bims-imseme 2026-02-22 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2026–02–22
33 papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Metabolic Checkpoints in CD8+ T Cells within the Tumor Microenvironment: A Comprehensive Review and Emerging Insights.
SLC1A5-mediated kynurenine metabolism drives AHR-FANCD2 axis to remodel chromatin and induce T cell exhaustion in lung adenocarcinoma.
High efficiency CRISPR knock-in demonstrates that TCF1 is insufficient to reverse T cell exhaustion.
Nonoxidative pentose phosphate pathway regulates CD8+ T cell immunity by maintaining NADPH homeostasis.
Phenotypic and functional heterogeneity of naïve CD8+ T cells in human peripheral blood during aging.
Regulating the regulators via targeting CD38 in the tumor microenvironment.
Transduction of Batf family members provides distinct functions to mouse CD8+ T cells.
"Metabolic memory" of aging: anchoring, transmission, and frontiers of transgenerational intervention.
The insider's perspective: The intracellular complosome and immune cell dynamics in cancer.
Low intensity vibration as a novel strategy to normalize age-related deficits in T cell proliferation, activation, and function.
16-h fasting optimizes cancer immunotherapy in mice and humans.
The adenylyl cyclase activator forskolin pretreatment reprograms CAR-T cells toward a stem-like state to enhance solid tumor therapy.
Spilling the T: T cells in tauopathy mechanisms, disease progression, and therapeutic horizons.
Cancer-associated fibroblasts promote immune evasion in pancreatic cancer via miR-181b-5p/STING/LGALS1 pathway.
Nondestructive, High-Resolution T Cell Characterization and Subtyping via Deep-UV Microscopy.
Visceral adiposity, metabolic health and aging.
CD4+ T cells in cancer: dual roles, exhaustion, and therapeutic breakthroughs.
Age-related mitochondrial energy metabolism reprogramming occurs in granulosa cells during ovarian aging.
Interrupting T-Cell Memory Ameliorates Exaggerated Metabolic Response to Weight Cycling.
Roles of immune cell metabolism in rheumatoid arthritis.
A PI3Kδ-Foxo1-FasL signaling amplification loop rewires CD4+ T cell signaling and differentiation.
A novel attenuated CD122-biased IL-15 mutein promotes strong NK and T cell dependent anti-tumor immunity.
Loss of PINK1 impairs mitophagy and accelerates ovarian aging independent of Parkin.
Epigenetic profiling of hematopoietic stem cells from male mice identifies KDR and PU.1 as regulators of aging transcriptome and caloric restriction response.
Induction of IL-9-producing CD8+ T cells by ascochlorin derivatives.
TIPE2 knockdown enhances the anti-tumor efficacy of NKG2D CAR-T cells against pancreatic cancer via activating NF-κb signaling pathway.
Collagen-bearing exosomes from breast cancer-associated fibroblasts promote T cell dysfunction.
TGFβ-activated PDHB promotes mitochondrial pyruvate metabolism and contributes to human endoderm differentiation via ATP-dependent BRG1.
Transcriptional and functional HBV-specific CD8 T cell changes from disease to functional cure in HBeAg-negative chronic hepatitis B.
CCL5hi-CD4+ T cells Regulate Macrophage Polarization and Promote Immunotherapy Response in Bladder Cancer.
Drug-controlled CAR T cells through the regulation of cell-cell interactions.
Gene expression changes in lymphocytes and monocytes from patients with traumatic brain injury.
Advancing CAR-T therapy in prostate cancer: overcoming the tumor microenvironment and enhancing efficacy.

Int J Biol Sci. 2026 ;22(4): 1950-1973

Metabolic Checkpoints in CD8+ T Cells within the Tumor Microenvironment: A Comprehensive Review and Emerging Insights.

Jiaqi Ai, Yiheng Du, Qianqian Xue, Wenbei Peng, Qiong Zhou.

  In recent years, a growing number of evidence suggests that cancer is a metabolic disease. Metabolic reprogramming is a hallmark of the TME, where various nutrients, including glucose, lipids, and amino acids, play key roles in regulating tumor development by acting on both tumor cells and immune cells. T cells are the core mediators of anti-tumor immunity. Especially CD8+ T cells are considered the primary immune cells involved in the anti-tumor immune response. Upon stimulation by tumor antigens and other immune cells, CD8+ T cells undergo metabolic reprogramming through signaling pathways. Metabolites or metabolic checkpoints induce epigenetic changes in key genes, altering the differentiation and effector function of CD8+ T cells. This review first elaborates on the anti-tumor functional characteristics and metabolic profiles of CD8+ T cells at different stages of differentiation in the TME. Then we focus on the roles of key metabolites and metabolic checkpoints in shaping CD8+ T cell differentiation, functionality, and immune responses, specifically through glucose, lipid, and amino acid metabolism. Finally, we discuss the reasons for heterogeneity in the effects of metabolic checkpoints on CD8+ T cells and explore potential clinical applications of metabolic checkpoints in treatment. Understanding the correlation between CD8+ T cell metabolism and anti-tumor immunotherapy may facilitate the development of new strategies to enhance the efficacy of CD8+ T cell-based cancer treatments.

Keywords:  CD8+ T cell; cancer; checkpoint; immunotherapy; metabolism

DOI:  https://doi.org/10.7150/ijbs.125206
Cell Commun Signal. 2026 Feb 16.

SLC1A5-mediated kynurenine metabolism drives AHR-FANCD2 axis to remodel chromatin and induce T cell exhaustion in lung adenocarcinoma.

Yifei Zhu, Haoji Wang, Yanxi Yao, Hongdou Ding, Li Xu, Xinnan Xu.

   BACKGROUND: Kynurenine, a byproduct of tryptophan breakdown, is linked to immune suppression during cancer development. This study explores the involvement of the amino acid transporter solute carrier family 1 member 5 (SLC1A5) in kynurenine-mediated T cell exhaustion in LUAD and delves into its functional mechanism.
METHODS: RNA-sequencing analysis was employed to identify transcriptome differences between T progenitor and terminal exhausted T cells (TPEX vs. TEX). The SLC1A5 expression was detected in T cells following L-kynurenine (L-ky) treatment. Mouse LUAD cells LLC were implanted into wild-type (WT), SLC1A5 knockout (SLC1A5-/-), SLC1A5flox/flox (SLC1A5fl/fl), or CD8⁺ T cell-specific SLC1A5 conditional knockout (SLC1A5cko) mice, followed by L-ky treatment, to examine the effect of SLC1A5cko on L-ky-mediated tumorigenesis and T cell exhaustion. Interacting proteins of AHR, a core transcription factor in the kynurenine pathway, were explored by liquid chromatography/mass spectrometry and bioinformatics.
RESULTS: SLC1A5 is upregulated in TEX, and its expression in CD8+ T cells was increased by L-ky treatment dose-dependently. The tumorigenic activity of LLC cells, under L-ky treatment stimulation, was suppressed in both SLC1A5-/- and SLC1A5cko mice, accompanied by increased T cell activity within tumors. CD8+ T cells extracted from SLC1A5cko mice also showed reduced L-ky uptake and increased cytotoxicity in vitro. Mechanistically, AHR recruits the chromatin modifying enzyme FANCD2 to enhance SLC1A5 expression, promoting chromatin accessibility in T cells and cell exhaustion.
CONCLUSION: This study suggests that SLC1A5 is upregulated in TEX, which modulates kynurenine metabolism and induces T cell exhaustion through the AHR-FANCD2 axis-mediated chromatin remodeling.

Keywords:  AHR-FANCD2 interaction; CD8+ T cell exhaustion; Kynurenine; LUAD; SLC1A5

DOI:  https://doi.org/10.1186/s12964-026-02732-3
Nat Commun. 2026 Feb 17.

High efficiency CRISPR knock-in demonstrates that TCF1 is insufficient to reverse T cell exhaustion.

Maria N de Menezes, Amanda X Y Chen, Nihali Kulkarni, Shienny Sampurno, Nicole Y L Saw, Kah Min Yap, Iván Pérez-Núñez, Sara Roth, Christian Deo T Deguit, Brandon Haugen, Kelly M Ramsbottom, Isabelle Munoz, Paul A Beavis, Ian A Parish.

CD8+ T cell exhaustion is a regulatory state triggered by chronic antigen stimulation in both cancer and persistent infection. The less differentiated stem-like sub-populations of exhausted T cells have been heavily studied given their importance to the efficacy of current immunotherapies. While the transcription factor TCF1 is both necessary and sufficient for formation and maintenance of these stem-like populations, it remains unclear whether TCF1 can actively de-differentiate more terminally exhausted subsets back into a stem-like state. To address this question, here we utilize and optimize a high efficiency CRISPR knock-in methodology, compatible with mouse in vivo exhaustion models, to engineer T cells that either constitutively over-express TCF1, or conditionally over-express TCF1 following differentiation of the cells into a CX3CR1+ intermediate-exhausted state. Strikingly, we find that only constitutive, and not conditional, TCF1 over-expression can increase the size of the stem-like T cell pool. Thus, while TCF1 can slow stem-like T cell differentiation, it is insufficient to revert more differentiated cells back into a stem-like state.

DOI: https://doi.org/10.1038/s41467-026-69671-y
Proc Natl Acad Sci U S A. 2026 Feb 24. 123(8): e2526325123

Nonoxidative pentose phosphate pathway regulates CD8+ T cell immunity by maintaining NADPH homeostasis.

Jingyu Feng, Qian Zhang, Li Luo, Zhichao Gu, Wen Liu, Jingsong Xu, Mengxin Qi, Zhongji Meng, Lin Li, Liangliang Lin, Zhuoshun Yang, Huafeng Zhang.

  NADPH is essential for cellular biosynthesis and redox balance in CD8+ T cells. Here, we demonstrate that the nonoxidative pentose phosphate pathway (non-oxPPP), mediated by transketolase (TKT) and transaldolase (TALDO1), is critical for CD8+ T cell activation, proliferation, and memory formation by maintaining NADPH homeostasis. Metabolomic profiling and isotopic tracing revealed upregulated non-oxPPP flux in effector (Teff) and memory (Tm) CD8+ T cells, enabling a pentose cycle that amplifies NADPH yield and sustains metabolic fitness for T cell immunity. Genetic knockdown or pharmacological inhibition of Tkt or Taldo1 impaired NADPH production, leading to ribose-5-phosphate (R5P) accumulation, oxidative stress, reduced lipid synthesis, mitochondrial dysfunction, and compromised Teff cell proliferation, cytokine production, and antitumor efficacy. Conversely, enhancing non-oxPPP activity promoted Tm differentiation, persistence, and recall responses. Targeting the non-oxPPP represents a promising strategy to enhance cancer immunotherapy and vaccine efficacy by bolstering T cell effector and memory responses.

Keywords:  CD8+ T cell; NADPH; memory T cell; nonoxidative pentose phosphate pathway

DOI:  https://doi.org/10.1073/pnas.2526325123
Front Aging. 2026 ;7 1765665

Phenotypic and functional heterogeneity of naïve CD8+ T cells in human peripheral blood during aging.

Luca Pangrazzi, Patrizia Pehl, Lotti Hoffmann, Martin Bachmann, Gabriele Chelini, Michael Keller, Brigitte Jenewein, Maria Cavinato, Birgit Weinberger.

  Naïve CD8+ T cells are key players of adaptive immunity, but their heterogeneity and age-related changes are not fully understood. This study aimed to compare naïve CD8+ T cell subsets defined by different combinations of markers, namely, NCCR7 (CD45RA+CCR7+), NCD28 (CD45RA+CD28+), NCD27 (CD45RA+CD27+), and phenotypically most "true-naïve"-like, NTN (CD45RA+CCR7+CD28+CD27+CD57-). Peripheral blood was harvested from donors of various ages and the phenotype of the four subsets of naïve CD8+ T cells was analyzed. NCD27 and NTN cells showed similar phenotypes with low expression of differentiation markers, pro-inflammatory cytokines, and effector molecules. Furthermore, they exhibited optimal mitochondrial fitness, low senescence markers, reduced apoptosis, and high proliferation potential. Hierarchical clustering identified cluster one including NCD27 and NTN, with lower expression of differentiation markers and pro-inflammatory molecules, and cluster 2, including NCCR7 and NCD28 cells, in which these parameters were more expressed. Age-related changes were observed in all subsets, although they were less pronounced for the NCD27 and NTN subsets. Taken together, this study demonstrates significant heterogeneity among naïve CD8+ T cell subsets, with NTN cells representing the most bona fide naïve phenotype and NCD27 showing a partially similar phenotype. These findings significantly enhance our understanding of naïve CD8+ T cell biology and function.

Keywords:  T cells; adaptive immunity; aging; immunosenescence; naïve T cells

DOI:  https://doi.org/10.3389/fragi.2026.1765665
Front Immunol. 2026 ;17 1745988

Regulating the regulators via targeting CD38 in the tumor microenvironment.

Navnita Dutta, Nabanita Halder, Eduardo Nunes Chini, Sungjune Kim, Alak Manna.

  The immunosuppressive tumor microenvironment (TME) remains a major barrier to effective cancer immunotherapy. Among the central regulators of immune suppression, CD38, a multifunctional ectoenzyme and surface glycoprotein, has emerged as a pivotal orchestrator. CD38 is abundantly expressed on regulatory T cells (Tregs), regulatory B cells (Bregs), myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and tumor-associated neutrophils (TANs), where it enhances survival, metabolic fitness, and suppressive activity. Invariant natural killer T (iNKT) cells, which can either promote or suppress antitumor immunity, also express CD38 upon activation, suggesting a role for CD38 in directing their context-dependent fate within the TME. Mechanistically, CD38 regulates immune suppression through NAD+ hydrolysis, calcium signaling, and promotion of fatty acid oxidation (FAO) while impairing effector T-cell glycolysis and mitochondrial fitness under chronic hypoxia-conditions that favor exhaustion rather than enhanced cytotoxicity. By depleting extracellular NAD+, CD38 diminishes glycolysis and mitochondrial oxidative phosphorylation in effector T cells, while sustaining regulatory cell persistence through FAO. Its enzymatic products, cyclic ADP-ribose (cADPR) and NAADP, further mobilize calcium fluxes that reinforce suppressive function. CD38 also integrates with hypoxia-driven pathways; in CD38+ Bregs, stabilization of HIF-1α and induction of FAO-related genes such as CPT1A and PPARα/γ promote angiogenesis, immune-evasion, and therapeutic resistance. Therapeutically, targeting CD38 with monoclonal-antibodies, small-molecule inhibitors, or combinations with checkpoint blockade and macrophage-reprogramming agents has shown promise. Such interventions reverse immune suppression, restore effector T cell activity, and enhance tumor responsiveness to immunotherapy. In summary, CD38 functions as both a metabolic regulator and an immunologic checkpoint, coordinating suppressive networks and shaping iNKT cell fate. These multifaceted roles position CD38 as a transformative target for next-generation immunotherapies.

Keywords:  Breg; CD38; NAD; metabolism; tumor micro environment (TME)

DOI:  https://doi.org/10.3389/fimmu.2026.1745988
Int Immunol. 2026 Feb 17. pii: dxag009. [Epub ahead of print]

Transduction of Batf family members provides distinct functions to mouse CD8+ T cells.

Kenta Kondo, Mina Kumode, Hiroki Satooka, Koji Terada, Yusuke Sano, Nobuhito Nitta, Daisuke Okuzaki, Kensuke Takada, Takako Hirata, Hidetaka Kosako, Akira Andoh, Makoto Murata, Yasutoshi Agata.

  Members of the Batf family, including Batf, Batf2, and Batf3, play critical roles in various immune cell types. Several studies have suggested redundant functions, as they can compensate for each other's functions. Here, we show that transduction of Batf family members confers distinct functional characteristics on CD8+ T cells. Batf- and Batf2-transduced CD8+ T cells exhibited effector and memory-like phenotypes, respectively. Notably, Batf3-transduced CD8+ T cells showed both effector- and memory-like phenotypes in response to effector- and memory-associated cytokines, respectively, and superior anti-tumor activity in vivo among Batf family members. Our results demonstrated that each Batf family member has distinct functions in CD8+ T cells. These findings help us understand the roles of the Batf family members in CD8+ T cells and contribute to the development of optimized adoptive T cell therapies against cancer.

Keywords:  infection; tumor immunity

DOI:  https://doi.org/10.1093/intimm/dxag009
Biogerontology. 2026 Feb 21. pii: 60. [Epub ahead of print]27(2):

"Metabolic memory" of aging: anchoring, transmission, and frontiers of transgenerational intervention.

Yue Zhao.

  Cellular senescence is the core cytological basis for organismal aging and the development of age-related diseases. Accumulating evidence indicates that senescent phenotypes can be maintained long-term even after the removal of senescence-inducing stressors, and may even affect daughter cells and offspring. This review systematically proposes an integrated theoretical framework of "aging metabolic memory", explaining the persistence, transmissibility, and potential heritability of aging from a systems biology perspective. First, it elaborates on how mitochondrial metabolic reprogramming reshapes the cellular epigenetic landscape (DNA methylation, histone modification) by altering the homeodynamics of key metabolites (NAD⁺, α-ketoglutarate, succinate, etc.), thereby forming stable senescence imprints; second, it in-depth analyzes the mechanisms by which the senescence-associated secretory phenotype (SASP) and extracellular vesicles (EVs) act as "memory carriers" to achieve intercellular transmission and systemic spread of senescent phenotypes; on this basis, combined with the latest progress in epigenetics, it proposes and demonstrates a hypothetical model for the transgenerational transmission of aging metabolic memory through germ cells, exploring its biological significance and evolutionary implications; finally, it systematically sorts out and prospects novel aging intervention strategies based on "memory intervention" (rather than mere elimination), including metabolic resetting, epigenetic remodeling, transmission blocking, and germ cell-targeted intervention. This review summarizes the spatiotemporal dynamic characteristics of aging and may provide multi-dimensional intervention pathways for the precise prevention and treatment of age-related diseases and the promotion of healthy aging.

Keywords:  Aging intervention; Cellular senescence; Epigenetics; Extracellular vesicles; Metabolic memory; Senescence-associated secretory phenotype

DOI:  https://doi.org/10.1007/s10522-026-10410-7
Clin Transl Med. 2026 Feb;16(2): e70628

The insider's perspective: The intracellular complosome and immune cell dynamics in cancer.

Alexandra Bennion, Joanne Lysaght, Niamh Lynam-Lennon.

  Complement is increasingly recognised as a driver and modulator of antitumour immunity, with context-dependent effects across T cells, myeloid subsets, stromal elements and tumour cells. Although best known for pathogen clearance and membrane attack complex (MAC) formation, complement also acts intracellularly via the 'complosome' to regulate cellular homeostasis and gene expression. Complosome activity may dampen antitumour responses by rewiring single-cell metabolism and transcription, altering nutrient flux and fostering an immunosuppressive microenvironment. Here, we synthesise advances in intracellular and extracellular complement, with emphasis on complement component 3 (C3) and receptors (C3aR1, C5aR1/CD88, C5aR2/C5L2), highlighting how these pathways shape T-cell metabolism, exhaustion programmes and inflammatory tone within tumours. Evidence indicates that tonic C3/C5 signalling restrains cytotoxicity via C5aR1-driven myeloid recruitment and cytokine cascades, while complosome signalling tunes T-cell activation thresholds and bioenergetics. We outline considerations for selectively modulating intracellular versus extracellular complement, propose cell-type-resolved biomarker strategies and identify opportunities for complosome-directed therapies in cancer, integrating roles across T cells, macrophages, B cells, neutrophils, NK cells, regulatory T cells, dendritic cells, myeloid-derived suppressor cells and cancer-associated fibroblasts. KEY POINTS: Intracellular complement (complosome) shapes the tumor immune microenvironment. Complosome's role in cancer is underrecognized yet central to tumor immunity. C3/C5-driven complosome signals rewire T cell activation, fate, and metabolism. Complosome activity can promote pro-tumor immune cell function. Blocking the complosome, alone or with checkpoint inhibitors, unveils a new tumor target.

Keywords:  C3; C3a; C5; C5a; cancer immunity; complement system; complosome; immune cells; immunotherapy; intracellular complement; tumour microenvironment

DOI:  https://doi.org/10.1002/ctm2.70628
Sci Rep. 2026 Feb 17.

Low intensity vibration as a novel strategy to normalize age-related deficits in T cell proliferation, activation, and function.

Christopher P Ashdown, Ankur Sikder, Andreas G Kaimis, Meilin E Chan, Brian S Sheridan, Clinton T Rubin.

Age related decline in number, activation, and function of T lymphocytes are hallmarks of immune dysfunction. Exercise is often described as the single best intervention to protect and promote robust immune function during aging. While these benefits are often presumed to be an indirect byproduct of increased metabolism, exercise may also deliver a direct benefit to the immune cell through its innate sensitivity to mechanical signals. We tested the hypothesis that mechanical stimulation, delivered non-invasively using low intensity vibration (LIV, at: 2 h of 30 Hz, 0.7 g) could augment T cell expansion without disrupting their phenotype, as well as improve the status of aged, dysfunctional, T cells. As compared to sham-handled controls, LIV increased proliferation 59% in T cells isolated from elderly patients (69.3y ± 2.6) while increasing expansion by only 13% in T cells harvested from young subjects (22.7y ± 3.8). T cell activation and production of pro-inflammatory cytokines (e.g., IL-2 by + 25%; p < 0.05) were also increased by LIV. Exploring whether this in vitro influence could translate to an in vivo model of aging, 4w of 30 min/d of LIV applied to 18-month-old mice resulted in significant increases in T cell activation as compared to sham-handled controls (102% increase in CD25 & 44.2% increase in CD69; p < 0.05). LIV also improved T cell anti-viral functionality, as 18-month-old mice pre-treated with 4w of LIV prior to infection with an Influenza A virus exhibited 18% less weight loss at 12d compared to sham-handled controls, a critical indication of a more robust immune system. These data suggest that extremely low magnitude mechanical signals, introduced non-invasively using LIV, represent a novel, non-drug therapeutic strategy for ameliorating age-related declines in immune function.

DOI: https://doi.org/10.1038/s41598-026-40154-w
Cell Metab. 2026 Feb 19. pii: S1550-4131(26)00014-8. [Epub ahead of print]

16-h fasting optimizes cancer immunotherapy in mice and humans.

Sheng Chen, Tianyi Hu, Kaixiang Zhu, Yue Liu, Yidong Yang, Xiangyuan Li, Jinjie He, Wenyu Cui, Zhexu Chi, Weiwei Yu, Duojiao Chen, Zhen Wang, Jian Zhang, Ruya Sun, Dehang Yang, Siqi Dai, Qianzhou Yu, Quanquan Wang, Qian Xiao, Junbin Qian, Kefeng Ding, Di Wang.

  Dietary interventions hold promise for cancer therapy but often require prolonged, poorly tolerated regimens. Furthermore, how transient nutrient deprivation affects the metabolic interplay between tumor and immune cells within the tumor microenvironment (TME) remains unknown. Here, we introduce a brief, 16-h fasting regimen that enhances immunotherapy efficacy in both mice and humans. We found that this transient nutrient stress alters tumor-cell nutrient preferences, creating a metabolic window that can be leveraged to augment treatment. Mechanistically, short-term fasting induces intratumoral accumulation of isoleucine, which reconfigures CD8+ T cell epigenetic programs and phospholipid remodeling, thereby licensing enhanced anti-tumor capacity. In patients receiving neoadjuvant immunotherapy, short-term fasting was able to enhance CD8+ clonal expansion and cytotoxic programs. These findings establish a clinically feasible, well-tolerated dietary regimen that counters nutrient competition in the TME and that provides a tractable path to strengthen existing immunotherapy regimens.

Keywords:  diet intervention; immune checkpoint therapy; immunometabolism; tumor metabolism; tumor microenvironment

DOI:  https://doi.org/10.1016/j.cmet.2026.01.015
Int J Biol Macromol. 2026 Feb 17. pii: S0141-8130(26)00875-5. [Epub ahead of print] 150949

The adenylyl cyclase activator forskolin pretreatment reprograms CAR-T cells toward a stem-like state to enhance solid tumor therapy.

Jialu Hong, Muya Zhou, Shichu Xu, Zhengling Wang, Yuting Liu, Xiaoyu Li, Luxia Xu, Wenwen Chen, Jinhua Hu, Shengjing Xu, Feiyan Pan, Zhigang Guo.

  Chimeric antigen receptor (CAR)-T cell therapy has achieved remarkable success in hematological malignancies; however, its efficacy against solid tumors remains limited, primarily due to T cell exhaustion. Enhancing memory-like properties and stemness of T cells has emerged as a promising strategy to overcome this barrier. In this study, we demonstrate that Forskolin, a stem cell-inducing compound, reprograms CAR-T cells toward a memory-like state characterized by elevated stemness. Forskolin-pretreated CAR-T cells exhibited enriched memory phenotypes, reduced exhaustion, and enhanced anti-tumor activity both in vitro and in vivo. Transcriptomic profiling further revealed upregulation of CXCR4 and BCL6 following Forskolin treatment, and functional blockade of these pathways attenuated the beneficial effects of Forskolin, underscoring their critical roles in reinforcing CAR-T cell stemness. Our findings highlight a novel strategy that integrates stem cell-reprogramming agents to enhance CAR-T cell stemness and provide potential therapeutic targets to improve the efficacy of CAR-T cell therapy against solid tumors.

Keywords:  Chimeric antigen receptor (CAR)-T cell therapy; Forskolin; Solid tumor; Stem cell-reprogramming, memory T cell

DOI:  https://doi.org/10.1016/j.ijbiomac.2026.150949
Mol Neurodegener Adv. 2026 ;2(1): 14

Spilling the T: T cells in tauopathy mechanisms, disease progression, and therapeutic horizons.

Megan E Bosch, Jason D Ulrich.

  Primary and secondary tauopathies are major causes of dementia characterized by the abnormal accumulation of microtubule-associated protein tau. Tau aggregation initiates neuronal dysfunction and death, while despite the distinct and pathological features of individual tauopathies, accumulating evidence shows that these disorders converge on shared mechanistic pathways marked by chronic inflammation and progressive neuronal loss. The innate immune response has been extensively studied in this context, yet the contribution of the adaptive immune system, particularly T cells, has only recently gained attention. In this review, we examine emerging evidence for adaptive immune involvement in tauopathies, including mechanisms that drive T cell activation and infiltration into the central nervous system, their effector functions once within the parenchyma, and how these responses interact with innate immune signaling. We also highlight potential therapeutic strategies aimed at modulating adaptive immunity in primary and secondary tauopathies. Current findings suggest that tau accumulation and glial-driven neuroinflammation creates an environment that promotes the activation and recruitment of effector T cells into the tauopathy brain. Importantly, blocking or reshaping the T cell responses shows promise for mitigating neurodegeneration, highlighting the adaptive immune system as a potential therapeutic target.

Keywords:  Adaptive immune response; T cells; Tauopathies

DOI:  https://doi.org/10.1186/s44477-026-00020-5
Cancer Lett. 2026 Feb 17. pii: S0304-3835(26)00094-7. [Epub ahead of print]644 218331

Cancer-associated fibroblasts promote immune evasion in pancreatic cancer via miR-181b-5p/STING/LGALS1 pathway.

Shaobo Zhang, Yuanyuan Guo, Haoran Qi, Mengyao Wu, Yumeng Hu, Gaoyuan Lv, Yuxin Ye, Jing Han, Qiong Zeng, Yueran Du, Binghe Xu, Mingyang Liu.

  Pancreatic cancer remains one of the deadliest malignancies, characterized as a natural "immune desert". Despite the remarkable advances of cancer immunotherapy in recent years, it shows minimal efficacy in this cancer type. Cancer-associated fibroblasts (CAFs) play a crucial role in pancreatic cancer progression and immune regulation. Although their clinical potential has garnered significant attention, their specific functions and underlying mechanisms remain poorly defined. Here, we elucidate a mechanism by which CAFs reprogram PC cells to suppress CD8+ T cells. We found that CAFs enhance the CD8+ T cell-suppressive function of PC cells in vitro, and CAFs drive tumor progression by reduced and dysfunctional CD8+ T cells in vivo. Mechanistically, CAF-derived miR-181b-5p targets SEC24C (a key transporter for the STING) in PC cells to inhibit the STING phosphorylation. The inhibition of STING phosphorylation blocks YY1 nuclear translocation, thereby de-repressing SUSD2 and LGALS1 transcription. The upregulated LGALS1 is then secreted via SUSD2 assistance, ultimately suppressing CD8+ T cell function and inducing apoptosis. Our findings define a stromal-immune axis in pancreatic cancer, linking miR-181b-5p from CAFs to the establishment of an immune-suppressive niche via the STING pathway in tumor cells, thereby revealing this cascade as a targetable mechanism to counteract immune evasion.

Keywords:  CAFs; CD8(+) T cells; Immune evasion; Pancreatic cancer; miR-181b-5p

DOI:  https://doi.org/10.1016/j.canlet.2026.218331
BME Front. 2026 ;7 0227

Nondestructive, High-Resolution T Cell Characterization and Subtyping via Deep-UV Microscopy.

Viswanath Gorti, Caroline E Serafini, Aaron D Silva Trenkle, Kaitlyn McCubbins, Isaac LeCompte, Gabriel A Kwong, Francisco E Robles.

Objective and Impact Statement: We establish deep-ultraviolet (UV) microscopy as a fast, label-free, and simple imaging approach for assessing T cell viability, activation state, and subtype with high accuracy. Introduction: T cell characterization is critical for understanding immune function, monitoring disease progression, and optimizing cell-based therapies. Current technologies to characterize T cells, such as flow cytometry, require fluorescent labeling and are typically destructive endpoint measurements. Nondestructive, label-free imaging methods have been proposed but face limitations with throughput, specificity, and system complexity. Methods: In this work, we use static deep-UV images to characterize T cell viability and activation state and dynamic deep-UV time series to quantify intracellular activity for assessment of T cell subtype (CD4+ and CD8+). Results: T cell viability and activation state predicted from static deep-UV images showed strong agreement with flow cytometry, with a correlation of R 2 > 0.97. Dynamic deep-UV images revealed unique intracellular activity that enabled accurate subtyping of CD4+ and CD8+ T cells, with a sensitivity and specificity of ~90%, corroborating recent studies on metabolic activity differences between these subtypes. Conclusion: Together, deep-UV microscopy offers a powerful tool for high-throughput immune cell characterization, with broad applications in immunology research, immune monitoring, and development of emerging cell-based therapies.

DOI: https://doi.org/10.34133/bmef.0227
Nat Aging. 2026 Feb 19.

Visceral adiposity, metabolic health and aging.

Laurence T Maeyens, James F Nelson, Shangang Zhao.

Visceral adipose tissue (VAT) is increasingly recognized as a metabolically active organ that contributes to systemic metabolic dysfunction and aging. Accumulation of VAT is thought not merely to be a biomarker of but also a causal contributor to impaired metabolic health and reduced lifespan. In this Review, we summarize evidence from both animal and human studies to evaluate whether this causal relationship truly holds. Our assessment indicates that VAT is not inherently harmful; rather, its pathogenicity is context dependent and emerges under specific conditions, including lipid spillover combined with impaired preadipocyte differentiation, chronic inflammation, genetic susceptibility, hormonal changes and aging. We further explore how VAT-derived cytokines, exosomes, adipokines and lipotoxic metabolites mechanistically mediate its harmful effects. Lastly, we outline both established and emerging strategies aimed at reducing VAT burden or neutralizing its pathological impact. These insights highlight the view of VAT as a modifiable and context-sensitive contributor to metabolic disease and aging, and a promising target for promoting metabolic health and longevity.

DOI: https://doi.org/10.1038/s43587-026-01076-4
Cancer Biol Med. 2026 Feb 16. pii: j.issn.2095-3941.2025.0414. [Epub ahead of print]23(1):

CD4+ T cells in cancer: dual roles, exhaustion, and therapeutic breakthroughs.

Yangyang Zhang, Jingli Xu, Siwei Pan, Yuqi Wang, Qianyu Zhao, Ziyang Huang, Can Hu, Xiangdong Cheng.

  In recent years the crucial role of CD4+ T cells in tumor immunomodulation has garnered increasing recognition. While conventional cancer immunotherapy research has predominantly focused on the cytotoxic function of CD8+ T cells, emerging evidence has now shown that CD4+ T cells enhance antitumor immunity by delivering co-stimulatory signals, secreting cytokines, and promoting cytotoxic T lymphocyte (CTL) activation and display unique immunoregulatory capabilities through direct tumor cell killing or remodeling of the tumor microenvironment. The high heterogeneity and functional plasticity of CD4+ T cell subsets significantly influence clinical responses to immunotherapy with underlying mechanisms involving multi-level regulatory networks, including epigenetic modulation and metabolic reprogramming. Deciphering the functional heterogeneity of CD4+ T cells and the interactions with the tumor microenvironment will provide essential mechanistic insights for next-generation immunotherapies, such as immune checkpoint inhibitors and chimeric antigen receptor T (CAR-T) therapies, thereby advancing personalized treatment paradigms.

Keywords:  Mechanism of differentiation; T cell exhaustion; dual role; immunotherapeutic strategies; translational clinical applications

DOI:  https://doi.org/10.20892/j.issn.2095-3941.2025.0414
Front Endocrinol (Lausanne). 2026 ;17 1726339

Age-related mitochondrial energy metabolism reprogramming occurs in granulosa cells during ovarian aging.

Mengyu Shi, Zhicheng Jia, Xinxin Yang, Wenlong Qi, Xinwei Sun, Yongqian Li, Peixuan Wang, Ying Guo.

   Objective: Ovarian aging is an inevitable age-associated biological phenomenon.Enhancing clinical pregnancy outcomes in women with advanced maternal age (AMA) has emerged as a critical research priority in reproductive medicine. The current study seeks to unravel the mechanism governing mitochondrial energy metabolism reprogramming in granulosa cells (GCs) during age-associated ovarian aging.
Methods: We conducted an age-stratified prospective observational study involving GC samples from 10 young infertile women (young group: 21-34 years) and 10 infertile women with AMA (AMA group: 35-42 years), all undergoing in vitro fertilization-embryo transfer (IVF-ET). Participants were recruited from November 2023 to November 2024. Additionally, an in vitro oxidative stress-induced senescence model was established using hydrogen peroxide (H2O2)-treated human ovarian granulosa-like tumor cell line (KGN cells) to further investigate metabolic disturbances and mitochondrial reactive oxygen species (mtROS) levels in senescent GCs.
Results: High-resolution targeted metabolomics revealed 25 statistically significant metabolite alterations in ovarian GCs, indicating profound dysregulation of core energy metabolism pathways-particularly oxidative phosphorylation (OXPHOS), glycolysis, and the tricarboxylic acid (TCA) cycle. Compared to the young group, the AMA group exhibited upregulated glycolytic metabolites alongside downregulated OXPHOS and TCA cycle intermediates. These findings were further validated in an H2O2-induced KGN cells senescence model, where treated cells demonstrated: (1) increased senescence-associated β-galactosidase (SA-β-gal) activity, (2) elevated extracellular acidification rate (ECAR) and lactate (Lac) production, (3) reduced oxygen consumption rate (OCR), (4) depleted glucose and pyruvate(Pyr) pools, and (5) heightened mtROS generation relative to control group.
Conclusions: Collectively, our research demonstrates that GCs undergo mitochondrial energy metabolism reprogramming, characterized by a metabolic shift from OXPHOS to glycolysis, during ovarian aging. These observations suggest that age-associated glycometabolic perturbations may represent a novel therapeutic target for infertility in women with AMA.

Keywords:  KGN cells; female infertility; granulosa cells; mitochondrial energy metabolism reprogramming; ovarian aging

DOI:  https://doi.org/10.3389/fendo.2026.1726339
Diabetes. 2026 Feb 17. pii: db250605. [Epub ahead of print]

Interrupting T-Cell Memory Ameliorates Exaggerated Metabolic Response to Weight Cycling.

Jamie N Garcia, Matthew A Cottam, Alec S Rodriguez, Anwar F Hussein Agha, Heather L Caslin, Nathan C Winn, Alyssa H Hasty.

Weight cycling has been demonstrated, in humans and animal models, to increase cardiometabolic disease and disrupt glucose homeostasis. Both obesity itself and weight cycling cause adipose tissue inflammation and metabolic dysfunction. Studies show that even after weight loss, increased numbers of lipid-associated macrophages and memory T cells persist in adipose tissue and become more inflammatory on weight regain. This suggests that the immune system retains an obesogenic memory, which may contribute to the elevated inflammation and metabolic dysfunction associated with weight cycling. We show that blocking the CD70-CD27 axis, critical for the formation of immunologic memory, decreases the number of memory T cells and T-cell clonality within adipose tissue after weight loss and weight cycling. Furthermore, although CD70-/- mice have metabolic responses to stable obesity similar to those of wild-type mice, they are protected from the worsened glucose tolerance associated with weight cycling. Our data are the first to support mitigating the metabolic consequences of weight cycling through an immunomodulatory mechanism. We propose a new avenue of therapeutic intervention targeting memory T cells to minimize the adverse consequences of weight cycling. These findings are timely, given the increasing use of weight-loss drugs, which may lead to more instances of human weight cycling.
ARTICLE HIGHLIGHTS: We aimed to address a critical gap in understanding how persistent immune changes with weight cycling contribute to worsened metabolic health. We wanted to determine whether disrupting immune memory formation could prevent the accumulation and reactivation of memory T cells in adipose tissue and thereby protect against the metabolic dysfunction associated with weight cycling. In targeting the CD70-CD27 axis, thereby inhibiting T-cell memory formation, we were able to mitigate the exacerbated glucose intolerance observed in wild-type weight-cycled mice. This study highlights the potential to address the negative metabolic effects of weight cycling through an immunomodulatory approach, offering a novel therapeutic target by disrupting obesogenic immune memory.

DOI: https://doi.org/10.2337/db25-0605
Front Immunol. 2026 ;17 1763130

Roles of immune cell metabolism in rheumatoid arthritis.

Rui Xie, Zeping Chen, Shufang Deng, Xiaofeng Jiang, Yue Feng, Wei Zhao.

  Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation and progressive joint destruction. Recent advances reveal that immune cell metabolism plays a pivotal role in shaping RA pathogenesis. Aberrant glycolysis, lipid reprogramming, and amino acid catabolism drive functional alterations in T cells, B cells, macrophages, neutrophils, and fibroblast-like synoviocytes (FLSs), promoting inflammatory cytokine production, angiogenesis, and autoantibody generation. Key metabolites-such as lactate, succinate, and glutamine-not only serve as energy substrates but also act as immunomodulatory signals via the HIF-1α, PI3K/AKT/mTOR, and NF-κB pathways, exacerbating immune dysfunction and tissue damage. The plasticity of metabolic states contributes to Treg/Th17 imbalance, proinflammatory macrophage polarization, and FLS hyperactivation. Targeting these metabolic checkpoints has shown promise in restoring immune tolerance and alleviating disease severity. This review summarizes the complex interplay between immune cell metabolism and RA pathophysiology, highlights mechanistic insights into immunometabolic reprogramming, and discusses emerging metabolic interventions that may complement conventional RA therapies.

Keywords:  immune cell; inflammation; metabolism; reprogramming; rheumatoid arthritis; synovial inflammation

DOI:  https://doi.org/10.3389/fimmu.2026.1763130
J Exp Med. 2026 Apr 06. pii: e20252154. [Epub ahead of print]223(4):

A PI3Kδ-Foxo1-FasL signaling amplification loop rewires CD4+ T cell signaling and differentiation.

Dominic P Golec, Pedro H Gazzinelli-Guimaraes, Daniel Chauss, Kang Yu, Hiroyuki Nagashima, Anthony C Cruz, Tom Hill, Sundar Ganesan, Jennifer L Cannons, Jillian K Perry, Luis Nivelo, Ilin Joshi, Nicolas Pereira, Fabrício Marcus Silva Oliveira, Yufan Zheng, Makheni Jean Pierre, Kirk M Druey, Justin B Lack, Eric V Dang, Thomas B Nutman, Alejandro V Villarino, John J O'Shea, Behdad Afzali, Pamela L Schwartzberg.

While inputs regulating CD4+ T helper (Th) cell differentiation are well defined, the integration of downstream signaling with transcriptional and epigenetic programs that define Th lineage identity remains incompletely resolved. PI3K signaling is a critical regulator of T cell function; activating mutations affecting PI3Kδ result in an immunodeficiency with multiple T cell defects. Using mice expressing activated PI3Kδ, we found aberrant expression of proinflammatory Th1 signature genes under Th2-inducing conditions, both in vivo and in vitro. This dysregulation was driven by a PI3Kδ-IL-2-Foxo1 signaling amplification loop, fueling Foxo1 inactivation, loss of Th2 lineage restriction, and extensive epigenetic reprogramming. Surprisingly, ablation of Fasl, a Foxo1-repressed gene, normalized both Th2 differentiation and TCR signaling. BioID and imaging revealed Fas interactions with TCR signaling components, which were supported by Fas-mediated potentiation of TCR signaling that could occur in the absence of FADD. Our results highlight Fas-FasL signaling as a critical intermediate in phenotypes driven by activated PI3Kδ, thereby linking two key pathways of immune dysregulation.

DOI: https://doi.org/10.1084/jem.20252154
Mol Cancer Ther. 2026 Feb 17.

A novel attenuated CD122-biased IL-15 mutein promotes strong NK and T cell dependent anti-tumor immunity.

Mengmeng Sun, Shuang Wang, Yue Wu, Ruipu Xin, Shangting Zhang, Bo Huang, Yan Chen, Yu Liang, Tengfei Yu, Jianqing Xu, Jijie Gu, Lei Wu.

Interleukin-15 (IL-15) potentiates NK and T cell immunity and has huge potential for tumor immunotherapy. However, the clinical prospects of IL-15 has been hindered by poor pharmacokinetics and systemic immune-related toxicities. Here we report the development of a novel CD122-biased IL-15 mutein, V0013, generated by the truncating four C-terminal amino acids (I111, N112, T113 and S114) of IL-15. V0013 retains the overall cytokine structure and has intact binding to the critical CD122 receptor subunit, but exhibits significantly reduced overall potency. In vivo, V0013 demonstrates a prolonged half-life, improved safety and sustained pharmacodynamic effects. As a single agent, V0013 effectively promotes NK cell-driven anti-tumor immunity and enhances therapeutic efficacy of antibodies. Further mechanistic studies reveal that the interaction with specific receptor subunits dictates the function and potency of IL-15 mutein. CD122 is essential for IL-15-mediated signaling and prescribes its preference to NK and memory CD8+ T cells. Compared to an IL-15 mutein with similar attenuation but markedly weaker CD122 binding (weak-β IL-15), V0013 more closely resembles WT IL-15 functions, driving superior NK cell proliferation and survival. In a tumor model engrafted with T cells, V0013 selectively enhances memory but not naïve CD8+ T cells in tumor, leading to enhanced tumor inhibition compared to weak-β IL-15. RNAseq analysis further elucidates the critical role of CD122 in IL-15 signaling, and demonstrates that the mutein retaining intact CD122 binding elicits strong anti-tumor immunity. These findings support the therapeutic potential of the attenuated CD122-biased IL-15 mutein therapy for cancer and other diseases.

DOI: https://doi.org/10.1158/1535-7163.MCT-25-0625
Free Radic Biol Med. 2026 Feb 16. pii: S0891-5849(26)00121-8. [Epub ahead of print]248 29-42

Loss of PINK1 impairs mitophagy and accelerates ovarian aging independent of Parkin.

Xinxin Zeng, Huihui Xie, Wandi Zhang, Yongxing Yu, Mengchen Wang, Yuqing Jiang, Ruizhi Guo, Yingpu Sun, Qingling Yang.

  PINK1 and Parkin are central regulators of mitophagy, a quality-control process essential for mitochondrial homeostasis and implicated in aging. However, their specific roles in ovarian physiology remain unclear. Here, we show that Pink1 deletion in mice leads to decreased ovarian weight, diminished ovarian reserve, and reduced oocyte quality, accompanied by increased granulosa cell apoptosis, accelerated ovarian ageing, and impaired fertility. Pink1 deficiency also compromises ovulation efficiency, increases oocyte cytoplasmic fragmentation, and disrupts meiotic spindle assembly, resulting in markedly reduced developmental competence of early embryos. Mechanistically, bulk and single-cell RNA sequencing reveal that loss of PINK1 impairs mitophagy and promotes transcriptional signatures of ovarian aging. In contrast, Parkin deletion exerts minimal effects on mitophagy, mitochondrial function, or ovarian physiology. Together, these findings identify PINK1, but not Parkin, as a critical regulator of ovarian aging through modulation of mitophagy.

Keywords:  Mitophagy; Oocytes; Ovarian aging; PINK1; Parkin

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.02.024
Nat Commun. 2026 Feb 20.

Epigenetic profiling of hematopoietic stem cells from male mice identifies KDR and PU.1 as regulators of aging transcriptome and caloric restriction response.

Le Zong, Bongsoo Park, Ferda Tekin-Turhan, Wakako Kuribayashi, Mayuri Tanaka-Yano, Keefer Li, Isabel Beerman.

Caloric restriction (CR) provides anti-aging benefits but has also been reported to be associated with reduced immune function, and how hematopoietic stem cells (HSCs) potentially contribute to this decline remains unclear. Using lifelong and short-term CR in male mice, we found reducing the energy supply decreases total white blood cell production and shifts hematopoiesis towards myeloid and thrombo-erythroid lineages, prioritizing cells essential for survival (red blood cells, platelets, innate immune cells) over adaptive immunity. HSCs under CR enter cell cycle to support myeloid differentiation rather than self-renewal. Lifelong CR inhibits age-associated transcriptome changes in HSCs, though age-associated profiles appear shortly after ad libitum feeding. Epigenetic profiling identified KDR as a key CR response regulator, and Kdr knockdown in aged HSCs recapitulated the youthful transcriptome of lifelong CR HSCs. Finally, we show PU.1 acts as an intracellular regulator of CR response, controlling HSC self-renewal and differentiation through increased target gene binding under CR conditions.

DOI: https://doi.org/10.1038/s41467-026-69718-0
Br J Pharmacol. 2026 Feb 19.

Induction of IL-9-producing CD8+ T cells by ascochlorin derivatives.

Natsumi Imano, Mikako Nishida, Miho Tokumasu, Weiyang Zhao, Nahoko Yamashita, Heiichiro Udono.

   BACKGROUND AND PURPOSE: Ascochlorin (ASC) is an antiviral antibiotic from the fermented broth of Ascochyta viciae which exerts an inhibitory effect to cancers. Its impact on immune cells has not been examined. In this study, we obtained ASC derivatives with less cytotoxicity and determined whether they affected T cells, indicating possible immune-mediated antitumour effects.
EXPERIMENTAL APPROACH: Newly synthesised ASC derivatives were screened for inhibitory effects on T-cell antigen receptor (TCR)-stimulated proliferative responses using murine CD4+ and CD8+ T cells. Two compounds were identified that exhibited >10-fold less toxicity compared with ASC. N184, the less toxic of the two, was analysed for its in vivo antitumour effects, and in vitro effects on CD8+ T-cell proliferation, survival, cytokine production and exhaustion, using microscopy, qPCR and flow cytometry.
KEY RESULTS: N184 induced limited IL-9 production in CD8+ T cells following TCR stimulation, thereby improving cell survival. It also enhanced cytokine production in the late phase of proliferation and suppressed the induction of exhaustion. N184 suppressed tumour growth in mice in a CD8+ T cell-dependent manner. The effect was partially prevented by an IL-9-neutralising antibody.
CONCLUSION AND IMPLICATIONS: N184 induces differentiation of IL-9-producing CD8+ T cells in vitro and elicits antitumour immunity in an IL-9-dependent manner.

Keywords:  CD8 positive T lymphocytes; IFN‐γ; Tc9; ascochlorin derivative; cell survival; interleukin‐9; tumour immunity

DOI:  https://doi.org/10.1111/bph.70316
J Transl Med. 2026 Feb 14.

TIPE2 knockdown enhances the anti-tumor efficacy of NKG2D CAR-T cells against pancreatic cancer via activating NF-κb signaling pathway.

Muhammad Asad Farooq, Bingtan Du, Ying Zhou, Iqra Ajmal, Wenzheng Jiang.

   BACKGROUND: Tumor necrosis factor-α-induced protein 8-like 2 (TIPE2) is an intracellular immune checkpoint protein known to suppress T cell activation and effector function. Despite its role in limiting T cell responses, CAR-T cells are prone to TIPE2-mediated inhibitory signaling. We therefore hypothesized that inhibiting this immune checkpoint would enhance CAR-T cell anti-tumor function.
METHODS: To overcome TIPE2-mediated negative regulation, we engineered a novel second-generation NKG2D-based CAR-T cell by incorporating TIPE2-targeting shRNA sequences directly into the CAR construct. TIPE2 knockdown efficiency in the CAR constructs was measured by qPCR and western blot analysis. The functional and mechanistic properties of TIPE2-downregulated CAR-T cells were evaluated in vitro by flow cytometry, including analysis of activation, cytotoxicity, exhaustion, apoptosis, proliferation, and differentiation. Antitumor efficacy was further validated in vivo using a preclinical pancreatic cancer mouse model.
RESULTS: Flow cytometry analysis revealed that TIPE2-deficient CAR-T cells exhibited significantly higher expression of activation (CD69), degranulation (CD107a), cytotoxic (GzmB), and cytokine (IFN-γ) markers, resulting in more efficient tumor cell elimination compared to conventional CAR-T cells. TIPE2 silencing also reduced T cell exhaustion, lowered susceptibility to apoptosis, and enhanced proliferation when co-cultured with Panc-28 pancreatic cancer cells. Moreover, TIPE2 inhibition skewed CAR-T cells differentiation towards an effector phenotype (TEFF), characterized by higher T-bet expression and reduced Eomes production. Mechanistically, these functional enhancements were mediated by increased NF-κB signaling, as confirmed by elevated p-p65 expression and functional reversal upon NF-κB inhibition. Consistently, TIPE2-deficient CAR-T cells exhibited significantly improved anti-tumor efficacy in vivo compared to wild-type CAR-T cells.
CONCLUSION: We successfully developed TIPE2-downregulated NKG2D-CAR-T cells that exhibited enhanced activation and cytotoxicity while limiting apoptosis and exhaustion against NKG2D ligand-expressing pancreatic tumors, highlighting TIPE2 as a promising intracellular immune checkpoint target for optimizing CAR-T cell therapy in solid tumors.

Keywords:  CAR-T cell therapy; NF-κB signaling; NKG2D; Pancreatic cancer; TIPE2

DOI:  https://doi.org/10.1186/s12967-026-07831-w
Cancer Res Commun. 2026 Feb 19.

Collagen-bearing exosomes from breast cancer-associated fibroblasts promote T cell dysfunction.

Samir Jana, Matthew Lawton, Pin-Ji Lei, Harold Hui, Andrew Emili, Dennis Jones.

Cancer-associated fibroblasts (CAFs), a major component of the breast tumor microenvironment, drive immune evasion in various cancers by promoting T cell exclusion and dampening T cell activation. Previous studies have implicated CAF-derived soluble factors in mediating these immunosuppressive effects. Here, we investigated whether exosomes secreted by CAFs could suppress T cell activity. Inhibition of global exosome secretion in breast tumor-bearing mice significantly reduced tumor growth and increased tumor-infiltrating T cells with lower exhaustion marker expression. Conversely, administration of CAF-derived exosomes into tumors produced the opposite effects. Moreover, CAF exosomes associated with T cells in vivo and impaired T cell activation and cytotoxic potential in ex vivo assays. Proteomic and biochemical analyses of T cells exposed to CAF exosomes revealed dampened early T cell receptor signaling. Mass spectrometry identified an extracellular matrix signature on CAF exosomes. Depleting Type I and Type V collagens from CAF exosomes restored T cell proliferation, while overexpression of collagen in cancer cells led to its incorporation into exosomes, which suppressed T cell activation. These findings suggest that a signaling bridge between CAF exosomes and T cells, mediated by collagen, promotes T cell dysfunction, contributing to immune evasion in breast cancer.

DOI: https://doi.org/10.1158/2767-9764.CRC-25-0259
Nat Commun. 2026 Feb 17.

TGFβ-activated PDHB promotes mitochondrial pyruvate metabolism and contributes to human endoderm differentiation via ATP-dependent BRG1.

Liming Meng, Jing Lv, Ying Yi, Xianchun Lan, Chenchao Yan, Lihang Zhu, Jie Yang, Wei Jiang.

Cell fate determination is closely linked to metabolic state, yet how metabolic remodeling influences human pluripotent stem cells differentiation into three germ layers remains incompletely understood. Here, we reveal that definitive endoderm differentiation from human pluripotent stem cells requires a TGFβ-driven metabolic switch characterized by reduced lactate production and enhanced TCA cycle activity and oxidative phosphorylation, mediated by PDHB. Disruption of glucose utilization or pyruvate entry into the TCA cycle markedly impairs endoderm differentiation, whereas inhibition of lactate production enhances differentiation efficiency. Mechanistically, blockade of glucose metabolism or the TCA cycle reduces intracellular ATP levels, compromising the activity of BAF complex, an ATP-dependent chromatin remodeling complex centered on BRG1. This complex promotes chromatin accessibility and activates endodermal gene programs during differentiation. Together, these findings highlight metabolic reprogramming as a key regulator of human endoderm fate through ATP-dependent control of chromatin remodeling.

DOI: https://doi.org/10.1038/s41467-026-69510-0
JHEP Rep. 2026 Mar;8(3): 101705

Transcriptional and functional HBV-specific CD8 T cell changes from disease to functional cure in HBeAg-negative chronic hepatitis B.

Marzia Rossi, Andrea Vecchi, Camilla Tiezzi, Francesca Guerrieri, Marie Laure Plissonnier, Elisabetta Degasperi, Dana Sambarino, Diletta Laccabue, Arianna Alfieri, Elena Adelina Gabor, Amalia Penna, Valentina Reverberi, Anna Montali, Alessio Pelagatti, Sara Doselli, Benedetta Farina, Giuseppe Pedrazzi, Paola Fisicaro, Gabriele Missale, Pietro Lampertico, Carlo Ferrari, Massimo Levrero, Carolina Boni.

   Background & Aims: In chronic HBV infection, HBV-specific CD8 T cells are dysfunctional and comprise distinct subsets defined by phenotype and antigen specificity. We aimed to characterize the transcriptional and functional features of HBV-specific CD8 T-cell subsets in patients with HBeAg-negative chronic HBV infection who were either viremic (CHB) or had achieved spontaneous or nucleos(t)ide analogue (NUC)-induced HBsAg loss (RES), to better elucidate HBV-specific CD8 T-cell dysfunction and identify potential molecular targets for functional cure.
Methods: Gene expression profiles of PD1hiCD127low/- and PD1+CD127+ memory-like (ML) core18-27-specific CD8 T-cell subsets were analyzed by Nanostring, adapted for low-input samples in 5 patients with HBeAg-negative CHB and 6 with RES. An expanded cohort of 23 patients with CHB and 22 with RES was evaluated for phenotypic and functional profiling. Selected deregulated genes were functionally validated in an additional cohort of 14 patients with HLA-A2-negative CHB.
Results: Analysis of 84 genes concurrently expressed across all CD8 T-cell subsets identified an 11-gene signature describing a progressive transition from exhaustion-oriented PD1hiCD127low/- CD8 T cells in patients with CHB to memory-oriented ML CD8 cells in patients with RES, representing the two extremes of differentiation. Intermediate stages of memory differentiation were identified among ML CD8 T cells from patients with CHB, with high or low TOX expression (p <0.05 by Spearman's rank correlation). Higher frequencies of TOXlow ML CD8 cells in patients with CHB were associated with a greater serum HBsAg decline during NUC treatment compared to TOXhigh MLCHB (Δ slope p value = 0.003). Targeting selected deregulated genes with specific immune modulators significantly enhanced cytokine production by CD8 T cells, with response rates ranging from 30% to 86% of patients.
Conclusions: Distinct exhaustion signatures characterize HBV-specific CD8 T-cell subsets and vary across disease phases. These findings support the development of individualized transcriptional and functional correction strategies and identify novel immune modulators with potential for immune-based anti-HBV therapies.
Impact and implications: Exhausted HBV-specific CD8 T cells in chronic HBV infection are not a homogeneous population but comprise distinct subsets with differing capacities to control infection. This study identifies: (i) a transcriptional continuum of HBV-specific CD8 T-cell subsets spanning exhaustion to memory differentiation, reflecting disease progression and recovery in HBeAg-negative CHB; (ii) a core CD8 T-cell exhaustion gene signature characterized by progressively increased expression from memory-oriented to exhaustion-oriented subsets during active and resolution phases of disease; and (iii) the ability of targeted modulation of deregulated genes to restore antiviral CD8 T-cell function, with implications for the development of novel immune-based anti-HBV therapies. Overall, these findings advance our understanding of CD8 T-cell heterogeneity in chronic HBV infection and identify molecular targets for immunomodulatory strategies aimed at restoring CD8 T-cell functionality and achieving functional cure.

Keywords:  CD8 T-cell exhaustion; Chronic HBV infection; T-cell functional reconstitution; T-cell heterogeneity

DOI:  https://doi.org/10.1016/j.jhepr.2025.101705
Cancer Res. 2026 Feb 18.

CCL5hi-CD4+ T cells Regulate Macrophage Polarization and Promote Immunotherapy Response in Bladder Cancer.

Weiming Luo, Yapeng Wang, Haitao Wang, Ying-Ang Ji, Jian Zhang, Qiang Ran, Yangkun Ao, Jing Xu, Junying Zhang, Xiaoyan Cheng, Luofu Wang, Yao Zhang, Jun Zhang, Can Ai, Jun Qin, Jun Jiang, Weihua Lan, Qiuli Liu.

Immune checkpoint inhibitors (ICIs) have transformed cancer therapy, yet their efficacy remains limited to a subset of patients, underscoring the need for robust predictive biomarkers and deeper mechanistic insights into treatment resistance. In this study, we identified a population of CCL5hi-CD4+ T cells that were characterized by memory-like activation markers and strongly correlate with ICI therapeutic responses in bladder cancer. Functionally, these T cells enhanced antitumor immunity by promoting M1-like macrophage polarization through CCL5/CCR1 signaling. Importantly, tumor-derived prostaglandin E2 (PGE2) acted as a critical microenvironmental factor that suppressed the differentiation of CCR6hi-CD4+ T cells into immunostimulatory CCL5hi-CD4+ T cells, thereby driving resistance to ICI therapy. These findings extend the understanding of CD4+ T cell heterogeneity and its role in shaping immune responses to ICI. By elucidating that CCL5hi-CD4+ T cells enhance myeloid-mediated tumor control and that tumor-derived PGE2 disrupts CCL5hi-CD4+ T cell differentiation to promote immune evasion, this work highlights potential therapeutic strategies to improve ICI efficacy in bladder cancer.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-2220
Nat Chem Biol. 2026 Feb 19.

Drug-controlled CAR T cells through the regulation of cell-cell interactions.

Leo Scheller, Greta Maria Paola Giordano Attianese, Rocío Castellanos-Rueda, Raphaël B Di Roberto, Markus Barden, Melanie Triboulet, Morteza Hafezi, Sarah Ash, Sailan Shui, Elisabetta Cribioli, Patrick Reichenbach, Jimmy Maillard, Anthony Marchand, Sandrine Georgeon, Benita Wolf, Hinrich Abken, Sai Reddy, Bruno E Correia, Melita Irving.

Chimeric antigen receptor (CAR) T cell therapy is constrained by on-target, off-tumor toxicities and cellular exhaustion because of chronic antigen exposure. CARs incorporating small-molecule controlled on- and off-switches can enhance both safety and therapeutic efficacy but their design is limited by the scarcity of nonimmunogenic protein elements responsive to nonimmunosuppressive, clinically approved drugs with favorable pharmacodynamics. Here we combine rational design and library-based optimization of a protein-protein interaction (PPI) of human origin to develop venetoclax-controlled drug-regulated off-switch PPI (DROP)-CARs. DROP-CARs enable dose-dependent release of the tumor-targeting scFv and consequent reduction in T cell binding to the tumor cell. Additionally, we present proof of concept for a dual DROP-CAR controlled by different small molecules, as well as for logic-gated synthetic receptors enabling STAT3 signaling. We demonstrate in vitro and in vivo function of DROP-CAR T cells and conclude that the approach holds promise for clinical application.

DOI: https://doi.org/10.1038/s41589-026-02152-x
Sci Rep. 2026 Feb 15.

Gene expression changes in lymphocytes and monocytes from patients with traumatic brain injury.

Hiroshi Ito, Masakazu Ishikawa, Hisatake Matsumoto, Hiroshi Ogura, Daisuke Okuzaki, Jun Oda.

  Traumatic brain injury (TBI) can alter various immune functions, including immunosuppression, and constitutes a risk factor for nosocomial infections and organ dysfunction. Although TBI can induce a decline in immune cell function, the detailed mechanisms remains to be elucidated. We aim to explore transcriptional signatures associated with post-TBI immune alterations in a pilot cohort using a comprehensive transcriptome analysis of immune cells. Three patients with traumatic brain injury and acute subdural hematoma were admitted to our hospital. We focused on three major subsets of immune cells responsible for the immune response: CD4 + T cells, CD8 + T cells, and monocytes. We evaluated the changes in immune function after injury using comprehensive transcriptome analysis. Blood samples were collected immediately after admission and one week later, and the data were compared with those of healthy volunteers. CD4 + , CD8 + T cells, and monocytes, the expression of pathways involved in cellular metabolism-including oxidative phosphorylation, mTORC1 signaling, MYC targets V1 and V2, and the unfolded protein response-was downregulated on day 7 compared with day 1. These findings suggest a transition from marked immune activation and metabolic upregulation on day 1 to an attenuated immune response by day 7. In CD4 + T cells, pathways associated with tissue remodeling and repair, such as hedgehog signaling and epithelial-mesenchymal transition, were upregulated from days 1 to 7, indicating a shift from inflammatory responses toward inflammation resolution and tissue repair. In this pilot study, comprehensive transcriptome profiling suggests time-dependent transcriptional shifts in CD4⁺ T cells, CD8⁺ T cells, and monocytes after TBI. These findings should be interpreted as hypothesis-generating and provide a framework for larger, confirmatory studies.

Keywords:  Immunity; Lymphocyte; Traumatic brain injury

DOI:  https://doi.org/10.1038/s41598-026-39991-6
Front Oncol. 2026 ;16 1659869

Advancing CAR-T therapy in prostate cancer: overcoming the tumor microenvironment and enhancing efficacy.

Zhongze Zhou, Yongfeng Lao, Kun Zhao, Long Cheng, Xi Xiao, Wenxuan Li, Shuai Liu, Xiangbin Kong, Zhilong Dong.

   Background: Prostate cancer (PCa) is one of the most common malignancies in men, and metastatic castration-resistant PCa (mCRPC) has limited treatment options. While chimeric antigen receptor T (CAR-T) therapy has revolutionized treatment of hematologic cancers, its efficacy in PCa is constrained by factors such as scarce tumor-specific antigens, an immunosuppressive tumor microenvironment (TME), antigen heterogeneity, and safety issues (e.g., cytokine release syndrome).
Methods: We performed a comprehensive literature review of CAR-T therapy in PCa. We summarized known PCa-specific CAR targets, identified major TME-related and technical barriers, and highlighted recent advances in CAR engineering (including armored CAR-T cells, gene editing, and metabolic reprogramming) as well as combination approaches with other therapies.
Results: Emerging strategies show promise for overcoming these obstacles. Next-generation CAR designs, such as cytokine-armed CAR-T cells, may enhance T cell infiltration and persistence despite the suppressive TME. Modulating tumor metabolism and immune checkpoints can reverse T cell exhaustion. Multi-antigen CARs and targeted gene edits (for example, PD-1 disruption) may limit antigen escape. Early clinical trials in PCa have demonstrated CAR-T cells specifically recognizing prostate-associated antigens and eliciting antitumor immune responses, although durable remissions remain rare.
Conclusion: CAR-T therapy for prostate cancer is a rapidly advancing field. This review provides an updated perspective on CAR-T targets, engineering strategies, and combination approaches in PCa. Ongoing innovations in CAR design and therapeutic combinations offer the potential to develop more effective and durable CAR-T treatments for advanced prostate cancer.

Keywords:  CAR design; chimeric antigen receptor T-cell; immunotherapy; prostate cancer; tumor microenvironment

DOI:  https://doi.org/10.3389/fonc.2026.1659869