bims-imseme 2026-11-08 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2026–11–08
eighteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

T cell exhaustion in cancer.
In vitro NAD+ supplementation increases CD4+ and CD8+ T cell function in people with HIV.
miRNA delivery via nanowires restores functional responses in aged T cells.
Impact of habitual physical activity and age on T cell metabolism and activation via β2-adrenergic receptor modulation.
Senescent CD8 T effector memory cells are functionally impaired, enriched in aging and disease, and a barrier to immunotherapy.
Targeting alpha-ketoglutarate starvation within the tumor-immune microenvironment rescues T cell effector function in cancer immunotherapy.
Loss of T cell-intrinsic Keap1 alleviates colitis by suppressing Th17 differentiation and enhancing regulatory T cell functions.
T cell exhaustion in cancer: from functional decline to adaptive immune regulation.
Perivascular macrophages restrict CXCR4-dependent accumulation of stem-like CD8+ T cells in tumors and limit chemotherapy efficacy.
Spatiotemporal co-regulation of IL2 and TCR receptors reveals early antigen-driven synaptic synergy in human CD8+ T cells.
Neutrophils, NETs, and efferocytosis in aging: A resolution-failure axis driving inflammaging.
Taurine bolsters adoptive T cell therapy efficacy against hepatocellular carcinoma by reprogramming T cell function.
ITGAM+ Extracellular Vesicles Trigger CD8+ T Cell Activation via S100a9-Mediated Metabolic Reprogramming in Acute Kidney Injury.
Therapy-induced methionine competition in bladder cancer: MAT2A-SAM axis remodeling as a metabolic immune checkpoint.
NR2F6 functions as a key transcriptional checkpoint enforcing dysfunction of human CD3+ T cells and limiting CAR-T cell potency.
Decidua-accumulated effector-like memory CD8+ T cells orchestrate localized antimicrobial defense without compromising fetal tolerance.
Squeezing Treatment-Induced Metabolic Alterations in Melanoma Cells Are Accompanied by Impaired Cluster of Differentiation 8-Positive T Cell and Natural Killer Cell Antitumor Effector Functions.
Senescent T cells within the tumor microenvironment are a potent driver for tumor growth, stemness, and chemotherapy resistance.

Int J Hematol. 2026 Nov 02.

T cell exhaustion in cancer.

Yin Min Thu, Yosuke Togashi.

  T cell exhaustion is an antigen-driven differentiation program originally defined in chronic infection and now recognized as a major determinant of antitumor immunity. It is best characterized in CD8+ T cells, in which chronic stimulation induces functional impairment, inhibitory-receptor expression, transcriptional and epigenetic reprogramming, and metabolic dysfunction. Exhausted T cells are heterogeneous, ranging from progenitor populations that retain proliferative capacity and responsiveness to programmed cell death protein 1 (PD-1) blockade to terminally exhausted states with limited reversibility. In solid tumors, immune checkpoint blockade acts largely through tumor-reactive exhausted CD8+ T cells. In classic Hodgkin lymphoma, frequent loss of major histocompatibility complex (MHC) class I and retention of MHC class II suggest a greater contribution of cytotoxic CD4+ T cells, and PD-1 blockade may reinvigorate dysfunctional or exhaustion-like CD4+ T cells. Exhaustion also affects chimeric antigen receptor (CAR) T cell and bispecific T cell engager therapies, where repetitive stimulation impairs T cell persistence and function, and allogeneic hematopoietic cell transplantation, where donor T cell exhaustion may influence graft-versus-host disease and graft-versus-leukemia activity. This review summarizes the mechanisms and clinical significance of T cell exhaustion across solid and hematologic malignancies and how exhaustion state shapes therapeutic response.

Keywords:   T cell exhaustion; Bispecific T cell engagers; CAR T cell; Hematopoietic cell transplantation; Immune checkpoint blockade

DOI:  https://doi.org/10.1007/s12185-026-04304-0
HIV Med. 2026 Nov 02.

In vitro NAD+ supplementation increases CD4+ and CD8+ T cell function in people with HIV.

Guangming Li, Salma Sharaf, Yaoxian Lou, Lishan Su, Shyam Kottilil, Poonam Mathur.

   OBJECTIVES: HIV perturbs T cell homeostasis and disrupts immune function, increasing the risk of age-associated comorbidities. Ageing people with HIV (PWH) have exacerbated expression of CD38 on T cells, which depletes intracellular nicotinamide adenine dinucleotide (NAD+). We investigated whether boosting intracellular NAD+ could restore T cell homeostasis and function.
METHODS: We collected blood samples from virally suppressed PWH to determine the effects of in vitro NAD+ on CD38 expression and T cell function in response to anti-CD3/CD28 antibodies stimulation in PBMCs culture supplemented with IL-2 and IL-7.
RESULTS: We observed that NAD+ supplementation not only reduced expression of CD38 but also improved T cell function with an alleviated exhaustion phenotype in response to anti-CD3/CD28 antibodies stimulation.
CONCLUSIONS: If confirmed in clinical trials, NAD+ supplementation has the potential to restore T cell homeostasis and immune function in PWH and ameliorate age-associated comorbidities.

Keywords:  CD38; HIV; NAD +; T cell homeostasis and function

DOI:  https://doi.org/10.1111/hiv.70342
Cell Biomater. 2026 Jul 03. 100514

miRNA delivery via nanowires restores functional responses in aged T cells.

Zhonghao Dai, Shaylyn Grier, Zhe Zhong, Ameya Dravid, Joscelyn Mejías, Jean L Koff, Andrés J García, Ankur Singh.

Aging reshapes CD8+ T cell immunity by depleting naive populations, narrowing repertoire diversity, and promoting dysfunctional states, thereby weakening responses to infection or vaccination. This study presents a polyethyleneimine (PEI)-functionalized silicon nanowire platform for high-viability, non-viral delivery of single or multiplexed microRNAs (miRNAs) into resting aged CD8+ T cells. Nanowires enable transient modulation of transcriptional programs governing T cell activation, metabolism, proliferation, and differentiation. Delivering a single miRNA influences early activation and differentiation stages, while multiplexed miRNA delivery leads to a broader boost in activation responses, effector functions, metabolic health, and cell proliferation. In vivo, ex vivo-treated aged CD8+ T cells exhibit enhanced early effector priming following antigen exposure. Similarly, in aged human CD8+ T cells, multiplexed miRNA enhances activation and cytotoxic responses and sustains an effector-primed state during early activation and expansion. This method consistently improves function across donors aged from healthy individuals to those with current or past cancer.

DOI: https://doi.org/10.1016/j.celbio.2026.100514
Front Aging. 2026 ;7 1869552

Impact of habitual physical activity and age on T cell metabolism and activation via β2-adrenergic receptor modulation.

Amanda V Sardeli, Ana Ramkrapes, Jakob Boyes-Jensen, Jon Hazeldine, Helena Batatinha, Niharika A Duggal, Davide Calebiro, James E Turner.

   Background: Ageing impairs T cell function and responses to vaccines and infections. Effective T cell function requires rapid metabolic switching towards glycolysis, which becomes dysregulated with age. We have shown that physically active older adults have T cells that are more functional and metabolically fit. As exercise acutely elevates adrenaline and mobilises T cells via β2-adrenergic receptors (β2-AR), we hypothesise that habitual physical activity (PA) preserves β2-AR-mediated metabolic stimulation in T cells from older adults.
Methods: Older adults (≥65 years) with habitually high PA (HPA, n = 6) or habitually moderate PA (MPA, n = 6) were compared with young controls (18-35 years, n = 6). T cells were exposed to the β-agonist isoproterenol for 30 min to mimic acute exercise-like adrenergic stimulation, with or without the β2-AR blocker ICI-118,551. Following 1 h of rest, T cells were stimulated for 4 h in vitro with PMA and ionomycin. T cell activation (CD69), glucose transporter-1 (Glut1), intracellular cAMP concentrations under isoproterenol stimulation, and β2-AR mRNA expression were assessed.
Results: Older adults exhibited impaired CD8+ T cell activation and β2-AR blockade inhibited activation in all groups. Glut1 expression in CD8+ T cells was higher in older MPA than young, but did not differ from older HPA. In CD8+ T cells that were not stimulated with PMA and ionomycin, β2-AR blockade (with β-AR stimulation) increased Glut1 expression in all groups compared with β-AR stimulation alone, and this increase was greater in older HPA than MPA (p = 0.043). No group differences were observed in β2-AR mRNA expression or isoproterenol-induced β-AR cAMP responsiveness.
Conclusion: These exploratory findings indicate that individuals with higher levels of habitual PA have lower age-associated impairments in CD8+ T cell activation and metabolic switching in response to β stimulation. Interestingly, β2-AR blockade did not fully abrogate β stimulation, therefore future studies should investigate a potential influence of β1-AR in this modulation, to generate definitive conclusions.

Keywords:  T cell; adrenergic; aging; exercise; immunosenescence; lymphocyte; metabolism; physical activity

DOI:  https://doi.org/10.3389/fragi.2026.1869552
Proc Natl Acad Sci U S A. 2026 Nov 10. 123(45): e2617906123

Senescent CD8 T effector memory cells are functionally impaired, enriched in aging and disease, and a barrier to immunotherapy.

Paolo S Turano, Elizabeth Akbulut, Nica M Aquino, Luis Garza-Martínez, Sukhwinder Singh, Abraham Aviv, Simon Toupance, George S Yap, Patricia Fitzgerald-Bocarsly, Ricardo I Martínez-Zamudio, Utz Herbig.

  Senescent cells play important roles in various biological processes that promote fitness and health; however, their timely elimination by immune cells is critical to maintain tissue homeostasis and prevent disease. Despite this, senescent cells accumulate systemically with age, suggesting that certain immune cells also become senescent and dysfunctional during aging. In support of this, we previously demonstrated that CD8 T cells, immune cells capable of targeting senescent cells, increasingly develop characteristics of senescence with advancing age in humans. Here, we characterized the senescence state of human SA-βGal-expressing (SA-βGalhigh) CD8 T effector memory (EM) cells, their functional capabilities, and their enrichment in aging and disease. Single-cell RNA sequencing revealed that SA-βGalhigh CD8 T cells with unique transcriptional signatures develop in all stages of T cell differentiation, including in CD8 TEM cells, which increased in abundance with human aging. SA-βGalhigh CD8 TEM cells expressed various classical markers of senescence and were significantly impaired in their ability to proliferate, produce cytokines, and eliminate senescent human stromal cells. Gene signatures of senescent SA-βGalhigh CD8 TEM cells were enriched in CD8 T cells from older human donors, patients with age-related disorders, cancer, and in smokers. Furthermore, we show that T cell senescence is distinct from and dominant over T cell exhaustion, limiting the response of CD8 TEM cells to immune checkpoint blockade. Collectively, our study demonstrates that senescence impairs CD8 TEM cell function and reveals the involvement of senescent and dysfunctional CD8 TEM cells in aging, disease, smoking, and responses to immunotherapy.

Keywords:  T cells; aging; cancer; cellular senescence; immunosenescence

DOI:  https://doi.org/10.1073/pnas.2617906123
bioRxiv. 2026 Oct 27. pii: 2026.10.24.761570. [Epub ahead of print]

Targeting alpha-ketoglutarate starvation within the tumor-immune microenvironment rescues T cell effector function in cancer immunotherapy.

Katarina Benejova, Kristina Travis, Deepti Mathur, No Joon Song, Zihai Li, Mitch A Phelps, Elaine Mardis, Liza Makowski, David P Carbone, Dwight H Owen, Martin Benej.

Given its status as the leading cause of global cancer mortality, there is a critical need to enhance immunotherapy strategies for lung cancer to overcome widespread resistance to current treatments. Immunotherapy recruits the patient's immune system to attack and destroy cancer cells. While highly effective in a subset of patients, chronic exposure of immune cells to cancer cells leads to a progressive loss of effector T cell function and progression of T cell exhaustion; now considered two well-established hallmarks of immunotherapy resistance. The tumor-immune microenvironment (TIME)-driven differentiation into the exhausted T cell phenotype is marked by a loss of metabolic plasticity and epigenome-wide changes in distribution of repressive histone marks such as histone H3 subunit methylation at lysine 27 (H3K27me 3 ). Here, we studied how these processes are connected to metabolite availability within the TIME. In vitro , chronic antigen stimulation and hypoxia led to rapid loss of effector function, associated with a suppression of alpha-ketoglutarate (aKG) intracellular concentrations in T cells. Supplementation of cell-permeable aKG led to a rescue of effector cytokine production and to improved cytotoxic capacity despite chronic antigen stimulation and hypoxia. Increased intracellular aKG levels restored the activity of H3K27 demethylases UTX and JMJD3, consistent with epigenome-wide decreased H3K27me 3 . In vivo , dietary supplementation with commercially available calcium-aKG (Ca-aKG) supplements led to an elevation of serum and intratumoral aKG levels associated with a significant increase of immunotherapy effectiveness in mouse models of NSCLC. Clinical samples from patients with NSCLC contained significantly decreased serum aKG levels in older NSCLC patients (>65 years of age). Analysis identified a novel association between serum aKG levels and poor immunotherapy response. Thus, our work demonstrates that intratumoral metabolite "starvation" can be therapeutically exploited to improve immunotherapy outcomes in non-small cell lung cancer (NSCLC).

DOI: https://doi.org/10.64898/2026.10.24.761570
Redox Biol. 2026 Oct 27. pii: S2213-2317(26)00460-X. [Epub ahead of print]98 104461

Loss of T cell-intrinsic Keap1 alleviates colitis by suppressing Th17 differentiation and enhancing regulatory T cell functions.

Debolina Dasgupta, Aprajita Tripathi, Rachel Griffard-Smith, Michael S Dahabieh, Md Saiful Islam Saif, Badal C Roy, Emily Burt, Abigail Ellis, Ryan D Sheldon, Poojaben Dhorajiya, Shahid Umar, Devin Koestler, Russell G Jones, Kalyani Pyaram.

  Ulcerative colitis (UC) is a form of inflammatory bowel disease (IBD) characterized by chronic inflammation in the colon. In this study, we elucidate the roles of antioxidation proteins Kelch-like ECH-associated protein 1 (Keap1) and nuclear factor erythroid 2-related factor 2 (Nrf2) in modulating CD4+ T cell differentiation and intestinal inflammation in UC. Using mice with T cell-specific deletion of Keap1 or Nrf2, we demonstrate that T cell-intrinsic Nrf2 levels influence T helper (Th) cell differentiation, intestinal inflammation and colitis disease outcome. Loss of Keap1 in T cells suppressed proinflammatory Th1 and Th17 subset differentiation, while promoting induced regulatory T-cell (iTreg) generation in an Nrf2-dependent manner, thereby alleviating intestinal inflammation and protecting against colitis. Mechanistic analyses revealed that Keap1 deletion was associated with metabolic reprogramming in iTregs, characterized by increased glutamine utilization and enhanced mitochondrial respiration, suggesting that these metabolic changes may contribute to enhanced iTreg generation. Further, analyses of UC patient tissues and omics datasets revealed increased Nrf2 gene expression and enrichment of Nrf2-associated transcriptional signatures in colonic Tregs, correlating with Foxp3 expression. In summary, our findings identify Keap1-Nrf2 axis as an important regulator of iTreg generation and function, suggesting that targeting this pathway may represent a potential therapeutic strategy for IBD.

Keywords:  Antioxidation; CD4(+)T cells; Inflammatory bowel disease (IBD); Metabolism; Nrf2; Tregs

DOI:  https://doi.org/10.1016/j.redox.2026.104461
Mol Cancer. 2026 08 06. pii: 264. [Epub ahead of print]25(1):

T cell exhaustion in cancer: from functional decline to adaptive immune regulation.

Yanyang Wang, Yang Yu, Jing Zhuang, Ruijuan Liu, Changgang Sun.

  T cell exhaustion has traditionally been defined as a state of progressive functional impairment and specific epigenetic remodeling induced by chronic antigen stimulation. However, emerging multidisciplinary evidence indicates that exhaustion is not merely a terminal stage of functional failure; rather, it represents an evolutionarily conserved adaptive program designed to balance long-term immune surveillance with the limitation of excessive pathological damage. This review focuses on the positive regulatory roles of T cell exhaustion within the tumor microenvironment. It elucidates how the exhausted state avoids lethal inflammation by restraining excessive activation while preserving a durable progenitor pool, thereby ultimately establishing a homeostatic balance between sustained tumor control and host survival. Overall, a comprehensive understanding of the evolutionary principles underlying this adaptive program provides important guidance for the design of precision immunotherapies that balance efficacy and safety. Strategically targeting and harnessing these protective features may greatly optimize the clinical benefits of solid tumor treatment and guide the development of next-generation innovative immunotherapies.

Keywords:  Adaptive differentiation; Immune homeostasis; Progenitor exhausted T cells; T cell exhaustion; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12943-026-02767-7
Cell Stem Cell. 2026 Nov 04. pii: S1934-5909(26)00388-7. [Epub ahead of print]

Perivascular macrophages restrict CXCR4-dependent accumulation of stem-like CD8+ T cells in tumors and limit chemotherapy efficacy.

Tik Shing Cheung, Jit Sarkar, Dorothy D Yang, Karen T Feehan, William P M Lovell, Meriem Bahri, Jessica Boad, William Macmorland, Gregory Weitsman, Angela L Caipa Garcia, Joanne E Anstee, Lea Bornemann, Benjamin Jones, Athul Menon Kallayil, Pawan Dhami, Tony Ng, James N Arnold.

  The perivascular (Pv) niche coordinates immune-stromal interactions that facilitate cancer progression. Pharmacological inhibition or genetic inactivation of the enzyme heme oxygenase-1 (HO-1) in LYVE-1+ Pv tumor-associated macrophages (PvTAMs) synergizes with cytotoxic chemotherapy (CCT) to achieve immunological tumor control in murine breast cancer models. We investigated the tumor microenvironment (TME) during the transition to immunological control and identified an increase in stem-like TCF1+PD-1+CD8+ T cells and enrichment of tumor-selective effector T cells. Stem-like CD8+ T cells were clonally diverse and rapidly acquired a TCF1- differentiated phenotype in the TME. Their tumor accumulation depended on CXCR4 and was associated with a treatment-induced expansion of proliferating CXCL12+CD34+ Pv cancer-associated fibroblasts (CAFs). In human breast cancer, greater abundance of the stem-like CD8+ T cell program was associated with improved outcomes following CCT. These findings identify PvTAM HO-1 activity as a regulator of a stromal-stem-like T cell axis that limits chemotherapy efficacy and anti-tumor immunity.

Keywords:  CAF; CXCL12; CXCR4; chemotherapy and cancer; heme oxygenase-1; macrophage; perivascular; stem-like CD8(+) T cells; tumor microenvironment

DOI:  https://doi.org/10.1016/j.stem.2026.10.007
Nat Commun. 2026 Oct 07. pii: 11431. [Epub ahead of print]17(1):

Spatiotemporal co-regulation of IL2 and TCR receptors reveals early antigen-driven synaptic synergy in human CD8+ T cells.

Jesusa Capera, María Navarro-Pérez, Ashwin K Jainarayanan, Salvatore Valvo, Lina Chen, Panyu Fei, Sarah Flannery, Roman Fischer, Saso Cemerski, Simon Low, Steven N Quayle, Raymond J Moniz, Anish Suri, Michael L Dustin.

Interleukin 2 (IL2) promotes T cell proliferation and differentiation, making it a central target in immunotherapies. Following antigen recognition, IL2 receptor (IL2R) signaling polarizes towards the immunological synapse (IS). However, how IL2 function is integrated during earlier antigen-dependent T cell synapses remains unknown. Here, we employ a supported-lipid bilayer system and TIRF microscopy to monitor the IL2R subunits and their spatiotemporal organization relative to T cell receptor (TCR) at the IS of CD8+ T cells. We show that TCR and IL2 signaling overlap in space and time and synergize when simultaneously triggered. Using Immuno-STATs, a class of immunotherapeutics in clinical testing that co-deliver IL2 and peptide major histocompatibility complex (pMHC), we demonstrate synergistic TCR and IL2R signaling that drives efficient expansion of antigen-specific CD8+ T cells. Together, these findings establish the IS as a platform for coordinated cytokine and antigen receptor signaling, providing a mechanistic framework for more selective antigen-specific immunotherapies.

DOI: https://doi.org/10.1038/s41467-026-77110-1
Redox Biol. 2026 Oct 29. pii: S2213-2317(26)00456-8. [Epub ahead of print]98 104457

Neutrophils, NETs, and efferocytosis in aging: A resolution-failure axis driving inflammaging.

Dhruthi Reddy Mutyala, Ranu Surolia.

  Population aging is a defining demographic trend of the 21st century and is accompanied by a rising prevalence of chronic diseases, functional decline, and multimorbidity that impose substantial health and socioeconomic burdens worldwide. This demographic shift is characterized by a fundamental paradox in the immune system: immunosenescence, marked by declining immune function, and inflammaging, a state of chronic low-grade inflammation. While neutrophils are essential for antimicrobial defense and immune surveillance, their broader role in maintaining tissue homeostasis during aging is increasingly recognized. Here, we examine emerging evidence that age-related alterations in neutrophil fate and functional programming, including apoptosis, NETosis, and senescence-associated states, influence macrophage behavior and contribute to persistent inflammation. Recent studies further suggest that interactions between apoptotic neutrophils and macrophages are not merely mechanisms of cellular clearance but active processes that promote macrophage metabolic and functional reprogramming toward inflammatory resolution. We discuss how aging may perturb this neutrophil-macrophage axis through altered neutrophil programming, defective efferocytosis, and impaired resolution responses, while highlighting key unresolved questions regarding senescent neutrophil biology, neutrophil-specific efferocytic signaling, and macrophage metabolic reprogramming in aging tissues. These emerging insights also identify the neutrophil-macrophage resolution axis as a potential therapeutic target for restoring tissue homeostasis and promoting healthy aging.

Keywords:  Aging; Efferocytosis; Immunosenescence; Inflammaging; Macrophage reprogramming; Neutrophil extracellular traps; Resolution biology; Senescent neutrophils

DOI:  https://doi.org/10.1016/j.redox.2026.104457
Cancer Immunol Immunother. 2026 Aug 06. pii: 268. [Epub ahead of print]75(11):

Taurine bolsters adoptive T cell therapy efficacy against hepatocellular carcinoma by reprogramming T cell function.

Zhiming Zhang, Siwei Li, Mengjie Li, Li Gong, Xinyu Lu, Weikang Xu, An-An Chen, Yiyue Wang, Changsheng He, Guoheng Mo, Yuting Xie, Si-An Yue, Lei Huang, Chou Yang, Jinlin Hou, Wei Zhu.

  Adoptive T cell therapy for advanced hepatocellular carcinoma (HCC) is limited by the immunosuppressive tumor microenvironment, which impairs T-cell function. Overcoming this immunosuppression and restoring T-cell functionality are crucial for improving therapeutic efficacy. Here, we investigated the role of taurine in regulating alpha-fetoprotein (AFP)-specific T-cell receptor-engineered T cells (TCR-T) function. Metabolomic profiling revealed that intracellular taurine levels declined during the early phase of T-cell activation, while expression of the taurine transporter SLC6A6 increased over time. In addition, taurine abundance was lower in HCC tissues than in normal liver tissues in vivo, suggesting that taurine availability is reduced during both T-cell activation and tumor progression. Functionally, taurine supplementation enhanced the cytotoxic activity, persistence, and intratumoral infiltration of AFP-specific TCR-T, while reducing exhaustion and apoptosis after repetitive tumor stimulation. In contrast, taurine-limited conditions impaired T-cell proliferation and survival, attenuated antitumor activity in vitro and in vivo, and promoted an exhaustion-prone phenotype. Taurine supplementation also partially restored the function of β-alanine-preconditioned T cells. Mechanistically, transcriptomic and proteomic analyses identified PI3K-AKT signaling as a key pathway associated with taurine-mediated T-cell regulation. Taurine-limited T cells showed reduced AKT phosphorylation and developed a metabolically stressed state characterized by increased mitochondrial respiration, glycolytic activity, reactive oxygen species production and mitochondrial structural abnormalities during activation. Together, these findings identify taurine availability as an important metabolic regulator of engineered T-cell fitness and support taurine-based metabolic conditioning as a potential strategy to improve TCR-T therapy for HCC.

Keywords:  Adoptive T cell; Hepatocellular carcinoma; SLC6A6; Taurine

DOI:  https://doi.org/10.1007/s00262-026-04503-y
J Extracell Vesicles. 2026 Nov;pii: e70404. [Epub ahead of print]15(11):

ITGAM+ Extracellular Vesicles Trigger CD8+ T Cell Activation via S100a9-Mediated Metabolic Reprogramming in Acute Kidney Injury.

Yu-Qi Fu, Yi-Lin Zhang, An-Ran Shen, Ning Li, Jing Song, Yan Bao, Si-Meng Wang, Ding-Ding Xue, Min Wu, Bin Wang, Yi Wen, Tao-Tao Tang, Lin-Li Lv, Bi-Cheng Liu.

  Acute kidney injury (AKI) is a prevalent condition with limited therapeutic options, in which sustained renal injury driven by inflammation remains a central pathological challenge. Here, we identify a specific subset of extracellular vesicles (EVs) as the critical link translating early myeloid inflammation into metabolically fuelled CD8+ T cell pathogenicity. Using single-EV surface proteomics via a proximity barcoding assay in a murine ischemia-reperfusion injury model, we mapped the renal EV landscape and discovered a myeloid-derived ITGAM+ EV subset with markedly increased abundance after injury. Using a CD63-PAGFPITGAM-KI reporter mouse that genetically enhances ITGAM+ EV release, we further validated that these EVs interact with CD8+ T cells in the renal lymphatic niche, driving their pro-inflammatory activation. Proteomic profiling pinpointed S100a9 as the functional cargo on these ITGAM+ EVs. Mechanistically, EV-delivered S100a9 stabilized the mitochondrial aspartate-glutamate carrier Slc25a12 in recipient CD8+ T cells, thereby enhancing glutamate metabolism to fuel a pathogenic transcriptional program. Pharmacological inhibition of S100a9 with tasquinimod, combined with genetic loss of S100a9 in bone marrow-derived myeloid cells, established the necessity of EV-associated S100a9 in driving CD8+ T cell activation. Our findings establish ITGAM+ EVs as essential mediators of pro-metabolic and pro-inflammatory signal in AKI and highlight the S100a9-Slc25a12 axis as a promising therapeutic target for intercepting sterile inflammation.

Keywords:  CD8+ T cell; ITGAM+ EVs; acute kidney injury; metabolic reprogramming

DOI:  https://doi.org/10.1002/jev2.70404
Front Immunol. 2026 ;17 1965813

Therapy-induced methionine competition in bladder cancer: MAT2A-SAM axis remodeling as a metabolic immune checkpoint.

Chengyuan Zhang, Zhe Zhang, Jianbin Bi.

  Bladder cancer is increasingly treated with platinum chemotherapy, immune checkpoint blockade, and antibody-drug conjugates, but treatment resistance remains common. Methionine connects nutrient availability with S-adenosylmethionine (SAM) production, methylation, redox homeostasis, and lymphocyte function. In cisplatin-resistant tumor cells, MAT2A stabilization sustains a SAM-dependent program of stem-like renewal and drug resistance. Concurrently, increased SLC7A6-associated methionine uptake can create a tumor methionine sink that lowers methionine and SAM in CD8+ T cells, weakens H3K79me2-STAT5 signaling, and impairs effector function. Separately, methionine-sensitive YTHDF1 signaling suppresses RIG-I-dependent innate sensing and increases PD-L1 translation. A layered metabolic immune checkpoint is proposed to explain how these convergent but non-equivalent mechanisms link treatment-selected tumor fitness, nutrient competition, and reduced immune visibility. The framework exposes a context-dependent therapeutic paradox: methionine restriction may weaken tumor adaptation but compromise T-cell fitness, whereas SAM restoration may support antitumor immunity while also fueling malignant cells. Therefore, treatment-state biomarkers should guide compartment-selective targeting and intervention timing.

Keywords:  CD8+ T cells; MAT2A; SLC7A6; YTHDF1; bladder cancer; cisplatin resistance; immunotherapy; methionine metabolism

DOI:  https://doi.org/10.3389/fimmu.2026.1965813
iScience. 2026 Nov 20. 29(11): 117982

NR2F6 functions as a key transcriptional checkpoint enforcing dysfunction of human CD3+ T cells and limiting CAR-T cell potency.

Jiří Koutník, Thomas Gruber, Dorothee Freimark, Dominik Humer, Daniel Schreiber, Isabel Hölzl, Viktor Lang, Nino Tokic, Tajana Sajinovic, Dominik Wolf, Nikolaus Thuille, Kerstin Siegmund, Victoria Klepsch, Gottfried Baier.

  Although nuclear receptor subfamily 2 group F member 6 (NR2F6) regulates lymphocyte activation in murine models, its function in human T cells remains incompletely defined. Here, we identify NR2F6 as a T cell receptor (TCR)-inducible transcriptional checkpoint that limits effector potency in human CD3+ T cells, including chimeric antigen receptor (CAR) T cells. In an anti-EGFR CAR-T cell-A549 co-culture model, enforced NR2F6 expression, mimicking its upregulation in tumor-infiltrating lymphocytes, markedly impairs killing under repeated tumor challenge. In polyclonal T cells, NR2F6 overexpression and CRISPR-Cas9-mediated ablation produced directionally opposing effects, supporting its role as a negative regulator of activation, differentiation-associated programs, and cytokine production. Mechanistically, transcriptomic, epigenomic, and nuclear protein analyses are consistent with suppression of NFAT-, AP-1-, and NF-κB-associated pathways and reveal context-dependent changes in TCF-1-associated readouts. Collectively, these findings position NR2F6 as a signaling-integrated transcriptional checkpoint that contributes to dysfunctional T cell states and may promote tumor immune evasion in humans.

Keywords:  CAR-T cells; NR2F6; T cell dysfunction; TCF-1/TCF7; immune checkpoint; transcriptional regulation

DOI:  https://doi.org/10.1016/j.isci.2026.117982
J Clin Invest. 2026 Nov 05. pii: e202874. [Epub ahead of print]

Decidua-accumulated effector-like memory CD8+ T cells orchestrate localized antimicrobial defense without compromising fetal tolerance.

Lu Liu, Xixi Huang, Tingxuan Yin, Xianyang Hu, Hailin Yu, Guohua Zhu, Chunfang Xu, Jiajia Chen, Jiangyuan Du, Hongyan Wang, Qingyu Wu, Wei Zhang, Feng Wang, Huimei Wu, Meirong Du.

  Deciphering immune privilege at the maternal-fetal interface is essential for understanding how reproductive success and host defense are simultaneously maintained. Decidualization, occurring within the specialized stromal tissue encapsulating the fetus and placenta, shapes local immune adaptation required for healthy pregnancy. Here, we identify a decidua-enriched effector-like memory CD8+ T cell subset marked by CD45RA in humans and CX3CR1 in mice. These cells preferentially accumulate in the decidua, which harbors a CX3CL1-dominant chemokine niche, and disruption of Cx3cr1 or uterine Cx3cl1 impaired their decidual recruitment and tissue localization. Human CD45RA+ and murine CX3CR1+ decidual memory CD8+ T cells shared conserved transcriptional and functional features, including enhanced cytotoxic potential and limited inflammatory cytokine production. Functionally, CX3CL1-mediated CD8+ T cell accumulation improved local control of prenatal Listeria monocytogenes infection and reduced infection-associated fetal loss. In contrast, fetal antigen-specific CD8+ T cell accumulation and fetal resorption occurred independently of uterine CX3CL1. Together, our findings define the maternal-fetal interface as an active immunological gatekeeper, that compartmentalizing CD8+ T cell-mediated antimicrobial adaptive immunity through the conserved CX3CL1-CX3CR1 axis, supporting pathogen-specific defense while preserving fetal tolerance.

Keywords:  Adaptive immunity; Cellular immune response; Chemokines; Immunology; Reproductive biology

DOI:  https://doi.org/10.1172/JCI202874
Cancer Immunol Immunother. 2026 Aug 06. pii: 269. [Epub ahead of print]75(11):

Squeezing Treatment-Induced Metabolic Alterations in Melanoma Cells Are Accompanied by Impaired Cluster of Differentiation 8-Positive T Cell and Natural Killer Cell Antitumor Effector Functions.

Yu Jing, Yunlong Bi.

   BACKGROUND: The physical microenvironment of solid tumors exerts compressive forces on cancer cells, but how such mechanical stress contributes to melanoma immune evasion remains largely unknown. This study investigates whether compression-induced nuclear deformation and metabolic reprogramming facilitate immune escape and explores the regulatory role of microphthalmia-associated transcription factor (MITF).
METHODS: A three-dimensional (3D) melanoma spheroid model was established and subjected to microfluidic-based compressive stress. Nuclear morphology and cellular stiffness were evaluated using confocal microscopy and atomic force microscopy. Transcriptome sequencing and The Cancer Genome Atlas Skin Cutaneous Melanoma (TCGA-SKCM) transcriptomic analyses, together with differentially expressed gene (DEG) analysis, Gene Set Enrichment Analysis (GSEA), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, Seahorse metabolic assays, and flow cytometry, were used to identify key metabolic pathways and evaluate cluster of differentiation 8-positive (CD8+) T cell and natural killer (NK) cell function. MITF was silenced via lentiviral short hairpin RNA (shRNA) to determine its functional involvement.
RESULTS: Squeezing (Sqz) treatment triggered marked nuclear elongation, reduced cellular stiffness, and enhanced both mitochondrial oxidative phosphorylation and glycolysis in melanoma cells. These metabolic alterations were accompanied by impaired interferon-gamma (IFN-gamma) and Granzyme B production in CD8+ T cells and reduced NK cell effector activity, together with increased immune cell apoptosis. Public TCGA-SKCM analyses further supported an association between high MITF expression, reduced cytotoxic immune signatures, lower immune infiltration, and MITF-related metabolic pathway enrichment. MITF knockdown attenuated nuclear deformation, suppressed metabolic overactivation, restored mitochondrial membrane potential, and rescued CD8+ T cell- and NK cell-mediated cytotoxicity.
CONCLUSION: Sqz-induced metabolic alterations in melanoma cells are accompanied by impaired CD8+ T cell and NK cell antitumor effector functions. MITF may act as an important molecular link connecting nuclear mechanotransduction, metabolic reprogramming, and immune escape, suggesting a potential strategy for counteracting physical stress-driven immunosuppression.

Keywords:  Compression; MITF; Melanoma; Metabolic reprogramming; Nuclear deformation; Tumor microenvironment

DOI:  https://doi.org/10.1007/s00262-026-04495-9
Cell Rep Med. 2026 Nov 06. pii: S2666-3791(26)00558-6. [Epub ahead of print] 103141

Senescent T cells within the tumor microenvironment are a potent driver for tumor growth, stemness, and chemotherapy resistance.

Yuanqin Zhang, Xia Liu, Yixuan Xie, Lei Zhao, Myung Sik Jeon, Lisha Ai, Jingqin Luo, David A Ford, Hazar Abusalamah, R Alex Harbison, Cody Huffman, Jialin Guo, Iris He, Allison Mulvehill, Craig A Buchman, Sidharth V Puram, Benjamin A Garcia, Mark A Varvares, Marco Colonna, Guangyong Peng.

  T cell senescence is an important dysfunctional state associated with tumor progression, but whether senescent T (Tsen) cells directly reprogram tumor cell behavior remains unknown. Here, single-cell transcriptomic analyses identify abundant Tsen cells across breast, colorectal, and lung cancers. Tsen cells actively promote tumor growth, metastasis, stemness, and chemotherapy resistance by reprogramming tumor cells in vitro and in vivo. Mechanistically, lipid-enriched senescence-associated secretory phenotypes (SASPs) from Tsen cells drive metabolic remodeling and activate STAT1/STAT3 signaling in tumor cells, establishing a pro-tumorigenic state. Therapeutically, depletion of Tsen cells or disruption of tumor lipid metabolic reprogramming suppresses Tsen-mediated tumor progression and metastasis in vivo. Our findings establish Tsen cells as active orchestrators of tumor cell biological functions through lipid-rich SASP-dependent intercellular communication and reveal a previously unrecognized mechanism linking immune senescence to cancer progression. Targeting Tsen cells or their metabolic crosstalk with tumor cells can enhance anti-tumor immunity and improve therapeutic responses.

Keywords:  SASP; T cell exhaustion; T cell senescence; cancer immunotherapy; cancer stem cells; chemotherapy resistance; immune checkpoint blockade; lipid metabolism; tumor microenvironment; tumor reprogramming

DOI:  https://doi.org/10.1016/j.xcrm.2026.103141