal. Adoptive T cell therapy can supplement tumor-reactive T cells, but accurately identifying tumor-reactive CD8⁺ T cells within tumor-infiltrating lymphocytes (TILs) remains challenging. CD39 (ENTPD1) is a rate-limiting enzyme in adenosine metabolism, leading to the view that CD39 is associated with immune suppression because of the inhibitory function of adenosine in tumor immunity. However, its role in tumor-reactive CD8⁺ TIL endures as controversial. In this study, we reassess the tumor-reactive potential of CD39⁺CD8⁺ TILs using clonotype-resolved single-cell multi-omics. Compared to CD39⁻CD8⁺ TILs, CD39⁺CD8⁺ TILs exhibited features of proliferation, activation, and T cell-mediated cytotoxicity, alongside reduced TCR clonal diversity and increased TCR clonal expansion, indicating tumor reactivity. TCR-T cells engineered with TCRs from CD39⁺CD8⁺ TILs mediated robust antigen-specific killing in vitro. Importantly, reinfusion of CD39⁺CD8⁺ TILs significantly inhibited tumor growth and demonstrated favorable safety in vivo. At the patient level, we further demonstrated that CD39⁺CD8⁺ TILs are enriched for effector programs and pathways linked to T-cell activation and cytotoxicity, and exhibit reduced TCR clonal diversity with pronounced clonal expansion. The intratumoral abundance of CD39⁺CD8⁺ TILs also correlated with earlier tumor stage and improved overall survival, and a CD39⁺CD8⁺ TIL-derived gene signature predicted ICI response and prognosis, supporting CD39 as a practical biomarker to enrich tumor-reactive CD8⁺ TILs and to improve adoptive cell transfer strategies in future clinical practice.
    Keywords:  CD39 (ENTPD1); TIL therapy; adoptive cell therapy; bladder cancer; single-cell sequencing analysis; tumor-infiltrating lymphocyte
    DOI:  https://doi.org/10.7150/ijbs.130389
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