bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2026–03–22
forty-one papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. S1P-S1PR1 signaling impairs CD8+ T cell metabolism and effector function in tumors.
  2. The AICL-KLRF1 axis supports CD4-CD8 T cell communication and cytokine competence in pre-exhausted CD8+ T cells.
  3. Proteasome-guided haem signalling axis contributes to T cell exhaustion.
  4. Functional Type I and Type II interferon crosstalk restricts progenitor exhausted CD8 T cells through spatial exclusion and checkpoint enforcement.
  5. A post-translational regulatory map of chronic antigen-driven human T cell dysfunction.
  6. DGAT1 mediates sex-specific CD8+ T cell antitumour responses.
  7. TCR-NF-κB signaling activates the SENP1-NR4A1 axis to fine-tune effector activation of CD8+ T cells.
  8. Transient loss of KLF2 expression is essential for CD8 effector T cell expansion.
  9. Dynamic regulation of BACH2 enhances CAR T cell function.
  10. Oxidizing to optimize stemness and antitumor immunity.
  11. Metabolic, epigenetic, and immune crosstalk in ovarian aging.
  12. The iterative shrinkage thresholding algorithm reveals dynamic aging trajectories of human T lymphocytes via multidimensional spectral flow cytometry analysis.
  13. CD93-targeted resveratrol-loaded PLGA nanoparticles remodel CD8⁺ T cell metabolism through AIF-mediated oxidative phosphorylation to overcome lung cancer immunotherapy resistance.
  14. Beyond drug delivery: nanoparticles as active modulators of immunometabolism for treating inflammatory diseases.
  15. METTL16-mediated m6A modification of LYRM2 drives breast cancer progression by inducing CD8+ T cell dysfunction via Glycolysis.
  16. Improving lymphopoiesis in aged bone marrow.
  17. Sustained nitric oxide production by engineered E. coli remodels the tumor microenvironment and potentiates immunotherapy.
  18. Two Costimulations Are Better Than One: Role of Endogenous CD28 in 4-1BB CAR T Cells.
  19. Editorial: Lipids in immunometabolism.
  20. Prodrug-tethered lipid nanoparticles for synergistic messenger RNA cancer immunotherapy.
  21. Mitochondrial β-carbonic anhydrase is a conserved metabolic rheostat for branched-chain amino acid catabolism and metabolic flexibility.
  22. Do metabolic fluxes change with age?
  23. Pan-cancer analysis reveals HDAC1 as a key regulator of immune infiltration and T cell exhaustion.
  24. Keratinocyte-derived Exosomal LKB1 Drives Vitiligo Progression by Activating CD8+ T Cells.
  25. Albumin-Bound STING Agonist Reprograms HSPCs to Antitumor Neutrophils Enhancing CD8+ T Cell Immunity.
  26. The hypoxic tumor microenvironment: Functional and metabolic reprogramming of key immune populations.
  27. Chromatin reorganization drives overexpression of a Btaf1 variant underpinning hematopoietic aging.
  28. [Metallophilic macrophages of the splenic marginal zone: myeloid sentinels capable of cross-priming CD8+ T cell antitumor immunity].
  29. TCR-pMHC recognition mediates target phagocytosis by T cells.
  30. Loss of p53 exacerbates autoimmunity by reprogramming propionyl-CoA metabolism and histone modifications in Treg cells.
  31. KLHL6: a proteostatic guardian against T-cell exhaustion.
  32. Renaissance of antiviral CD8+ T cell immunity in vaccination and disease.
  33. T cells in osteoarthritis; drivers, repairers or bystanders in osteoarthritis?
  34. Reactivating exhausted tumor-infiltrating T cells by a bispecific DC-T cell engager in mice.
  35. T cell-intrinsic VISTA expression promotes resistance to CTLA-4 blockade by restricting CD8+ T cell responses.
  36. Systems Biology of Metabolic Dysregulation in Ankylosing Spondylitis Using scRNA-Seq Data.
  37. DUSP6 ablation restores CAR T-cell fitness impaired by tumor CD58 loss through invigoration of AP-1 signaling.
  38. The roles and heterogeneity of CD8+ T cells in inflammatory bowel disease: A narrative review of insights from single‑cell transcriptomics (Review).
  39. Preclinical comparison of non-signaling domain in CD19 CAR T cell with interleukin-7 receptor alpha signaling domain.
  40. Engineering BiTE-inspired IPSC-exosomes to potentiate CAR-T cell therapy against lung cancer.
  41. Dengue infection elicits skin tissue-resident and circulating CD8+ T cells associated with protection from hospitalization.
  1. EMBO Rep. 2026 Mar 19.
    S1P-S1PR1 signaling impairs CD8+ T cell metabolism and effector function in tumors.
    Debashree Basak, Puspendu Ghosh, Anupam Gautam, Ishita Sarkar, Arpita Bhoumik, Soham Chowdhury, Shaun Mahanti, Anwesha Mandal, Rajeswari Chakraborty, Anwesha Kar, Snehanshu Chowdhury, Krishna Kumar, Shubhrajit Barman, Senthil Kumar Ganesan, Saikat Chakrabarti, Sandip Paul, Shilpak Chatterjee.
      Sphingosine-1-phosphate receptor 1 (S1PR1) signaling has been linked to the regulation of immunosuppressive cell populations within the tumor microenvironment (TME); however, its role in shaping anti-tumor CD8⁺ T cell responses remains poorly defined. Herein, we demonstrate that intratumoral CD8⁺ T cells express S1PR1, with expression predominantly enriched in the terminally exhausted subset. Transcriptomic profiling, combined with pharmacological inhibition and genetic knockdown, reveals that S1PR1-S1P signaling activates the PERK (protein kinase R (PKR)-like endoplasmic reticulum kinase)-CHOP (C/EBP homologous protein) axis of the endoplasmic reticulum stress response. CHOP, in turn, upregulates transcription of Map3k13 and Map3k15, triggering downstream MAPK signaling and culminating in activation of p38MAPK. Activation of this pathway impairs CD8⁺ T cell metabolism and effector function while increasing apoptotic susceptibility. This ultimately limits the persistence and accumulation of functional CD8⁺ T cells within the TME, thereby compromising their responsiveness to anti-PD-1 therapy. Targeting the S1PR1-S1P axis or its downstream effectors offers a promising strategy to improve cancer immunotherapy outcomes.
    Keywords:  CD8+ T Cells; ER Stress; S1P-S1PR1
    DOI:  https://doi.org/10.1038/s44319-026-00734-3
  2. EMBO Rep. 2026 Mar 18.
    The AICL-KLRF1 axis supports CD4-CD8 T cell communication and cytokine competence in pre-exhausted CD8+ T cells.
    Matthias Barone, Stefan Peidli, Anika Neuschulz, Karla Riesterer, Christina Iwert, Laia Junquera, Somesh Sai, Olufemi Bolaji, Diana Bakoueva, Christine Appelt, Benedikt Obermayer, Bertram Klinger, Alexandra Trinks, Anja Sieber, Nils Blüthgen, Birgit Sawitzki.
      Memory-like or precursor exhausted (Tpex) CD8+ T cells are a critical reservoir in chronic infections and cancer, yet the signals sustaining their cytokine production remain unclear. Here, we identify KLRF1 as part of a CD4-CD8 communication axis that supports cytokine production in late-differentiated human CD8+ T cells. KLRF1 is upregulated in late-differentiated CD8+ T cells, and neutralizing KLRF1 reduces TNF and IFN-γ production. Differentiated CD4+ T cells express the KLRF1 ligand AICL, and in co-culture only AICL+ - not AICL⁻ - CD4+ T cells enhance cytokine output in CD8+ T cells. Using spatial proteomics of lung adenocarcinoma and adjacent tissue, we found that CD4+ AICL+ and CD8+ KLRF1+ T cells are enriched and spatially interacting in non-tumor regions, whereas both populations are reduced within tumor tissue. Single-cell RNA-seq of tissue samples and scRNA/ATAC analyses of circulating immune cells further showed that CD8+KLRF1+ T cells display a Tpex-like transcriptional and chromatin-accessibility profile. Together, these data identify the AICL-KLRF1 axis as a CD4+-CD8+ communication pathway that supports cytokine competence in late-differentiated CD8+ T cells.
    Keywords:  Cytotoxic T Cell; KLRF1; T Cell Exhaustion; Tumor Immunology
    DOI:  https://doi.org/10.1038/s44319-026-00732-5
  3. Nature. 2026 Mar 18.
    Proteasome-guided haem signalling axis contributes to T cell exhaustion.
    Yingxi Xu, Yangtao Shangguan, Yu-Ming Chuang, Tzu-Hsuan Chang, Wenbing Liu, Jhan-Jie Peng, Josep Garnica, Leling Xie, Pei-Chun Hsueh, Mei-Chun Lin, Yi-Hao Wang, Karina Lobo Hajdu, Yibo Wu, Maryam Akrami, Chen Wang, Anna Kohl, Alfred Zippelius, Wei Qi, Min Wang, Bugi Ratno Budiarto, Shih-Yu Chen, Zhengtao Xiao, Panagiota Vardaka, Rahul Roychoudhuri, Zhiliang Bai, Rong Fan, Santiago Carmona, Yi-Ru Yu, Christoph Scheiermann, Jianxiang Wang, Ping-Chih Ho.
      The accumulation of depolarized mitochondria commits T cells to exhaustion1-3, yet the precise mechanism remains unclear. Here we find that exhausted CD8+ T cells increase proteasome activity owing to the accumulation of depolarized mitochondria, which drives the selective degradation of mitochondrial proteins and the release of regulatory haem through haemoprotein breakdown. In turn, increased regulatory haem disrupts BACH2-mediated transcriptional regulation, thereby exacerbating T cell exhaustion and compromising stemness-like properties. Inhibition of nuclear import of regulatory haem prevents BACH2 degradation and enhances the anti-tumour efficacy of antigen-specific T cells. We find that the therapeutic efficacy of human CD19+ chimeric antigen receptor (CAR)-T cells in patients with B cell acute lymphoblastic leukaemia negatively correlates with the proteasome gene signature in their CAR-T cells. Manufacturing CAR-T cells in the presence of bortezomib, an FDA-approved proteasome inhibitor, prevents T cell exhaustion and improves therapeutic efficacy. Our findings identify a proteasome-guided haem signalling axis, governed by mitochondrial integrity, as a regulator of CD8+ T cell exhaustion and propose innovative therapeutic strategies that exploit this pathway to optimize adoptive cellular immunotherapy.
    DOI:  https://doi.org/10.1038/s41586-026-10250-y
  4. bioRxiv. 2026 Mar 03. pii: 2026.03.01.708869. [Epub ahead of print]
    Functional Type I and Type II interferon crosstalk restricts progenitor exhausted CD8 T cells through spatial exclusion and checkpoint enforcement.
    Siran Liu, Heidi J Elsaesser, Rene Quevedo, Diala Abd-Rabbo, Bruna C Bertol, Wenxi Xu, Melissa Yi Ran Liu, Sabelo Lukhele, Sara Lamorte, Tracy L McGaha, David G Brooks.
      Type I interferon (IFN-I) and interferon-γ (IFNγ) are central regulators of antiviral immunity, yet how they cooperatively govern CD8 T cell fate during chronic infection remains unresolved. Here, we uncover a previously unrecognized, spatially encoded interferon circuit that actively constrains progenitor exhausted CD8 T cells (Tpex) during chronic LCMV infection. Persistent IFN-I signaling indirectly restricts Tpex expansion by enforcing their sequestration within PDL1-rich B cell niches of lymphoid tissue and by suppressing T cell-derived IFNγ. Blockade of IFN-I signaling enables Tpex migration into T cell zones of splenic follicles driving IFNγ production, which in turn sustains PDL1 expression on myeloid cells to re-impose local inhibitory pressure. Combined IFN-I and IFNγ blockade disrupts this feedback, promoting coordinated niche redistribution of Tpex and checkpoint remodeling that drives robust Tpex expansion. Single-cell transcriptomics reveal that this layered IFN-I-IFNγ interplay establishes a regulatory balance that constrains Tpex proliferation while preserving effector-like transcriptional programs in their progeny effector CD8 T cells, ultimately preventing premature terminal differentiation. Thus, interferons orchestrate the coordinated T cell-myeloid regulatory circuit that integrates tissue organization, cytokine feedback, and checkpoint control to regulate CD8 T cell exhaustion during chronic infection.
    DOI:  https://doi.org/10.64898/2026.03.01.708869
  5. bioRxiv. 2026 Mar 06. pii: 2026.03.04.709614. [Epub ahead of print]
    A post-translational regulatory map of chronic antigen-driven human T cell dysfunction.
    Hiroyuki Kojima, Charlotte R Wayne, Luis F Somarribas Patterson, Henry Sanford, Tzu-Jou Chen, Ya-Hui Lin, Joshua D Schoenfeld, Lisa H F McGary, Yan-Ting Chen, Korbinian N Kropp, Beatrice Zhang, Jahan Rahman, Tiffany L Zhang, Nathalie Ropek, Cameron Roberts, Yuxi Ai, Kartikeya M Menon, A Ari Hakimi, Jiankun Lyu, Christopher A Klebanoff, Omar Abdel-Wahab, Santosha A Vardhana, Ekaterina V Vinogradova.
      T cells exposed to persistent antigen in the context of chronic viral infections or cancer lose self-renewal and cytotoxic capacity. Several transcriptional, epigenetic, and metabolic drivers of this process have been identified. However, the post-transcriptional regulatory mechanisms influencing the proteome of dysfunctional T cells are not well understood. Here we present a time-resolved molecular landscape of human T cells during the development of chronic antigen-driven dysfunction. Persistent T cell receptor stimulation significantly remodeled the proteome, including changes in canonical T cell exhaustion-associated proteins and proteins related to mitochondrial function, redox homeostasis, nucleotide metabolism, and cell-cycle progression. Dysfunctional T cells displayed activation of stress response pathways that were recapitulated in vivo ; targeting these pathways altered the cytotoxic capacity of T cells during persistent tumor exposure. Our comprehensive proteomic resource reveals unique post-transcriptional changes in dysfunctional T cells and lays the groundwork for novel cysteine-directed therapeutics to enhance cancer immunotherapy.
    DOI:  https://doi.org/10.64898/2026.03.04.709614
  6. Nat Metab. 2026 Mar 20.
    DGAT1 mediates sex-specific CD8+ T cell antitumour responses.
    Alaa Madi, Hui Shi, Min Su, Ahmed Mady, Boqiong Lv, Haiyan Wang, Bing Yang, Zhenni Yan, Xiaomeng Jin, Lingling Wu, Mengyue Lv, Marvin Hering, Sicong Ma, Alessa Mieg, Ferdinand Zettl, Xin Yan, Kerstin Mohr, Nora Knabe, Gernot Poschet, Karsten Richter, Nikolai Schleußner, Rene-Filip Jackstadt, Sonja Loges, F Nina Papavasiliou, Xi Wang, Jingxia Wu, Guoliang Cui.
      Fatty acid (FA) oxidation plays an important role in T cell responses. However, whether DGAT1-mediated FA esterification to triacylglycerol also regulates T cell function remains unclear. Here we uncover a sexually dimorphic requirement for DGAT1 expression in CD8+ tumour-infiltrating lymphocyte function. In female mice, T cell-specific Dgat1 deficiency improves mitochondrial metabolic fitness and expands the pool of progenitor exhausted CD8+ T (Tex) cells to sustain antitumour responses. In male mice, however, Dgat1 deficiency leads to FA peroxidation, endoplasmic reticulum (ER) stress and CD8+ Tex cell death. We show that these effects are mediated by androgen receptor (AR) signalling. Deletion of Ar, overexpression of glutathione peroxidase 4, or inhibition of ER stress-induced cell death rescues Dgat1-deficient CD8+ T cell survival and promotes antitumour responses in male mice. Overall, this study suggests that DGAT1 detoxifies AR signalling in male mice to protect against ER stress-induced cell death and maintain T cell stemness, and uncovers sex-specific metabolic adaptations in the tumour microenvironment.
    DOI:  https://doi.org/10.1038/s42255-026-01462-7
  7. Cell Rep. 2026 Mar 13. pii: S2211-1247(26)00180-4. [Epub ahead of print]45(3): 117102
    TCR-NF-κB signaling activates the SENP1-NR4A1 axis to fine-tune effector activation of CD8+ T cells.
    Cen Jiang, Yuquan Yang, Jing Tian, Zi Liang, Qiuju Fan, Qi Wang, Lei Shen, Shengdian Wang, Jianli He, Jinke Cheng.
      T cell receptor (TCR) signaling plays a crucial role in T cell activation by creating a negative controlling mechanism to limit the strength of immune activation; however, the underlying mechanisms remain to be fully elucidated. Here, we identify the small ubiquitin-like modifier (SUMO)-specific protease 1 (SENP1) as a target of the TCR-NF-κB signaling pathway that negatively regulates TCR-induced CD8+ T cell activation. SENP1 deficiency promotes the early occurrence of TCR-induced CD8+ T cell proliferation and effector gene expression. Mechanistically, the nuclear receptor NR4A1 is identified as a deSUMOylation target of SENP1 during this process. SENP1-mediated deSUMOylation of NR4A1 enhances its suppressive effect on the expression of TCR-induced effector genes in CD8+ T cells. Deficiency in the SENP1-NR4A1 axis markedly enhances the CD8+ T cell response against L. monocytogenes infection. Collectively, these findings identify SENP1 as a crucial regulator that integrates TCR-NF-κB signaling with NR4A1 activity to fine-tune the CD8+ T cell-mediated immune response.
    Keywords:  CD8(+) T cell; CP: immunology; NR4A1; SENP1; SUMOylation; T cell receptor
    DOI:  https://doi.org/10.1016/j.celrep.2026.117102
  8. J Immunol. 2026 Mar 17. pii: vkag008. [Epub ahead of print]215(3):
    Transient loss of KLF2 expression is essential for CD8 effector T cell expansion.
    Geoffrey S Kansas.
      How T cell expansion, migration, and differentiation are coordinately controlled remains incompletely understood. The KLF2 transcription factor is critical for expression of cell surface molecules, which control lymphocyte traffic, and has been postulated to function as a mediator of T cell quiescence. KLF2 expression is rapidly and transiently silenced in activated T (and other) cells via proteolytic degradation and transcriptional silencing, but why recently activated T cells need to turn off KLF2 expression has remained unknown. Here, functions of transient KLF2 loss have been investigated using a novel mouse model in which expression of a KLF2 point mutant which cannot be proteolytically degraded or transcriptionally silenced is turned on by cre-mediated recombination, such that KLF2 expression and function is continuously maintained in T cells. In response to infection with LCMV, generation of CD4 effector T cells was only slightly decreased. In contrast, generation of CD8 effector T cells was sharply reduced, an effect which was intrinsic to CD8 T cells. Despite this, CD8 T cell proliferation in vitro was only modestly inhibited by constitutive KLF2 expression. These findings document an essential requirement for KLF2 downregulation in expansion of CD8 T cells in vivo, identify unanticipated differences between CD4 and CD8 T cells in their requirements for KLF2 downregulation, and suggest that mechanisms distinct from repression of proliferation underlie the failure of activated CD8 T cells to expand in response to viral infection.
    Keywords:  T cell differentiation; T cells; transcription factors
    DOI:  https://doi.org/10.1093/jimmun/vkag008
  9. Mol Ther Oncol. 2026 Mar 19. 34(1): 201164
    Dynamic regulation of BACH2 enhances CAR T cell function.
    Tien-Ching Chang, John M Warrington, Nathan Singh.
      
    DOI:  https://doi.org/10.1016/j.omton.2026.201164
  10. Cell Chem Biol. 2026 Mar 19. pii: S2451-9456(26)00067-X. [Epub ahead of print]33(3): 280-281
    Oxidizing to optimize stemness and antitumor immunity.
    Julian J Lum.
      In this issue of Cell Chemical Biology, Pang et al.1 address the question of how effector CD8⁺ T cells acquire stem-like durability. They uncover a redox-driven metabolic program in which NQO1-mediated cycling of lawsone enhances pentose phosphate pathway, remodels mitochondrial function, and connects effector differentiation to sustained antitumor immunity.
    DOI:  https://doi.org/10.1016/j.chembiol.2026.02.011
  11. iScience. 2026 Mar 20. 29(3): 114733
    Metabolic, epigenetic, and immune crosstalk in ovarian aging.
    Jing Li, Qianhui Liao, Yan Yang, Kang Wang, Weiai Liu, Fang Zhou, Huiping Liu, Ye Zhang.
      Ovarian aging, marked by follicle depletion and oocyte quality decline, involves complex metabolic alterations. This review synthesizes evidence that dysregulated metabolic reprogramming, encompassing energy, lipid, and nutrient metabolism, drives ovarian functional decline. Central to this process is a self-reinforcing "metabolism-epigenetics-immunity" triangular network, where mitochondrial dysfunction and NAD+ depletion disrupt epigenetic regulation and activate chronic inflammation, collectively accelerating follicular atresia and hormonal dysfunction. By integrating this mechanistic framework, we highlight emerging intervention strategies targeting metabolic hubs, such as mitochondrial rescue and senescent cell clearance, which offer new avenues for preserving ovarian function. This work provides a conceptual foundation for developing personalized strategies to mitigate reproductive aging and its systemic health impacts.
    Keywords:  epigenetics; human metabolism; immunity
    DOI:  https://doi.org/10.1016/j.isci.2026.114733
  12. Int Immunopharmacol. 2026 Mar 14. pii: S1567-5769(26)00320-6. [Epub ahead of print]176 116476
    The iterative shrinkage thresholding algorithm reveals dynamic aging trajectories of human T lymphocytes via multidimensional spectral flow cytometry analysis.
    Yan Chen, Junxiang Shu, Hongjie Liu, Ying Jiao, Minyan He, Xianfeng Zha, Rong Guo, Chunyu Huang, Zhiqiang Liu, Guangqiang Li, Yafang Li, Li Shi, Meiji Chen, Xin Tang, Mingyue Zhang, Jie Qin, Yan Xu, Zheng Xiang, Zhinan Yin.
      Immunosenescence is a fundamental hallmark of aging, characterized by differential susceptibility across immune cell lineages. T lymphocytes are particularly vulnerable; however, the distribution and dynamics of aging-associated immune markers across T cell subsets remain incompletely characterized. In this study, we enrolled 462 healthy individuals stratified into six groups spanning 20 to over 70 years. Using multiparametric spectral flow cytometry, we systematically characterized T lymphocyte subsets, capturing both immunophenotypic diversity and functional status. We identified a progressive age-associated decline in the frequencies of CD8+, γδ+, and Vδ2+ T cells, alongside an increase in CD4+ T cells. Aging was marked by the reduction of naive T cells and an expansion of terminally differentiated effector memory populations. Among all subsets, CD8+ T cells exhibited the greatest sensitivity to age-associated immunophenotypic remodeling, characterized by reduced expression of CD27 and CD28, and increased expression of senescence-associated surface markers including CD57 and KLRG1, together with elevated cytotoxic effector molecules including IFN-γ and granzyme B. Using these parameters, we defined 10 immune biomarkers through machine learning approaches that accurately predicted chronological age (R2 = 0.81, P < 0.001). We further reconstructed the trajectory of T cell aging using ISTA-based sparse coding, which can capture aging-related immunophenotypic patterns in over 80% of individuals across age groups. Together, these findings demonstrate the dynamic remodeling of T lymphocytes across the human lifespan and provide a foundation for immune age modeling and risk stratification for unhealthy aging.
    Keywords:  Aging-related immune markers; Immune function; Immunosenescence; Iterative shrinkage and threshold algorithm (ISTA); T lymphocytes
    DOI:  https://doi.org/10.1016/j.intimp.2026.116476
  13. J Nanobiotechnology. 2026 Mar 14.
    CD93-targeted resveratrol-loaded PLGA nanoparticles remodel CD8⁺ T cell metabolism through AIF-mediated oxidative phosphorylation to overcome lung cancer immunotherapy resistance.
    Zhou Jiang, Yuning Li.
      Lung cancer (LC) remains a leading cause of cancer-related mortality worldwide, and the limited efficacy of immunotherapy due to treatment resistance underscores the urgent need for new therapeutic strategies. In the present study, CD93-targeted poly(lactic-co-glycolic acid) (PLGA) nanoparticles encapsulating resveratrol (CD93-NPs@RSV) were developed to remodel the metabolic fitness of CD8+ tumor-infiltrating lymphocytes. The nanoparticles were precisely engineered and characterized using dynamic light scattering, transmission electron microscopy, and in vivo imaging, which confirmed their stability and tumor-targeting capability. Mechanistic studies revealed that CD93-NPs@RSV suppressed CD93 expression, facilitated apoptosis-inducing factor (AIF) mitochondrial translocation, and activated oxidative phosphorylation (OXPHOS), thereby enhancing T cell function in the tumor microenvironment. Transcriptomic and proteomic analyses further confirmed regulation of the CD93-AKT-PAK5-AIF signaling axis. In a Lewis LC model, CD93-NPs@RSV significantly inhibited tumor progression and displayed strong synergy with anti-PD-1 therapy, resulting in improved survival outcomes. Collectively, our study demonstrates that CD93-NPs@RSV provide a powerful nanotechnology-driven approach to reverse immunotherapy resistance by reprogramming T cell metabolism. These findings establish a promising paradigm for precision cancer immunotherapy and underscore the translational potential of targeted nanomedicine in overcoming therapeutic bottlenecks in LC.
    Keywords:  CD93-targeted nanoparticles; Lung cancer immunotherapy resistance; Mitochondrial metabolic reprogramming; Oxidative phosphorylation; Resveratrol
    DOI:  https://doi.org/10.1186/s12951-026-04216-5
  14. J Drug Target. 2026 Mar 16. 1-33
    Beyond drug delivery: nanoparticles as active modulators of immunometabolism for treating inflammatory diseases.
    Hailing Wang, Ahequeli Gemingnuer, Yinan Wang, Yan Liu, Xin Meng.
      Immunometabolism is central to chronic inflammatory diseases, with metabolic reprogramming including dysregulated glycolysis, mitochondrial dysfunction, and excessive ROS production driving pathology in conditions like IBD, rheumatoid arthritis, and psoriasis. Although metabolic regulators hold therapeutic promise, their efficacy is limited by poor site-specific delivery and bioavailability. Nanotechnology-based platforms (e.g., liposomes, polymeric nanoparticles, nanoemulsions, metal nanoparticles) address these barriers by enhancing bioavailability and forming a protein corona that modulates nanoparticle uptake by macrophages and T cells, directly influencing metabolic fate. Advanced organelle-targeting strategies such as mitochondria-directed liposomes and lysosome-responsive polymers enable precise metabolic rescue by restoring mitochondrial respiration or modulating nutrient-sensing pathways. By targeting key metabolic nodes including HIF-1α, mTOR, and AMPK, nanocarriers actively shift immune cells from pro-inflammatory glycolysis toward anti-inflammatory oxidative phosphorylation, minimizing toxicity and restoring immune homeostasis. Thus, nanocarriers function not as passive delivery vehicles but as sophisticated immunometabolism modulators. Despite progress, a comprehensive review bridging nanomaterial design and metabolic intervention remains lacking. This review addresses that gap by highlighting nanoscale phenomena such as stimulus-responsive release, membrane perturbation, and organelle-specific targeting.
    Keywords:  Immune Modulation; Inflammatory Diseases; Metabolic Reprogramming; Nanoparticles; Targeted Drug Delivery
    DOI:  https://doi.org/10.1080/1061186X.2026.2647069
  15. J Bioenerg Biomembr. 2026 Mar 18.
    METTL16-mediated m6A modification of LYRM2 drives breast cancer progression by inducing CD8+ T cell dysfunction via Glycolysis.
    Mao Li, Haipeng Shen, Tianya Zhang, Xin Jin, Gaopei Jin, Yihao Cai.
      
    Keywords:  Breast cancer; CD8+ T cells; Glycolysis; LYRM2; METTL16
    DOI:  https://doi.org/10.1007/s10863-026-10100-6
  16. Curr Opin Hematol. 2026 Mar 19.
    Improving lymphopoiesis in aged bone marrow.
    Anna Konturek-Ciesla, David Bryder.
       PURPOSE OF REVIEW: Aging is associated with impaired B lymphopoiesis and T lymphopoiesis, contributing to immunosenescence and poor immune recovery. Although this decline can be attributed to intrinsic hematopoietic stem cell aging, growing evidence indicates that lymphoid failure reflects constraints operating across multiple levels of the hematopoietic system. This review frames age-associated lymphopoiesis decline as a systems-level problem and outlines conceptual avenues for therapeutic intervention.
    RECENT FINDINGS: Age-associated lymphoid failure is increasingly attributed to inflammatory suppression, dominance of dysfunctional stem and progenitor states, and compromised extramedullary support. These insights provide a framework for interventions that restore immune competence by rebalancing hematopoiesis or selectively replacing compromised stem cell function.
    SUMMARY: Age-associated lymphoid decline arises from coordinated constraints across the bone marrow niche, stem and progenitor composition, and extramedullary lymphoid support, rather than intrinsic stem cell exhaustion alone. Targeting these bottlenecks in a context-dependent manner offers multiple routes to improve lymphopoiesis and restore immune competence in aging.
    Keywords:  hematopoietic stem and progenitor cells; immune aging; lymphopoiesis; regeneration
    DOI:  https://doi.org/10.1097/MOH.0000000000000923
  17. Nat Biotechnol. 2026 Mar 18.
    Sustained nitric oxide production by engineered E. coli remodels the tumor microenvironment and potentiates immunotherapy.
    Shuyu Xu, Tianjiao Zhang, Yang Song, Mengxin Wang, Ruiqi Wu, Mofan Li, Haonan Wang, Xinxin Xie, Qingfeng Chen, Xiaotu Ma, Xiaolong Liang.
      Tumor immunotherapy is often compromised by an immunosuppressive tumor microenvironment (TME) characterized by abnormal vasculature and exhausted T cells. Here, given the role of nitric oxide (NO) in favorably remodeling the TME, we engineered Escherichia coli Nissle 1917 (ECN) with a synthetic arginine-NO circuit (ECN-NO) that modifies the arginine synthesis pathway to constitutively synthesize arginine and enable sustained NO production. Specifically, deletion of the arginine repressor ArgR relieved feedback inhibition of arginine biosynthesis, whereas co-expression of argininosuccinate synthase and lyase (ArgG/ArgH), together with Bacillus subtilis nitric oxide synthase (BsNOS), enabled sustained NO production through enhanced arginine regeneration. Intratumoral colonization of ECN-NO significantly enhanced the antitumor efficacy of anti-programmed cell death ligand 1 (αPD-L1) immunotherapy, resulting in durable tumor regression across multiple solid tumor mouse models. Mechanistically, ECN-NO induced vascular normalization and dendritic cell recruitment, alleviated tumor immunosuppression and synergized with αPD-L1 to expand functional CD8+ T cells, reverse T cell exhaustion and promote memory T cell formation, establishing antitumor immunity for at least 120 days.
    DOI:  https://doi.org/10.1038/s41587-026-03054-y
  18. Blood Cancer Discov. 2026 Mar 18. OF1-OF2
    Two Costimulations Are Better Than One: Role of Endogenous CD28 in 4-1BB CAR T Cells.
    Mohamad Hamieh, Michel Sadelain.
      Liberman and colleagues identify endogenous CD28 signaling as a regulator of 4-1BB chimeric antigen receptor (CAR) T-cell function by promoting metabolic fitness, proliferation, and sustained antitumor function. These findings highlight the cooperative integration of CD28 and 4-1BB signaling to harness CAR T-cell potency, persistence, and therapeutic efficacy. See related article by Lieberman et al., p. XX .
    DOI:  https://doi.org/10.1158/2643-3230.BCD-25-0491
  19. Front Immunol. 2026 ;17 1812630
    Editorial: Lipids in immunometabolism.
    Francesco Nicoli, Anshu Agrawal, Fabrizia Bonacina, Gareth S D Purvis.
      
    Keywords:  T cell metabolism; immunometabolism; lipid metabolism; macrophage polarization; metabolic diseases; sphingolipids
    DOI:  https://doi.org/10.3389/fimmu.2026.1812630
  20. Nat Nanotechnol. 2026 Mar 18.
    Prodrug-tethered lipid nanoparticles for synergistic messenger RNA cancer immunotherapy.
    Qiangqiang Shi, Ningqiang Gong, Jinjin Wang, Rohan Palanki, Qiuxian Zheng, Mohamad-Gabriel Alameh, Garima Dwivedi, Benjamin Davis, Jilian Melamed, Zhangyi Luo, Junchao Xu, Christian G Figueroa-Espada, Lulu Xue, Ye Zeng, Xuexiang Han, Dongyoon Kim, Qinyuan Chen, Hannah Yamagata, Hannah C Geisler, Rakan El-Mayta, Il-Chul Yoon, Drew Weissman, Michael J Mitchell.
      Regulating T cell phenotypes between activation and exhaustion remains a significant challenge for messenger RNA-based cancer immunotherapy. A potential approach to improve anti-cancer T cell activity is to co-deliver interleukin-12 (IL-12), to stimulate effector T cells, and indoleamine 2,3-dioxygenase (IDO) inhibitor, to suppress T cell exhaustion. Here we design prodrug ionizable lipid nanoparticles (pLNPs), via a library of prodrug ionizable lipids (pILs), incorporating an intracellularly cleavable IDO inhibitor within the pIL structure and encapsulating IL-12 messenger RNA. The lead pIL shows enhanced mRNA transfection over a clinically utilized ionizable lipid, as well as strong immunomodulatory effects via release of the IDO inhibitor. In a subcutaneous colon cancer mouse model, pLNP drives complete regression of primary tumours by eliciting effector T cell infiltration while reducing exhaustion, induces a memory T cell response and stimulates a systemic immune response that allows for regression of distal tumours in this study. These results highlight the promise of pLNPs for small-molecule drug and mRNA combination cancer immunotherapy.
    DOI:  https://doi.org/10.1038/s41565-025-02102-z
  21. New Phytol. 2026 Mar 15.
    Mitochondrial β-carbonic anhydrase is a conserved metabolic rheostat for branched-chain amino acid catabolism and metabolic flexibility.
    Naveen Sharma, Thomas D Sharkey, Federica Brandizzi.
      Carbonic anhydrases (CAs) are ubiquitous metalloenzymes that catalyze the reversible hydration of CO2, enabling fundamental processes in organisms across all domains of life. Among all CAs, the role of mitochondrial βCA remains poorly understood. Here, we identify a mitochondrial βCA, βCA6, as a key regulator of branched-chain amino acid (BCAA) catabolism and metabolic flexibility during carbon starvation in Arabidopsis thaliana. Loss of βCA6 triggers hypersensitivity to prolonged darkness, marked by accelerated Chl degradation, early senescence, impaired BCAA degradation, and disrupted carbon-nitrogen remobilization. Transcriptomic and metabolic profiling revealed elevated expression of BCAA catabolic enzymes, as well as BCAA accumulation and reduced glutamate levels, indicating defective carbon-nitrogen remobilization. βca6 loss-of-function mutants exhibited a striking hypersensitivity to exogenous BCAAs, supporting a central role of βCA6 in BCAA homeostasis. These findings uncover a previously unrecognized function for mitochondrial CA in maintaining energy balance under dark stress. Given the evolutionary conservation of mitochondria and BCAA metabolism, our work highlights a broadly relevant mechanism by which eukaryotes integrate core metabolic pathways with environmental adaptation.
    Keywords:  Arabidopsis thaliana; BCAA; carbon stress; carbonic anhydrase; mitochondria
    DOI:  https://doi.org/10.1111/nph.71056
  22. Trends Endocrinol Metab. 2026 Mar 17. pii: S1043-2760(26)00013-5. [Epub ahead of print]
    Do metabolic fluxes change with age?
    Sebastian J Hofer, Anna Katharina Simon, Frank Madeo.
      Metabolomes change with age. Yet, fluxomics points to a contradiction: Jankowski et al. in Cell Metabolism report shifts in metabolite concentrations in aged mice, alongside largely preserved metabolite fluxes, evoking important questions on the nature of age-related metabolic disturbances. We discuss how this might recalibrate our understanding of aging metabolism.
    Keywords:  age-associated diseases; aging; autophagy; geroscience; metabolism
    DOI:  https://doi.org/10.1016/j.tem.2026.01.013
  23. Discov Oncol. 2026 Mar 17.
    Pan-cancer analysis reveals HDAC1 as a key regulator of immune infiltration and T cell exhaustion.
    Xiaoyang Wang, Fengjin Liu, Wenxia Tian, Xueming Chao, Yun Li, Lin Deng, Shuaichao Sui, Meiling Gao.
      
    Keywords:  Class I histone deacetylase; HDAC1; Immune infiltration; Pan-cancer analysis; T cell exhaustion; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s12672-026-04869-6
  24. Inflammation. 2026 Mar 16.
    Keratinocyte-derived Exosomal LKB1 Drives Vitiligo Progression by Activating CD8+ T Cells.
    Chaoshuai Zhao, Ran Liu, Chuang Gao, Bin Chen, Shu Nie, Xi Tan, Xingyu Mei, Zhouwei Wu.
      
    Keywords:  CD8+ t cells; Exosomes; Keratinocytes; LKB1; Vitiligo
    DOI:  https://doi.org/10.1007/s10753-026-02479-6
  25. Adv Sci (Weinh). 2026 Mar 19. e23603
    Albumin-Bound STING Agonist Reprograms HSPCs to Antitumor Neutrophils Enhancing CD8+ T Cell Immunity.
    Jinsong Tao, Hong-Yi Zhao, Chengyi Li, Hanning Wen, Fang Ke, Qiuxia Li, Miao He, Bo Wen, Zhongwei Liu, Kai Sun, Wei Gao, Duxin Sun.
      Tumor-associated immunosuppressive neutrophils, termed polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), compromise cancer immunotherapy. Emerging evidence indicates that neutrophil fate can be programmed as early as the hematopoietic stem and progenitor cell (HSPC) stage. Reprogramming HSPCs toward antitumor neutrophils offers a promising therapeutic strategy. Here, we demonstrate that an albumin-bound STING agonist (Nano ZSA-51D) reprograms HSPCs to generate antitumor neutrophils, enhancing MHC I-mediated CD8+ T cell immunity and sensitizing tumors to α-PD1 immunotherapy. Nano ZSA-51D expands HSPCs and reprograms them toward granulocyte-monocyte progenitors for neutrophil development. It further converts immature (CD101-) and mature (CD101+) neutrophils into a CD14+ICAM-1+ subset through STING-NF-κB-TNF-α signaling, enhancing tumor infiltration and antitumor activity. These neutrophils upregulate interferon signaling and MHC I antigen presentation, thereby boosting tumor-specific CD8+ T cell responses. Notably, both adoptive transfer of Nano ZSA-51D-reprogrammed neutrophils and systemic Nano ZSA-51D treatment synergizes with α-PD1 therapy to achieve complete remission of colon tumors through neutrophil- and CD8+ T cell-dependent mechanisms, with potent efficacy also validated in otherwise immune-resistant pancreatic cancer models. Our findings establish a therapeutic strategy to reprogram HSPCs toward antitumor neutrophils, highlighting the potential of targeting early hematopoiesis to rewire neutrophil fate in cancer immunotherapy.
    Keywords:  CD8+ T cell immunity; STING agonist; antigen presentation; antitumor neutrophils; cancer immunotherapy; hematopoietic stem and progenitor cells
    DOI:  https://doi.org/10.1002/advs.202523603
  26. Pathol Res Pract. 2026 Mar 09. pii: S0344-0338(26)00094-4. [Epub ahead of print]282 156443
    The hypoxic tumor microenvironment: Functional and metabolic reprogramming of key immune populations.
    Amirhossein Faghih Ojaroodi, Samin Shokravi, Shabnam Eskandarzadeh, Armin Ghahremanzadeh, Fatemeh Alizadeh, Farinaz Amirikar, Golnaz Mobayen, Danial Mahrooghi, Masoud Lahouty, Karim Shamsasenjan, Mehdi Talebi.
      Tumor-induced hypoxia remains a pivotal characteristic of the tumor microenvironment (TME), significantly impacting immune cell functionality by fostering immunosuppression, tumor advancement, and resistance to therapies. This review consolidates established and emerging insights into how hypoxia, chiefly orchestrated by hypoxia-inducible factors (HIFs), metabolically and functionally reprograms key immune populations such as B cells, CD4 + T-cells, CD8 + T-cells, natural killer (NK) cells, regulatory T-cells (Tregs), and macrophages. We examine hypoxia-driven metabolic adaptations, signaling alterations, and evasion strategies, including enhanced glycolysis, lactate accumulation, and immune checkpoint upregulation. Furthermore, we integrate cutting-edge findings, such as hypoxia's modulation of NK cell cytotoxicity, immune metabolic reprogramming in the TME, HIF-mediated immune modulation, effector T-cell transcriptomic shifts akin to non-responsive tumor-infiltrating lymphocytes, and autophagy-dependent MHC-I suppression for immune evasion. These advancements underscore therapeutic opportunities in targeting hypoxia to bolster antitumor immunity and mitigate immunotherapy resistance in cancer.
    Keywords:  Anti-tumor response; HIF signaling; Hypoxia; Immunomodulation; Immunotherapy; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.prp.2026.156443
  27. Nat Commun. 2026 Mar 18.
    Chromatin reorganization drives overexpression of a Btaf1 variant underpinning hematopoietic aging.
    Le Zong, Bongsoo Park, Yaqiang Cao, Fei Ma, Ferda Tekin-Turhan, Wakako Kuribayashi, Keji Zhao, Isabel Beerman.
      Age-associated hematopoietic stem cell (HSC) dysfunction is accompanied by dramatic transcription changes, but it remains unclear whether specific transcripts could orchestrate these HSC aging phenotypes. Here, we perform epigenetic profiling in male mice to investigate the regulatory mechanisms underlying the HSC aging transcriptome and screen for potential aging driver genes. We identify a looping structure formed between part of the Btaf1 gene and the whole Ide gene in old HSCs which is accompanied by overexpression of a shorter variant of Btaf1 (nBtaf1). Mechanistically, elevated expression of nBtaf1 drives the aging-associated overexpression of HSC and megakaryocyte progenitor (MkP) signature genes via regulating TBP binding at their promoters, which contributes to HSC expansion and elevated MkP production in aged mice. ShRNA-mediated knockdown of nBtaf1 restores a younger HSC transcriptome and specifically represses aging-associated HSC expansion and elevated MkP production. In summary, our data provide high resolution analysis of a dysregulated HSC aging epigenome and reveal a Btaf1 variant that drives HSC aging phenotypes in mice.
    DOI:  https://doi.org/10.1038/s41467-026-70787-4
  28. Med Sci (Paris). 2026 Mar;42(3): 248-250
    [Metallophilic macrophages of the splenic marginal zone: myeloid sentinels capable of cross-priming CD8+ T cell antitumor immunity].
    François-Xavier Mauvais, Peter van Endert.
      
    DOI:  https://doi.org/10.1051/medsci/2026029
  29. Mechanobiol Med. 2026 Mar;4(1): 100177
    TCR-pMHC recognition mediates target phagocytosis by T cells.
    Xiangcheng Chen, Maximilian Wang, Ning Jiang.
      T cells are traditionally viewed as non-phagocytic lymphocytes that recognize antigens via the T cell receptor (TCR) and mediate cytotoxicity at the immunological synapse, while phagocytosis is performed by professional phagocytes such as macrophages and dendritic cells. Here we show that peptide-MHC (pMHC) recognition alone is sufficient to drive rapid, antigen-specific phagocytosis by Jurkat T cells. We generated CD8+ Jurkat cells expressing a class I-restricted human TCR (SVAR16) with intermediate-to-high 2-dimensional (2D) affinity for the SARS-CoV-2 epitope HLA∗A2:01-YLQ and used a micropipette system to control and image T cell interaction with pMHC coated beads. Upon contact with cognate YLQ-coated beads, SVAR16 transduced CD8+ Jurkat cells consistently formed phagosomes within minutes and completely internalized beads with consistent kinetics. These results demonstrate that appropriately tuned TCR-pMHC interactions, supported by CD8 co-receptors, can convert a canonical CD4+ T cell line into an antigen-specific phagocyte. This work reports a novel effector function of T cells and suggests that TCR-engineering could convert CD4+ T cells into phagocytes, potentially revealing a new approach to T cell-based cancer immunotherapy.
    DOI:  https://doi.org/10.1016/j.mbm.2026.100177
  30. Cell Rep. 2026 Mar 15. pii: S2211-1247(26)00162-2. [Epub ahead of print]45(3): 117084
    Loss of p53 exacerbates autoimmunity by reprogramming propionyl-CoA metabolism and histone modifications in Treg cells.
    Siyi Xie, Taiqi Chen, Linfeng Li, Chunyu Tan, Peng Jiang.
      Metabolic regulation is central to the tumor suppressor function of p53. By analyzing the human patients with autoimmune diseases, we found that p53 expression was significantly reduced in Treg cells, negatively correlating with abnormally elevated BCL-6 levels. p53 loss causes dysregulated immune homeostasis and dampens Treg function in vitro and in vivo. Mechanistically, p53 transcriptionally activates ALDH6A1 expression and propionyl-CoA anabolism to upregulate functional Treg gene expression via histone propionylation. Treg-specific knockout of ALDH6A1 phenocopies the autoimmune responses of p53 deficiency, and propionyl-CoA restoration largely recovers Treg cell function in mice lacking p53 or ALDH6A1. Clinically, impaired p53-ALDH6A1-histone propionylation signaling is observed in patients with autoimmune diseases and correlates with poor efficacy of first-line therapies. Together, these findings reveal a direct connection between propionyl-CoA metabolism and histone modifications, which is governed by p53 and is crucial for Treg cell function and immune tolerance suppression.
    Keywords:  CP: immunology; CP: metabolism; Treg cells; autoimmunity; histone propionylation; p53; propionyl-CoA anabolism
    DOI:  https://doi.org/10.1016/j.celrep.2026.117084
  31. Trends Immunol. 2026 Mar 17. pii: S1471-4906(26)00034-7. [Epub ahead of print]
    KLHL6: a proteostatic guardian against T-cell exhaustion.
    Yang Pu, Xuetao Cao.
      Cheng et al.'s recent study identifies the Cullin3-RING E3 ubiquitin ligase complexes (CRL3) adaptor protein Kelch-like protein 6 (KLHL6) as a proteostasis regulator whose downregulation in chronically stimulated T cells leads to the accumulation of thymocyte selection-associated high mobility group box protein and phosphoglycerate mutase family member 5, driving T-cell dysfunction. This work positions T-cell exhaustion as a proteostatic disorder and highlights KLHL6 as a promising target for cancer immunotherapy.
    Keywords:  KLHL6; T-cell exhaustion; ubiquitination
    DOI:  https://doi.org/10.1016/j.it.2026.02.003
  32. Nat Rev Immunol. 2026 Mar 18.
    Renaissance of antiviral CD8+ T cell immunity in vaccination and disease.
    Victor Appay, Takuya Yamamoto, Asier Sáez-Cirión.
      Over the past 20 years, the limited efficacy of CD8⁺ T cell-based vaccines against viruses in clinical trials has shifted attention away from such strategies. However, recent findings have brought renewed appreciation for the central importance of CD8⁺ T cells in controlling both acute and chronic viral infections and in preventing severe or progressive disease. This work highlights shared features, such as effector functions and stemness properties, of effective CD8⁺ T cell responses against diverse viruses such as SARS-CoV-2 and HIV. A deeper understanding and simpler interpretation of the functional workings of CD8⁺ T cell-mediated immunity, combined with advances in immunological and biotechnological tools, are opening new avenues for eliciting optimal T cell responses, both for prophylactic and for therapeutic applications. Collectively, these developments revive optimism that vaccines and immunotherapies designed to harness robust CD8⁺ T cell responses could have a major role in combating emerging viral threats and in achieving long-term suppression of persistent infections such as HIV-1 to undetectable levels.
    DOI:  https://doi.org/10.1038/s41577-026-01284-4
  33. Arthritis Rheumatol. 2026 Mar 17.
    T cells in osteoarthritis; drivers, repairers or bystanders in osteoarthritis?
    Tonia L Vincent, Andrew P Cope.
      
    DOI:  https://doi.org/10.1002/art.70135
  34. Nat Commun. 2026 Mar 17.
    Reactivating exhausted tumor-infiltrating T cells by a bispecific DC-T cell engager in mice.
    Xuhao Zhang, Yu Gao, Wenbo Hu, Yong Liang, Xiaozhe Yin, Xiangjun Shi, Hongjia Li, Huiping Liao, Jingya Guo, Xiaohong Yu, Mingzhao Zhu, Hua Peng, Wenyan Wang, Yang-Xin Fu.
      Tumor infiltrating T cells (TIL) are key players in the anti-tumor immune response. However, chronic exposure to tumor-derived antigens drives the differentiation into 'exhausted' TILs. Whether intratumoral dendritic cells (DC) can mitigate TILs exhaustion and maintain function is unclear. Here, we develop a bispecific DC-T cell engager (BiDT), consisting of an anti-TIM3-IFN fusion protein, and demonstrate that, in preclinical mouse tumor models, this engager simultaneously targets TIM3 on exhausted TILs and activates DCs via the IFNAR receptor. Mechanistically, BiDT reactivates exhausted TIM3+TILs by preventing apoptosis through increased Bcl-2 expression and enhances DC function to reactivate T cells via IL-2 signalling and co-stimulatory CD80/86-CD28 interactions within the tumor microenvironment. Finally, to mitigate IFNα-induced toxicity, we engineer a Pro-BiDT engager featuring a pro-IFNα and report potent antitumor activity with reduced systemic toxicity. Thus, by bridging DC-T cells together, BiDT treatment enhances the critical communication pathways and cellular circuits necessary for effective anti-tumor immunity.
    DOI:  https://doi.org/10.1038/s41467-026-70876-4
  35. J Clin Invest. 2026 Mar 16. pii: e195668. [Epub ahead of print]136(6):
    T cell-intrinsic VISTA expression promotes resistance to CTLA-4 blockade by restricting CD8+ T cell responses.
    Cassandra Gilmour, Elizabeth DeLaney, Prerana B Parthasarathy, Dia Roy, Hieu M Ta, Amin Zakeri, Paolo Elguera Grandez, Sachin Patnaik, Keman Zhang, Ivan Juric, Rahul Rangan, Zahraa Al-Hilli, Anthony Tufaro, Booki Min, Samuel E Weinberg, Timothy A Chan, Natalie L Silver, Stefanie Avril, Tyler Alban, Li Lily Wang.
      V-domain immunoglobulin suppressor of T cell activation (VISTA) is an immune checkpoint protein that impairs antitumor T cell responses. While broadly expressed on myeloid cells and T cells, the specific contribution of T cell-intrinsic VISTA to antitumor immunity remains undefined. This study investigated the phenotypic and functional consequences of T cell-specific VISTA deletion in tumor-specific CD8+ T cells. Single-cell transcriptomic analysis, TCR repertoire profiling, and flow cytometry revealed that loss of T cell-intrinsic VISTA enhanced early priming and short-term expansion of CD8+ T cells, yet this initial advantage failed to confer durable tumor control. Persistent dysfunction in VISTA-deficient T cells was in part driven by trans-VISTA on myeloid cells, while CTLA-4 upregulation further constrained T cell responses. T cell-intrinsic VISTA deficiency cooperated with CTLA-4 blockade to improve T cell survival and broaden TCR repertoire diversity, resulting in more robust tumor regression than CTLA-4 inhibition alone. A transcriptional signature enriched in VISTA-deficient cytotoxic T cells correlated with favorable outcomes in cancer patients treated with existing immune checkpoint inhibitors. These findings collectively define T cell-intrinsic mechanisms by which VISTA enforces T cell dysfunction and underscore its potential as both a therapeutic target and a biomarker of resistance to current immunotherapies.
    Keywords:  Adaptive immunity; Cancer immunotherapy; Cellular immune response; Immunology; Oncology
    DOI:  https://doi.org/10.1172/JCI195668
  36. OMICS. 2026 Mar;30(3): 146-157
    Systems Biology of Metabolic Dysregulation in Ankylosing Spondylitis Using scRNA-Seq Data.
    Merve Yarıcı, Muhammed Erkan Karabekmez.
      Ankylosing spondylitis (AS) is a prevalent autoimmune disorder that primarily affects the spinal joints, leading to chronic pain. Defining immune cell programs that contribute to AS is essential for the discovery of translational targets. Because immune function depends on metabolic state, we analyzed single-cell RNA sequencing data from peripheral blood mononuclear cells (PBMCs) of patients with AS and healthy controls (HCs), and constructed genome-scale metabolic models for each immune cell type to quantify differences in pathway activity and reaction fluxes between diseased and healthy conditions. Across datasets, AS showed consistent metabolic reprogramming, with increased flux through purine metabolism, fatty acid degradation, and glycolysis in CD14 monocytes and T cell subsets, including CD4 memory, CD4 naive, and CD8 T cells, indicating coordinated shifts in energy production and biosynthetic demand. To extend these findings, we constructed cell-type-specific protein-protein interaction networks and evaluated differential connectivity. We identified 63 rewired protein hubs across nine immune cell types. RPS11 emerged as a central hub linked to translation and prior evidence of AS pathogenesis. This integrative systems biology approach connects cell-type-specific metabolic alterations with rewired interaction hubs in an accessible clinical compartment, suggesting that PBMC-based multiomics signatures may support future biomarker development and therapeutic prioritization in autoimmune diseases.
    Keywords:  ankylosing spondylitis; genome-scale metabolic models; network biology; scRNA-seq
    DOI:  https://doi.org/10.1177/15578100261424002
  37. Signal Transduct Target Ther. 2026 Mar 17. pii: 100. [Epub ahead of print]11(1):
    DUSP6 ablation restores CAR T-cell fitness impaired by tumor CD58 loss through invigoration of AP-1 signaling.
    Xinran Ma, Yang Zhang, Yao Wang, Fuxin Han, Yuting Lu, Chuan Tong, Yelei Guo, Jianshu Wei, Qi Zhu, Liang Dong, Zhi Cao, Zhenzhen Meng, Jinhong Shi, Zhiqiang Wu, Weidong Han.
      Primary resistance to chimeric antigen receptor (CAR) T-cell therapies has limited their widespread application. Our prior genome-wide CRISPR/Cas9 screening revealed that the loss of CD58, a crucial intrinsic resistance factor in tumors, resulted in insufficient immune synapse formation and impaired CAR T-cell activation and cytotoxicity. However, the specific signaling pathway and transcriptional changes associated with CAR T-cell dysfunction have not been addressed. Here, we revealed that AP-1-mediated activation was attenuated in CAR T cells impaired by tumor CD58 loss, driving a decrease in mitochondrial biogenesis, metabolic kinetic impairment, mitochondrial membrane potential loss and ROS accumulation. Moreover, this AP-1 attenuation triggered death receptor-independent apoptosis through the intrinsic mitochondrial pathway. In seeking therapeutic strategies, we pharmacologically and genetically blocked three distinct inhibitory phosphatases positioned upstream of AP-1 signaling. Multifaceted validation has demonstrated that dual specificity phosphatase 6 (DUSP6) blockade is an effective approach to supplement AP-1 signaling while notably reducing CAR T-apoptosis and enhancing mitochondrial fitness, proliferation and long-term cytotoxicity. The transcriptomic profiles of DUSP6-ablated CAR T cells revealed markedly upregulated T-cell activation signatures and enriched metabolic pathways. Clinically, bulk and single-cell RNA-seq analyses revealed that DUSP6 was downregulated in patients who responded to T-cell-based immunotherapy, implying its relevance to patient outcomes. Our findings repositioned CD58 not merely as an immune synapse component but also a metabolic checkpoint in CAR T-cell biology, the loss of which triggers AP-1-dependent mitochondrial derangement and creates a permissive landscape for intrinsic apoptosis, which can be ameliorated by ablation of the inhibitory phosphatase DUSP6. Crucially, DUSP6 ablation represents a promising engineering target to potentiate CAR T-cell efficacy in broader applications.
    DOI:  https://doi.org/10.1038/s41392-026-02597-5
  38. Int J Mol Med. 2026 May;pii: 130. [Epub ahead of print]57(5):
    The roles and heterogeneity of CD8+ T cells in inflammatory bowel disease: A narrative review of insights from single‑cell transcriptomics (Review).
    Rui Zhong, Jing Guo, Wujie Ye, Zhihui Deng, Huangan Wu, Qin Qi, Guona Li, Lu Zhu, Yan Huang, Luyi Wu.
      The present review investigates the role and characteristics of CD8+ T cells in inflammatory bowel disease (IBD) using single‑cell transcriptomics, revealing their pivotal functions and remarkable heterogeneity. In IBD, CD8+ T cells exhibit marked phenotypic and functional diversity, with distinct subpopulations exhibiting unique signaling pathway activation profiles that associate with varying clinical outcomes. Furthermore, CD8+ T cell subsets in IBD participate in complex crosstalk networks involving immune and non‑immune cells, modulating inflammatory responses and tissue homeostasis. The present review synthesizes the dynamic complexity of CD8+ T cell behavior in IBD and identifies promising therapeutic opportunities through targeted modulation of specific T cell subsets and their interactions within the colonic microenvironment.
    Keywords:  CD8+ T cells; biological techniques; immune therapy; inflammatory bowel disease; single‑cell RNA sequencing
    DOI:  https://doi.org/10.3892/ijmm.2026.5801
  39. Biomed Pharmacother. 2026 Mar 18. pii: S0753-3322(26)00253-2. [Epub ahead of print]198 119220
    Preclinical comparison of non-signaling domain in CD19 CAR T cell with interleukin-7 receptor alpha signaling domain.
    Pornlapat Keawvilai, Sirirut Jewmoung, Kristine Cate S Pe, Supannikar Tawinwung, Koramit Suppipat.
      Chimeric antigen receptor (CAR) T cells have emerged as an effective immunotherapy for hematologic malignancies. The non-signaling domain of CARs, comprising the spacer and transmembrane regions, is a key structural component that can be engineered to influence CAR expression and function. In this study, we evaluated three non-signaling domain configurations-IgG2.CH3/CD28, IgG2/CD28, and CD8/CD8-within a CD19 CAR construct incorporating 4-1BB and interleukin-7 receptor alpha (IL-7Rα) signaling domains. CARs incorporating the IgG2/CD28 domain exhibited reduced surface expression and diminished functional responses compared with IgG2.CH3/CD28 and CD8/CD8 constructs. The CD8/CD8 configuration supported the highest CAR expression and sustained surface density. In contrast, IgG2.CH3/CD28 CAR T cells displayed increased IL-2 and TNF-α secretion and enhanced CD107α upregulation following antigen stimulation. In a serial tumor cell rechallenge assay, IgG2.CH3/CD28 CAR T cells maintained cytotoxic activity and persistence compared with CD8/CD8 CAR T cells. In a NALM-6 xenograft model, IgG2.CH3/CD28 CAR T cells achieved durable tumor control and were associated with improved survival relative to CD8/CD8 CAR T cells. Collectively, these findings support the IgG2.CH3/CD28 non-signaling domain as a suitable structural component for CD19 CARs incorporating IL-7Rα signaling and provide insight into CAR design strategies aimed at improving T cell persistence and anti-leukemic activity.
    Keywords:  B-cell malignancies; CAR T cell; CD19; IL-7 receptor alpha (IL-7Rα); Non-signaling domain
    DOI:  https://doi.org/10.1016/j.biopha.2026.119220
  40. J Nanobiotechnology. 2026 Mar 17.
    Engineering BiTE-inspired IPSC-exosomes to potentiate CAR-T cell therapy against lung cancer.
    Ronghao Wang, Guining Fu, Haozhao Dou, Mingyuan Hu, Zhanglin Li, Junwen Gan, Jiasheng He, Xiaojian Li, Guihong Zhang, Xianjun Li, Tianchuan Zhu, Qingdong Cao.
      Chimeric antigen receptor T (CAR-T) cell therapy faces critical barriers in solid tumors, including poor infiltration, T cell exhaustion, and immunosuppressive microenvironments, resulting in response rates below 10%. Herein, we engineered an inhalable nanoplatform using induced pluripotent stem cell-derived exosomes (IEXOs) displaying bispecific PD-1/mesothelin (MSLN) single-chain variable fragments (scFv) and loaded with indole-3-propionic acid (IPA) for metabolic reprogramming. IEXOs demonstrated high yield and intrinsic antitumor properties, inhibiting Lewis lung carcinoma (LLC) cell proliferation and migration. The bispecific exosomes loaded with IPA (BIEXO@IPA) achieved efficient pulmonary delivery via nebulization with 79.3% tumor cell-specific uptake versus 47.9% for liposomes in orthotopic lung cancer models. BIEXO@IPA treatment reduced tumor burden by 87.9% and achieved 80% survival at 80 days. Mechanistically, BIEXO@IPA bridged PD-1+ T cells to MSLN+ tumor cells through bispecific engagement while expanding progenitor exhausted T (Tpex) cells and reducing regulatory T cells. When combined with CAR-T cells, BIEXO@IPA achieved 66.7% complete remission with 100% survival at 80 days and 83.3% resistance to tumor rechallenge. Safety assessments revealed minimal toxicity. This BIEXO@IPA platform represents a scalable, clinically translatable strategy that addresses fundamental CAR-T limitations in solid tumors through synergistic multimodal immunomodulation.
    Keywords:  Bispecific T cell engagers; Chimeric antigen receptor T cells; Exosomes; Immunotherapy; Indole-3-propionic acid; Induced pluripotent stem cells; Lung cancer
    DOI:  https://doi.org/10.1186/s12951-026-04242-3
  41. Sci Adv. 2026 Mar 20. 12(12): eaea7987
    Dengue infection elicits skin tissue-resident and circulating CD8+ T cells associated with protection from hospitalization.
    Noor Zayanah Hamis, Justin Sg Ooi, Ka-Wai Cheung, Valerie Chew, Michaela Gregorova, Eugenia Ziying Ong, Kuan Rong Chan, Tun-Linn Thein, Yee-Sin Leo, David Chien Boon Lye, Eng Eong Ooi, Laura Rivino.
      Dengue is spreading globally, and there is urgent need to define immune correlates of protection for this disease. Dengue infection first occurs in the skin following the bite of an infected mosquito; however, knowledge of host immune responses within this site remains sparse. We investigated the phenotypic, functional, and transcriptional profiles of skin and blood T cells in 73 patients with dengue and 10 healthy volunteers. We show that the skin T cell compartment undergoes marked reshaping and is strongly enriched with proliferating CD4+ and CD8+ T cells compared with the blood of patients. Activated skin CD8+ T cells expressed a core transcriptional signature of tissue-resident memory T (TRM) cells, supporting their differentiation to the TRM cell lineage during infection. The magnitude of skin and blood CD8+ T cell responses were associated with protection from hospitalization in this cohort. These data support a protective role of skin-resident and circulating CD8+ T cells in dengue and warrant evaluation of vaccination strategies inducing skin TRM cells to enhance protective immunity.
    DOI:  https://doi.org/10.1126/sciadv.aea7987
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