bims-imseme 2026-05-31 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2026–05–31
twenty-two papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

PI3Kδ inhibition alters CD8 T cell differentiation and reprograms the tumor microenvironment following adoptive immunotherapy.
Early sex-related transcriptional differences in CD8+ T cells responding to chronic viral infection reveal a sex bias in exhaustion.
Targeting UBE2F induces a resilience program enhancing CD8 T cell immunity.
Redirecting Cholesterol Metabolism During Ex Vivo Biomanufacturing Enhances the Metabolic Fitness and Antitumor Efficacy of CAR-T Cells.
Hypoxia Impairs CD8+ T Cell Fitness and Is Associated with a Dysfunctional CD8+ T Cell State in Pancreatic Cancer.
PD-1 regulates latent effector differentiation of thymic cytotoxic CD8+ T cells.
Supercharging the metabolic engine: mitochondrial engineering strategies for CAR-T persistence in solid tumors.
Image analysis of mitochondria during T lymphocyte and chimeric antigen receptor (CAR) effector responses.
Mitochondrial Transfer-Driven Immune Evasion in the Tumor Microenvironment.
CLEC2B-KLRB1 axis acts as an immune checkpoint, governing the exhaustion of CD8+ T cells and their resistance to immune checkpoint blockade.
Protein-dependent CD4+ T cell specialization and CD8+ T cell-driven IL-2 production in HIV.
Characterization of a Cytokine-Independent STAT5 Activator.
STUB1-mediated ubiquitination regulates Fli-1 stability and CD4⁺T cell activation during inflammation.
HDAC7 controls anti-viral and anti-tumor immunity by CD8+ T cells.
Cytokine-mediated intrinsic and extrinsic regulation of anti-tumor adoptive T cell therapy.
Wnt signaling as a regulator of memory T cells: implications for CAR-T cell therapy.
Age-related reduction of pyruvate dehydrogenase kinase 1 impairs T cell responses.
Lactylation landscape of mitochondrial proteins in myocardial infarction.
ZBP1 Drives CD8+ T cell-mediated anti-tumor immunity in head and neck squamous cell carcinoma.
Mitochondrial Stress Orchestrates Tumor Immune Evasion and Immunotherapy Resistance.
Covalent tumor anchoring spatially orchestrates antitumor immunity.
Mitochondrial drivers of stem cell aging and inflammaging.

J Immunol. 2026 May 14. pii: vkag108. [Epub ahead of print]215(5):

PI3Kδ inhibition alters CD8 T cell differentiation and reprograms the tumor microenvironment following adoptive immunotherapy.

Alexandrea Turnquist, Azka Javaid, Owen M Wilkins, Fred Kolling Iv, Patricia A Pioli, Chrystal M Paulos, Hildreth Robert Frost, Edward J Usherwood.

  T cell exhaustion remains a significant barrier to effective adoptive cell therapy in solid tumors. Here, we demonstrate that in vitro treatment with the PI3Kδ inhibitor CAL-101 generates T cells with enhanced stemness and metabolic fitness. These cells show increased mitochondrial dependence and spare respiratory capacity while maintaining normal basal metabolism. Under chronic antigen stimulation, CAL-101-treated T cells, including human T cells, resist terminal exhaustion and maintain stem-like properties. Using single-cell RNA sequencing and spatial transcriptomics of B16 melanoma tumors, we found that CAL-101-treated T cells preferentially differentiate into progenitor exhausted T cells within the tumor microenvironment. These cells demonstrate enhanced tumor infiltration and upregulate the Cxcl10/Cxcr3 signaling axis. The tumor microenvironment of tumors containing CAL-101-treated T cells show reduced glycolysis, oxidative phosphorylation, and proliferation, while exhibiting increased proinflammatory signaling and decreased presence of immunosuppressive tumor-associated macrophages. Single-cell analysis reveals that the CAL-10-treated T cells concurrently increase oxidative phosphorylation, proliferation, and immune signaling pathways. Mechanistically, CAL-101-treated T cells maintain high expression of stemness-associated genes (Tcf7, Slamf6) while resisting expression of genes associated with terminal exhaustion (Tim3, Mt1/2). These findings reveal the mechanisms behind how PI3Kδ inhibition generates T cells capable of establishing and maintaining an antitumor immune response, suggesting a promising strategy for improving adoptive cell therapy outcomes in solid tumors.

Keywords:  T cells; cancer; cytotoxic; memory; tumor immunity

DOI:  https://doi.org/10.1093/jimmun/vkag108
Front Immunol. 2026 ;17 1783098

Early sex-related transcriptional differences in CD8+ T cells responding to chronic viral infection reveal a sex bias in exhaustion.

Nyambura Kahia, Sean M Robertson, Megan Rodriguez, Paul Jerard Layug, Harman Vats, Kamali Kannan, Victor Spicer, Arzu Ozturk-Aptekmann, Olivia Wilkins, Janilyn Arsenio.

  CD8+ T cell diversity is essential to control infections and chronic antigen stimulation. In acute-resolving infection, effector cells mediate acute responses and memory cells provide long-lived protection against future exposures. In chronic infection and cancer, an altered state called exhaustion occurs. Exhausted CD8+ T cells are molecularly and functionally distinct from effector and memory cells. Differences in immune responses exist between biological sexes, however, how biological sex influences the timing and transcriptional programs of CD8+ T cell responses during chronic versus acute viral infection remains unknown. Here, we show that male and female CD8+ T cells exhibit transcriptional differences in their early responses during chronic but not acute viral infection in vivo. Using single-cell RNA-sequencing and immunophenotyping analyses, we show that female CD8+ T cells exhibit an early exhaustion-like program compared to males. These findings reveal new insights into sex-related differences in CD8+ T cell exhaustion development and early T cell responses that may contribute to sex differential immune responses.

Keywords:  CD8 T cells; T cell exhaustion; infection; scRNA-seq; sex differences

DOI:  https://doi.org/10.3389/fimmu.2026.1783098
J Exp Med. 2026 Jul 06. pii: e20252687. [Epub ahead of print]223(7):

Targeting UBE2F induces a resilience program enhancing CD8 T cell immunity.

Xiaonan Ma, Henan Guo, Yuting Jia, Na Yin, Min Peng.

Memory CD8 T cells (TMEM) and exhausted CD8 T cells (TEX) are essential for host defense against infection and cancer, yet their therapeutic potential is often limited by insufficient persistence and sustained functional capacity. Strategies to enhance the longevity of both populations remain scarce. Here, we demonstrate that ablation of UBE2F, a neddylation E2 enzyme, induces a resilience program in CD8 T cells that operates across both TMEM and TEX compartments, resulting in improved viral and tumor control. This resilience state is characterized by enhanced self-renewal and survival without perturbing the conventional CD8 T cell differentiation trajectories. Mechanistically, UBE2F deficiency inhibited neddylation of CUL5, leading to accumulation of JUNB and upregulation of IL-2Rβ. The increased IL-2Rβ expression hypersensitizes CD8 T cells to physiological IL-15, thereby conferring the resilience features. Together, these findings identify the UBE2F-CUL5-JUNB-IL-2Rβ axis as a conserved posttranslational mechanism regulating CD8 T cell longevity across memory and exhausted states, providing a novel strategy for enhancing antiviral and antitumor immunity.

DOI: https://doi.org/10.1084/jem.20252687
Int J Biol Sci. 2026 ;22(10): 5228-5245

Redirecting Cholesterol Metabolism During Ex Vivo Biomanufacturing Enhances the Metabolic Fitness and Antitumor Efficacy of CAR-T Cells.

Yuge Zhu, Jiaxin Tu, Shuang Li, Shance Li, Bufan Xiao, Xuantong Zhou, Guanyu Zhang, Xinyu Li, You He, Nan Wu, Zheming Lu, Chaoting Zhang.

  Chimeric antigen receptor T (CAR-T) cell therapy has revolutionized the treatment of hematologic malignancies; however, its efficacy in solid tumors remains limited, partly due to T cell exhaustion during ex vivo manufacturing. Emerging evidence suggests that cholesterol metabolism plays a critical role in T cell differentiation and function, yet its impact during CAR-T cell production is poorly understood. We investigated the effects of cholesterol modulation during ex vivo CAR-T cell expansion by using low-dose fluvastatin (FL), a clinically approved HMG-CoA reductase inhibitor. We found that cholesterol accumulation during ex vivo expansion promotes CAR-T cell exhaustion. Low-dose FL reduces cholesterol to physiological levels, preserving a less-differentiated, memory-enriched phenotype and attenuating exhaustion, thereby enhancing CAR-T cell cytotoxicity and persistence without affecting viability. In multiple xenograft models, FL-primed CAR-T cells demonstrate superior in vivo expansion, persistence, and tumor control. Mechanistically, FL enhances ERK1/2 phosphorylation to remodel CAR-T cell metabolism from glycolysis to oxidative phosphorylation. Inhibiting ERK1/2 or ATP synthesis abrogates these benefits, indicating that ERK1/2-dependent mitochondrial metabolism is required for CAR-T cell functional improvements conferred by FL. These findings establish cholesterol metabolism as a tunable axis during CAR-T cell manufacturing and propose a clinically feasible, GMP-compatible strategy to enhance CAR-T cell fitness and therapeutic efficacy.

Keywords:  CAR-T cells; cholesterol; low-dose FL; metabolic remodeling

DOI:  https://doi.org/10.7150/ijbs.132207
Cancers (Basel). 2026 May 08. pii: 1508. [Epub ahead of print]18(10):

Hypoxia Impairs CD8+ T Cell Fitness and Is Associated with a Dysfunctional CD8+ T Cell State in Pancreatic Cancer.

Ashley M Mello, Marina Pasca di Magliano, Kyoung Eun Lee.

  Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense stromal microenvironment and profound hypoxia, which contribute to therapeutic resistance. Using an in vitro system incorporating pancreatic cancer cells and cancer-associated fibroblasts (CAFs), we show that hypoxia suppresses CD8+ T cell accumulation and, in combination with cancer cell- and CAF-derived factors, further impairs T cell fitness by increasing cell death and reducing proliferation. Although the combination of hypoxia and cancer cell/CAF-derived factors enhances IFNγ and granzyme B expression in CD8+ T cells on a per-cell basis, the overall number of functional effector T cells is markedly reduced. Analysis of human PDAC single-cell RNA sequencing data corroborates these findings, revealing that CD8+ T cells enriched for hypoxia signatures exhibit elevated apoptosis and stress-response pathways. Furthermore, hypoxia is associated with downregulation of stemness-related genes and upregulation of terminal differentiation markers. Together, these data suggest that the integration of intrinsic hypoxic responses and extrinsic cues from tumor cells and CAFs impairs CD8+ T cell fitness and correlates with a terminally differentiated, dysfunctional T cell state.

Keywords:  CD8+ T cell; apoptosis; differentiation; exhaustion; fibroblast; hypoxia; pancreatic cancer; proliferation

DOI:  https://doi.org/10.3390/cancers18101508
Nat Commun. 2026 May 23.

PD-1 regulates latent effector differentiation of thymic cytotoxic CD8+ T cells.

Zhiming Mao, Jacob B Hirdler, Joanina K Gicobi, Li Ding, Mark A Maynes, Michelle A Hsu, Emilia R Dellacecca, Wenjing Zhang, Jacob J Teske, Ying Li, Aubrey Y Liew, Geoffrey Zhao, Adrian T Ting, Virginia M Shapiro, Fabrice Lucien-Matteoni, Henrique Borges da Silva, Daniel D Billadeau, Haidong Dong.

Durable T cell immunity against cancer depends on the continual replenishment of effector CD8⁺ T cells. Thymic output has been associated with favorable prognosis in cancer patients across a range of ages, suggesting that the thymus is an important source for replenishing T cells capable of controlling cancer progression. However, whether CD8⁺ T cells acquire effector potential within the thymus, and how thymic output of effector CD8⁺ T cells contribute to peripheral tumor immunity, remain unclear. In this study, we discover that thymic single-positive (SP) CD8⁺ T cells undergo latent effector differentiation following thymic selection, but this process is subject to PD-1 regulation. We further demonstrate that PD-1 limits the contribution of thymic output of CD8⁺ T cells in shaping the TCR repertoire within the tumor tissues for tumor immunosurveillance. Although PD-1 inhibition facilitates the expansion of effector CD8⁺ T cells in the periphery, these cells gradually lose antitumor activity within tumors due to accelerated exhaustion in the absence of PD-1. Thus, while latent effector differentiation of thymic CD8⁺ T cells enables a rapid response to malignant cells in the periphery, PD-1 restrains this process to prevent overt or terminal effector differentiation, which may compromise balanced and durable peripheral immunity.

DOI: https://doi.org/10.1038/s41467-026-73392-7
Front Immunol. 2026 ;17 1822668

Supercharging the metabolic engine: mitochondrial engineering strategies for CAR-T persistence in solid tumors.

Soohyun Chun, Sanghyeon Yu, Hyun Gu Lee, Man S Kim.

  Chimeric antigen receptor (CAR)-T cell therapy has achieved remarkable success in hematological malignancies, yet its efficacy in solid tumors is severely limited by the metabolically hostile tumor microenvironment (TME). Within this landscape, CAR-T cells undergo rapid functional exhaustion driven by mitochondrial dysfunction and metabolic insufficiency. This mini-review synthesizes emerging mitochondrial engineering strategies designed to restore metabolic fitness and persistence. We first examine the newly identified metabolic-epigenetic axis, where the pathological mitochondrial translocation of P4HA1 and the concomitant accumulation of oncometabolite succinate lock T cells in an exhausted state, and discuss how targeting this pathway restores progenitor subsets. Furthermore, we explore genetic reprogramming approaches, including "Envirotune" platforms that couple hypoxia-sensing elements (HRE) with enhanced glutamine transport (SLC38A2), and CRISPR-identified targets such as RHOG and FAS that prevent fratricide and apoptosis to preserve effector pools. Finally, we highlight the frontier of organelle medicine, focusing on intercellular mitochondrial transfer via tunneling nanotubes (TNTs) mediated by Talin-2, and emerging computational strategies to detect mitochondrial hijacking risk. By integrating these metabolic interventions, next-generation CAR-T cells can be engineered to overcome the TME's metabolic barriers, transforming them from transient effectors into long-lived, highly effective therapeutic agents.

Keywords:  CAR-T cell therapy; T cell exhaustion; immunometabolism; metabolic reprogramming; metabolic-epigenetic axis; mitochondrial engineering; solid tumors; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2026.1822668
Methods Cell Biol. 2026 ;pii: S0091-679X(26)00022-1. [Epub ahead of print]207 19-51

Image analysis of mitochondria during T lymphocyte and chimeric antigen receptor (CAR) effector responses.

Javier Ruiz-Navarro, Víctor Calvo, Manuel Izquierdo.

  Mitochondria play a central role in cellular metabolism, ATP production, and redox homeostasis, all of which are essential for sustaining T lymphocyte and CAR-T cell effector functions. Mitochondrial dysfunction has been linked to T cell and CAR-T cell exhaustion, reduced cell expansion capacity, and impaired tumor clearance. To investigate the contribution of mitochondria to T lymphocyte and CAR-T cell functionality, this protocol leverages advanced imaging analysis techniques to assess different parameters related to mitochondrial dynamics, structure and function, which may serve as indicators of both metabolic activity and the exhausted state of T cells. Specifically, the protocol focuses on measuring mitochondrial morphology, energization state, and mitochondrial translocation in the three-dimensional space. The image-based methodologies described in this protocol will contribute to a deeper understanding of mitochondrial regulation during T-cell and CAR-T cell responses. This knowledge will facilitate the identification of key metabolic vulnerabilities and support the refinement of therapeutic strategies to enhance T lymphocyte cytotoxic potential, ultimately improving clinical outcomes in T cell-based adoptive cancer immunotherapy.

Keywords:  Actin cytoskeleton; Chimeric antigen receptor; Immune synapse; Mitochondria; T lymphocytes

DOI:  https://doi.org/10.1016/bs.mcb.2026.01.022
Int Immunol. 2026 May 29. pii: dxag027. [Epub ahead of print]

Mitochondrial Transfer-Driven Immune Evasion in the Tumor Microenvironment.

Li Zhu, Yosuke Togashi.

  The tumor microenvironment (TME) is a complex landscape where metabolic interactions significantly dictate antitumor immunity. Immune evasion in cancer is typically discussed in terms of inhibitory receptors and ligands, suppressive cytokines, defective antigen presentation, and metabolic competition. However, recent evidence reveals that intercellular mitochondrial transfer adds a new mechanism of immune evasion in the TME. The mitochondrial fitness of T cells is central to sustained effector function, memory formation, and responsiveness to immune checkpoint blockade. Tumor cells can act as pathogenic mitochondrial donors, transferring functional or dysfunctional mitochondria to neighboring T cells via tunneling nanotubes and extracellular vesicles. This process involves a mitophagy imbalance that leads to the homoplasmic replacement of endogenous mitochondria, thereby driving T-cell senescence, impairing memory formation and long-term antitumor function, and ultimately weakening cancer immunosurveillance. Overall, mitochondrial transfer should be considered a new part of the tumor immune evasion framework. It also provides new therapeutic opportunities for improving cancer immunotherapy.

Keywords:  Mitochondrial transfer; T-cell exhaustion; immune checkpoint blockade; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1093/intimm/dxag027
J Immunother Cancer. 2026 May 28. pii: e013637. [Epub ahead of print]14(5):

CLEC2B-KLRB1 axis acts as an immune checkpoint, governing the exhaustion of CD8+ T cells and their resistance to immune checkpoint blockade.

Jie Cheng, Jiahua Lu, Zhaoya Gao, Yifeng Xiao, Pengju Chen, Mengting Zhou, Dandan Huang, Zihao Zhao, Xiaohui Zhang, Yuan Zhao, Ming Li, Jin Gu.

   BACKGROUND: Many patients with cancer benefit little from immune checkpoint blockade (ICB), a major obstacle to immunotherapy for decades. Finding alternative immune checkpoints that control CD8+ T-cell exhaustion is urgent if we are to improve the efficacy of immunotherapies, particularly in microsatellite stable (MSS) colorectal cancer (CRC) that is resistant to ICB.
METHODS: Spatial proximity is essential for suppressive ligand-receptor signaling. Here, we mapped the spatial tumor microenvironment of patients with MSS CRC at single-cell resolution and analyzed the cells interacting with exhausted CD8+ T cells to identify immune checkpoint ligand-receptor pairs. To investigate the function of this previously unrecognized immune checkpoint, we performed validation studies spanning cellular experiments, mouse models, and clinical patient samples.
RESULTS: We found that a subset of MSS CRC exhibits substantial CD8+ T-cell infiltration, but their function is suppressed. We identified CLEC2B (ligand)-KLRB1 (receptor) as a novel inhibiting ligand-receptor pair for CD8+ T cells. KLRB1 acts as an immune checkpoint receptor, increasing CD8+ T-cell exhaustion and facilitating immune escape in various human cancers. Binding of CLEC2B to KLRB1 initiates immunosuppressive signaling in CD8+ T cells. Clinically, CLEC2B-KLRB1 expression correlates positively with cancer progression and poor response to ICB, demonstrating that KLRB1+ CD8+ T cells are a key marker of the poorly responsive ICB subtype. Furthermore, blocking CLEC2B-KLRB1 signaling with antibodies enhances the antitumor function of CD8+ T cells, providing a potential immunotherapy target for ICB non-responders.
CONCLUSIONS: Our study revealed CLEC2B-KLRB1 as a previously unrecognized immune checkpoint axis that drives T-cell exhaustion specifically in ICB poor responsive MSS CRC. Blockade of KLRB1 with a therapeutic antibody reinvigorated CD8+ T-cell antitumor immunity, positioning this axis as a promising target for enhancing immunotherapy efficiency in malignancies, including CRC and other ICB-resistant cancers.

Keywords:  Colorectal Cancer; Immune Checkpoint Inhibitor; T cell

DOI:  https://doi.org/10.1136/jitc-2025-013637
iScience. 2026 Jun 19. 29(6): 115895

Protein-dependent CD4+ T cell specialization and CD8+ T cell-driven IL-2 production in HIV.

Jernej Pušnik, Falko M Heinemann, Andreas Heinold, Enrico Richter, Stefan Esser, Hendrik Streeck.

  Chronic HIV infection alters antiviral T cell responses and shapes their functional profiles. We combined HLA peptide tetramers with functional stimulation assays to characterize HIV-specific CD4+ and CD8+ T cells targeting immunodominant epitopes in chronically infected individuals. CD4+ and CD8+ T cells were present at comparable frequencies but showed distinct functional programs. CD4+ T cells displayed helper-associated features and were often functionally unresponsive, whereas CD8+ T cells exhibited cytotoxic profiles and were a major source of IL-2. CD4+ T cell functions were protein dependent: p24-specific cells were more cytotoxic and responsive, whereas gp120-specific cells preferentially expressed CXCR5. CD8+ T cell functions, particularly IL-2 and IFN-γ production inversely associated with viral load and positively associated with CD4+ T cell counts and the CD4/CD8 ratio. Collectively, these findings show CD8+ T cells as major IL-2 producers and protein-specific CD4+ T cell specialization, informing HIV vaccine and cure strategies.

Keywords:  Immunology; Molecular biology

DOI:  https://doi.org/10.1016/j.isci.2026.115895
Biomedicines. 2026 May 13. pii: 1097. [Epub ahead of print]14(5):

Characterization of a Cytokine-Independent STAT5 Activator.

Grace A Aleck, Yena Jin, Zehui Gu, Adam H Courtney.

  Background: Cytokine-induced JAK-STAT signaling becomes dysregulated in chronic human diseases, including cancer and autoimmunity, and contributes to immune cell dysfunction. A cytokine-independent approach to activating STAT proteins could "hardwire" pro-survival and effector programs in immune cells to sustain function within diseased tissues. Engineered variants of the herpesvirus saimiri tyrosine kinase interacting protein (TIP) can recruit the SRC family kinase (SFK) LCK to drive STAT phosphorylation and activation. Here, we evaluated the interactome of a TIP-derived, cytokine-independent STAT5 activator and determined whether it could induce STAT5 activation in immune cell lines and primary human CD8+ T cells. Methods: A STAT5 activator (aSTAT5) was characterized by proteomics using affinity purification mass spectrometry (AP-MS) to define its interactome and STAT5 binding specificity. STAT5 phosphorylation was assessed in hematopoietic cell lines and primary human CD8+ T cells. Results: Proteomic analysis confirmed preferential association of aSTAT5 with STAT5 relative to other proteins. In cell-based assays, aSTAT5 induced robust STAT5 phosphorylation in LCK-expressing NK-92 and Jurkat T cells, whereas phosphorylation was not observed in Raji B cells or RAW 264.7 macrophages despite expression of closely related SFKs and STAT5. Cytokine-independent STAT5 phosphorylation supported the viability of NK-92 cells and primary human CD8+ T cells during cytokine withdrawal and preserved the cytotoxic function of CAR T cells. Conclusions: We defined the interactome of a cytokine-independent STAT5 activator and demonstrated its capacity to maintain survival and function in human CD8+ T cells and NK-92 cells. These findings underscore the translational potential of engineered, cytokine-independent STAT5 activation for immune cell therapies.

Keywords:  CAR-T; LCK; NK cell; STAT5; T cell; T cell signaling; cytokine; kinase

DOI:  https://doi.org/10.3390/biomedicines14051097
Mol Med. 2026 May 26.

STUB1-mediated ubiquitination regulates Fli-1 stability and CD4⁺T cell activation during inflammation.

Pengfei Li, Liu Liu, Yan Wu, Meng Liu, Maria Trojanowska, Hongkuan Fan.

   BACKGROUND: Fli-1, a member of the ETS transcription factor family, has been implicated in multiple inflammatory and immune-related disorders, including sepsis, lupus, Alzheimer's disease, and post-traumatic stress disorder (PTSD). Recent studies further suggest a critical role for Fli-1 in CD4⁺ T cells in graft-versus-host disease, systemic sclerosis, and PTSD; however, its precise function and regulation during inflammatory CD4⁺ T cell responses remain incompletely understood.
METHODS: Wild-type and CD4⁺ T cell-specific Fli-1 knockout mice were administered LPS via intraperitoneal injection. Survival rates and splenic T cell activation were subsequently assessed. In vitro, cultured Jurkat and HEK cells were utilized to investigate the STUB1/Fli-1-related signaling pathway.
RESULTS: Here, we demonstrate that Fli-1 expression is markedly upregulated in splenic CD4⁺ T cells in a murine model of endotoxemia. CD4⁺ T cell-specific deletion of Fli-1 significantly improves survival and attenuates splenic CD4⁺ T cell activation. Mechanistically, we identify STUB1 as a novel E3 ubiquitin ligase for Fli-1 that promotes K27-linked ubiquitination and proteasomal degradation under basal conditions. Inflammatory stimulation disrupts the STUB1/HSP70 interaction, reducing STUB1-mediated ubiquitination and enhancing Fli-1 protein stability. Consistent with these findings, Fli-1 knockout reduces TNFα, IFNγ, and IL-10 expression, whereas STUB1 knockout enhances their expression in Jurkat cells. Gain- and loss-of-function studies further reveal that Fli-1 modulates NFκB signaling, a key pathway in T cell activation.
CONCLUSIONS: Collectively, our results identify the STUB1/Fli-1 axis as a previously unrecognized regulator of CD4⁺ T cell function and a potential therapeutic target for inflammatory diseases.

Keywords:  CD4+ T cells; Endotoxemia; Fli-1; NFκB; STUB1

DOI:  https://doi.org/10.1186/s10020-026-01494-5
Front Immunol. 2026 ;17 1816695

HDAC7 controls anti-viral and anti-tumor immunity by CD8+ T cells.

Cansu Yerinde, Jacqueline Keye, Hsiang-Jung Hsiao, Sibel Durlanik, Inka Freise, Franziska Nowak, Marilena Letizia, Stephan Schlickeiser, Benedikt Obermayer, Adrian Huck, Marie Friedrich, Hao Wu, Désirée Kunkel, Anja A Kühl, Sebastian Bauer, Andreas Thiel, Ahmed N Hegazy, Britta Siegmund, Rainer Glauben, Carl Weidinger.

  Class II histone deacetylases (HDAC) orchestrate T cell-dependent immune responses via the epigenetic control of genes and via the post-translational modification of cytoplasmic and nuclear proteins. However, the contribution of single HDAC family members to the differentiation and function of peripheral CD8+ T cells remains elusive. We here demonstrate that HDAC7-deficiency leads to the upregulation of immune checkpoint molecules, increased apoptosis and disturbed glutamine homeostasis of peripheral murine CD8+ T cells, which we could link to a MEF2D-dependent induction of FasL expression ultimately deterring the survival of HDAC7-deficient CD8+ T cells. Likewise, we observed in mouse models of lymphoma, that mice with a T cell-specific deletion of Hdac7 harbor impaired anti-tumor immune responses in syngeneic transfer models of lymphoma and we found that HDAC7 is required for CD8+ T cell-dependent memory recall responses in models of lymphocytic choriomeningitis virus infection. Taken together, we identify HDAC7 as a central regulator of cellular exhaustion and apoptosis of peripheral CD8+ T cells, controlling CD8+ T cell dependent anti-tumor and anti-viral immunity in mice.

Keywords:  CD8+ T cells; Eomes; FasL; HDAC7; apoptosis; cellular exhaustion; colitis; glutamine

DOI:  https://doi.org/10.3389/fimmu.2026.1816695
Cytokine Growth Factor Rev. 2026 May 17. pii: S1359-6101(26)00040-7. [Epub ahead of print]90 26-38

Cytokine-mediated intrinsic and extrinsic regulation of anti-tumor adoptive T cell therapy.

Jing Hu, Jiayue Qiu, Tommy Chen, Bingfei Yu.

  Adoptive T cell therapy has transformed the treatment of hematologic malignancies but fails to control solid tumors, where T cell dysfunction and an immunosuppressive tumor microenvironment (TME) remain the central barriers. Cytokines are essential regulators of both T cell fate and the TME, making cytokine engineering a key lever for overcoming these limitations. Here we review recent advances in intrinsic strategies that embed cytokine support directly into the engineered T cell product and extrinsic strategies that deliver cytokines to the tumor site to remodel the TME, providing a comprehensive analysis to guide rational strategy selection and combination. We further highlight synthetic cytokine and receptor designs that induce novel T cell states beyond the boundaries of natural T cell biology. Finally, we propose virtual cytokine networks as a framework for predicting patient-specific immune cascades triggered by any designed cytokine intervention, providing a path toward personalized cytokine-guided adoptive T cell therapy.

Keywords:  Adoptive T cell therapy; CAR-T therapy; Cancer immunotherapy; Cytokine engineering; Synthetic cytokine receptor; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.cytogfr.2026.05.002
Front Immunol. 2026 ;17 1843548

Wnt signaling as a regulator of memory T cells: implications for CAR-T cell therapy.

Tatiana Fourfouris, Ki Jun Lee, Samantha Hurwitz, Asher Ahdoot, Alexander Lee, Maiah Zarrabi, Michael Kahn, Yong-Mi Kim.

  Chimeric antigen receptor T-cell (CAR-T) therapy has achieved impressive remission rates in hematologic cancers, but long-term efficacy remains limited by insufficient CAR-T cell persistence. T cell factor 1 (TCF1) and lymphoid enhancer binding factor 1 (LEF1), transcription factors well known for their role in downstream Wnt/β-catenin signaling, have been found to regulate transcriptional and epigenetic memory programming important for CAR-T cell persistence and favorable patient outcomes. Activation of the Wnt/β-catenin in endogenous T cells was found to arrest effector differentiation and promote the formation of cluster of differentiation (CD) 8+ memory stem cells, characterized by strong proliferative and recall potential, key traits of persisting memory cells. Genetically engineered CAR-T cells are subject to the same transcriptional and epigenetic factors that govern memory development in endogenous T cells, providing a strong rationale for applying scientific findings from basic T cell biology to CAR-T cell engineering. With this in mind, recent studies have shown that there is clinical potential for Wnt-directed approaches to improve CAR-T cell memory phenotypes, persistence, and exhaustion. Here we review the role of Wnt/β-catenin signaling in T cell development and memory formation, examine clinical evidence linking Wnt/TCF1 activity to CAR-T cell persistence and patient outcomes, and discuss emerging genetic, epigenetic, and pharmacological strategies used to target this pathway in CAR-T cell manufacturing.

Keywords:  CAR-T cell persistence; CAR-T cells; LEF1; T cells; TCF1 (TCF7); Wnt/β-catenin signaling; memory T cells

DOI:  https://doi.org/10.3389/fimmu.2026.1843548
Front Immunol. 2026 ;17 1800870

Age-related reduction of pyruvate dehydrogenase kinase 1 impairs T cell responses.

Rajkumar S Kalra, Miho Tamai, Shukla Sarkar, Yong-Woon Han, Mio Miyagi, Daiki Sasaki, Hiroki Ishikawa.

  Aging is associated with impaired T cell immune responses, raising the susceptibility of the elderly to infections and cancers. Aged T cells exhibit impaired T cell responses to T cell receptor (TCR) stimulation accompanied by reduced glycolytic activity, but the molecular basis of these defects is largely elusive. Using data-independent acquisition (DIA) mass spectrometry-based proteomic analysis, we identified pyruvate dehydrogenase kinase 1 (PDHK1), a key glycolytic enzyme, as significantly downregulated in aged murine T cells. This loss of PDHK1 expression was confirmed in both CD4+ and CD8+ T cells from aged mice, regardless of their naïve or activated state. Consistent with this, aged T cells exhibited defects in the activation of glycolysis immediately after TCR stimulation. Furthermore, CRISPR-mediated Pdhk1 deletion in young T cells led to defective activation and effector molecule expression upon TCR stimulation, whereas enforced PDHK1 expression in aged T cells facilitated these responses. These data suggest that aging diminishes PDHK1 expression in T cells, contributing to impaired glycolysis and T cell responses, which can be therapeutically restored by PDHK1 overexpression.

Keywords:  DIA-MS; PDHK1; T cell activation; aerobic glycolysis; aging; metabolism

DOI:  https://doi.org/10.3389/fimmu.2026.1800870
Redox Biol. 2026 May 18. pii: S2213-2317(26)00224-7. [Epub ahead of print]94 104226

Lactylation landscape of mitochondrial proteins in myocardial infarction.

Ashlesha Kadam, Shiridhar Kashyap, Kunal Samantaray, Natasha Jaiswal, Shanikumar Goyani, Philip A Kramer, Pourhadi Hadi, Jingyun Lee, Cristina M Furdui, Pooja Jadiya, Dhanendra Tomar.

  Metabolic reprogramming is a hallmark of myocardial infarction (MI), in which cardiomyocytes shift from fatty acid oxidation to anaerobic glycolysis, leading to elevated lactate production and mitochondrial dysfunction. Lactylation, a recently discovered lysine post-translational modification, has emerged as a metabolic signaling mechanism; however, its role within mitochondria during MI remains poorly understood. Here, we mapped the mitochondrial lactylome following MI and examine how modulation of lactate transport influences mitochondrial metabolism and redox homeostasis. Using quantitative proteomics, we identify extensive remodeling of mitochondrial protein lactylation after MI, affecting enzymes involved in bioenergetics, redox regulation, and metabolic control. Pharmacological inhibition of monocarboxylate transporter-1 (MCT1) using AZD3965 further reshapes the mitochondrial lactylome, increasing lactylation of specific metabolic and redox-associated proteins without uniformly exacerbating mitochondrial dysfunction. Despite sustained impairment of global cardiac function, MCT1 inhibition attenuates post-MI fibrosis and inflammation and partially restores mitochondrial respiratory capacity. Consistent with in vivo findings, genetic or pharmacological inhibition of MCT1 in hypoxic cardiomyocyte-derived cells reduces mitochondrial reactive oxygen species, decreases inhibitory pyruvate dehydrogenase phosphorylation, and improves mitochondrial bioenergetics. Together, these findings reveal that mitochondrial lactylation is a context-dependent regulator of mitochondrial metabolism and redox balance following MI. Rather than acting solely as a pathological modification, lactylation integrates lactate availability with mitochondrial function to influence inflammatory and fibrotic remodeling, highlighting mitochondrial metabolic plasticity as a potential therapeutic target in ischemic heart disease.

Keywords:  AZD3965; Lactate; Lactylation; MCT1; Mitochondria; Myocardial infarction

DOI:  https://doi.org/10.1016/j.redox.2026.104226
PLoS Genet. 2026 May 26. 22(5): e1012107

ZBP1 Drives CD8+ T cell-mediated anti-tumor immunity in head and neck squamous cell carcinoma.

Yu Min, Ge Song, Lianlian Yang, Ling He, Shihong Xu, Kun Gao, Zheran Liu, Xingchen Peng, Lei Dai.

Head and neck squamous cell carcinoma (HNSCC) frequently resists PD-1 blockade due to an immunologically "cold" tumor microenvironment (TME). Here, we identify Z-DNA binding protein 1 (ZBP1) as a key immunoregulator that reprograms immune-suppressive TMEs. Integrated TCGA/SangerBox analyses revealed ZBP1 as a hub gene strongly correlated with cytotoxic CD8+ T cells (r = 0.48, p < 0.0001) and M1 macrophages (r = 0.39, p < 0.0001). Multi-model validation in 92 HNSCC specimens revealed elevated ZBP1 expression versus normal tissues (p < 0.01), co-localized with infiltrating CD8+/CD4+ T cells and CD68+ macrophages through multiplex immunofluorescence. Clinically, high ZBP1 predicted improved survival (HR = 0.61 for overall survival; HR = 0.45 for disease specific survival; p < 0.0001) and early-stage presentation (p = 0.004). Mechanistically, ZBP1 overexpression in SCC-7/MOC2 models suppressed tumor growth while enhancing IFN-γ+ CD8+ T cell activation and reducing M2 polarization (CD206+: 16.91% vs 38.19% in ZBP1-high vs control, p < 0.001). Single-cell transcriptomics uncovered ZBP1-driven TME remodeling through chemokine signaling networks and expanded effector T cell compartments, validated by 1.49-fold increased CD8+ T cell infiltration via flow cytometry. Spatial analysis revealed ZBP1 overexpression amplified immune cell crosstalk (1.65-fold interaction increase, p < 0.001), upregulating CD8+ T cell chemotaxis (CXCR3/CCR5-CCL5 axis) and effector functions (p < 0.0001). Concurrently, it suppressed immunosuppressive pathways (ARG1 ↓ /IDO1↓) through metabolic reprogramming, establishing ZBP1 as a dual regulator synchronizing lymphocyte recruitment and myeloid suppression. Our integrative approach bridges computational biology with functional validation, demonstrating ZBP1's capacity to convert "cold" tumors into immunologically active niches. This work positions ZBP1 as both a stratification biomarker for checkpoint inhibitor response and a therapeutic target for TME reprogramming in HNSCC.

DOI: https://doi.org/10.1371/journal.pgen.1012107
Cells. 2026 May 13. pii: 890. [Epub ahead of print]15(10):

Mitochondrial Stress Orchestrates Tumor Immune Evasion and Immunotherapy Resistance.

Ayhan Bilir, Berna Yıldırım, Mete Hakan Karalök.

  Mitochondrial stress has emerged as a key regulator of tumor-immune interactions, extending beyond its classical bioenergetic role to coordinate metabolic adaptation and immune regulation. Rather than merely accompanying tumor progression, mitochondrial dysfunction contributes to immune evasion and resistance to immunotherapy. Here, we propose that mitochondrial stress functions as a unifying axis governing three key determinants of anti-tumor immunity: immune visibility, immune cell fitness, and the metabolic architecture of the tumor microenvironment. Mechanistically, mitochondrial reactive oxygen species, mitochondrial DNA release, and mitophagy modulate antigen presentation and T cell function. We further highlight emerging experimental platforms, including 3D spheroid and organoid systems, that enable physiologically relevant investigation of mitochondria-driven tumor-immune interactions. Together, this perspective provides a mechanistic framework for understanding and targeting resistance to immune checkpoint blockade.

Keywords:  3D tumor models; PD-1/PD-L1 axis; immune checkpoint blockade; immunotherapy resistance; metabolic competition; mitochondria; mitochondrial stress; mitophagy; mtDNA–cGAS–STING; organoids; tumor immune evasion; tumor microenvironment

DOI:  https://doi.org/10.3390/cells15100890
bioRxiv. 2026 May 14. pii: 2026.05.13.724746. [Epub ahead of print]

Covalent tumor anchoring spatially orchestrates antitumor immunity.

Qingke Li, Hongfei Chen, Pan Zhang, Li Cao, Bingchen Yu, Lei Wang.

Protein immunotherapies can elicit potent tumor rejection, but reversible target engagement, incomplete tumor retention, and systemic leakage often erode spatial control. Here, we develop covalently anchored tumor immunotherapeutic proteins (CATIPs), a modular platform that uses proximity-enabled covalent chemistry to immobilize immune cues on tumor-cell surfaces after intratumoral administration. CATIPs combine tumor-targeting nanobodies with payloads for T cell engagement, co-stimulation, and cytokine support. In human PBMC-reconstituted NSG mice, CATIPs completely eradicated treated EGFR-positive tumors, outperforming matched non-covalent proteins while limiting redistribution, systemic T cell activation, cytokine release, xGVHD-associated morbidity, and on-target, off tumor toxicity. In immunocompetent melanoma models, CATIPs remodeled the tumor microenvironment, expanded antigen-specific CD8 + T cells, induced antigen-restricted abscopal control, and generated durable protection against local and metastatic rechallenge. CATIP-engineered tumor cells further functioned as whole-cell vaccines. Thus, covalent tumor anchoring converts local protein delivery into tumor-surface immune programming, enabling systemic, tumor-specific, durable antitumor immunity while limiting systemic immunopathology.

DOI: https://doi.org/10.64898/2026.05.13.724746
NPJ Aging. 2026 May 28.

Mitochondrial drivers of stem cell aging and inflammaging.

Jhommara Bautista, Andrés López-Cortés.

Mitochondria are increasingly recognized as master regulators of aging, integrating bioenergetics, redox control, stem cell fate, and innate immune signaling. This review synthesizes evidence that mitochondrial dysfunction is not only a hallmark but also an upstream driver of stem cell exhaustion and inflammaging. We discuss how age-associated mitochondrial DNA (mtDNA) mutations and clonal mosaicism impair respiration and reshape metabolite availability, thereby reprogramming long-lived epigenetic states that govern quiescence, lineage commitment, and regenerative output. In parallel, erosion of mitochondrial quality control (MQC), including fission-fusion balance, mitophagy, and the mitochondrial unfolded protein response (UPRmt), permits the persistence of reactive oxygen species (ROS)-producing organelles and lowers containment of mitochondrial danger signals. A central advance is that mitochondrial damage can be decoded as inflammation: cytosolic mtDNA and other mitochondrial damage-associated molecular patterns (mtDAMPs) activate cGAS-STING and NF-κB pathways, reinforcing senescence-linked cytokine circuits and chronic inflammatory tone. We further highlight nicotinamide adenine dinucleotide (NAD⁺) depletion as a metabolic bottleneck that compromises sirtuin-dependent resilience and can enforce mitochondrial dysfunction-associated senescence (MiDAS), linking redox collapse to altered senescence phenotypes and regenerative decline. Finally, we evaluate emerging mitochondria-targeted rejuvenation strategies, NAD⁺ repletion, mitophagy enhancers, mitochondrial transplantation/engineering, and precision elimination of mutant mtDNA using mitochondria-targeted transcription activator-like effector nucleases (mitoTALENs) or zinc-finger nucleases (mitoZFNs), emphasizing tissue-specific thresholds and context dependence for effective healthspan extension.

DOI: https://doi.org/10.1038/s41514-026-00422-5