bims-imseme 2025-12-28 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2025–12–28
seventeen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Deciphering the antitumor immune effects of succinate.
Modulating CD8⁺ T cell immunity through exercise: mechanistic insights and implications for precision immunotherapy.
Base-editing a single missense mutation in A20 enhances CAR-T cell efficacy.
Activated T cells degrade extracellular proteins to enhance effector functions.
CD47 signaling in aging and age-related diseases: mechanisms, challenges, and therapeutic opportunities.
RNA Modifications in T cell Immunity: Mechanisms, Disease Relevance, and Therapeutic Potential.
Emerging roles for methionine metabolism in immune cell fate and function.
AMPK agonism optimizes the in vivo activation and antileukemic efficacy of chimeric antigen receptor T cells.
Lipid-Gated "Phosphorylation Code" for TCR Graded Signaling and T-cell exhaustion.
Developing Topics.
Metabolic Reprogramming of Adaptive Immunity Induced by Viral Infections.
Basic Science and Pathogenesis.
T-cell apoptosis is more susceptible to overactivated neutrophils delivered-NETs-MPO/NE complex.
Prolonged Loss of Oxidative Phosphorylation and Mitochondrial Mass Characterize CD66b + Leukocytes from Patients with Sepsis.
Precise Control of Switchable Chimeric Antigen Receptor T Cells Allows Enhanced Safety and Less T Cell Exhaustion.
Spatial microbiome-metabolic crosstalk drives CD8+ T-cell exhaustion through the butyrate-HDAC axis in colorectal cancer.
Aging-Induced Dysfunction of Adipose Tissue and Skeletal Muscle and its link to Insulin Resistance.

Trends Endocrinol Metab. 2025 Dec 22. pii: S1043-2760(25)00265-6. [Epub ahead of print]

Deciphering the antitumor immune effects of succinate.

Ziyan Xia, Zhaoyi Li, Peng Jiang.

  Through metabolic remodeling, tumor cells can modulate neighboring CD8+ T cell function via metabolites. A recent study by Ma et al., published in Immunity, reveals that tumor-cell-derived succinate exhibits an antitumor immune effect, promoting the survival and stemness of CD8+ T cells by enhancing mitochondrial fitness and inducing epigenetic reprogramming.

Keywords:  CD8(+) T cell stemness; ICB therapy; epigenetic regulation; mitochondrial homeostasis; succinate

DOI:  https://doi.org/10.1016/j.tem.2025.12.001
Theranostics. 2026 ;16(5): 2539-2558

Modulating CD8⁺ T cell immunity through exercise: mechanistic insights and implications for precision immunotherapy.

Xinyuan Zhao, Xu Chen, Pei Lin, Yunfan Lin, Weiyao Feng, Meiyan Zou, Nina Li, Li Cui.

  CD8⁺ T lymphocytes are pivotal effectors of adaptive immunity, executing cytotoxic mechanisms essential for pathogen clearance, tumor surveillance and tissue protection. Their activity is shaped by antigenic stimulation, cytokine networks and the metabolic and structural architecture of the tissue microenvironment. Physical exercise has emerged as a potent, non-pharmacological modulator of CD8⁺ T cell biology, capable of influencing recruitment, activation, differentiation and functional persistence. Acute exercise mobilizes effector and memory subsets, enhances trafficking to peripheral tissues and transiently alters activation thresholds, while sustained training remodels subset composition, preserves mitochondrial competence and attenuates immunosenescence. These adaptations are orchestrated through integrated neuroendocrine, vascular and metabolic pathways that recalibrate chemokine gradients, nutrient availability and energetic support. However, the magnitude and direction of these effects are highly context-dependent, varying with host physiology, disease state and microenvironmental constraints. This Review integrates mechanistic and translational evidence across physiological and pathological settings-including cancer, infectious, neurological and metabolic diseases-to clarify when and how exercise can be leveraged to reinforce cytotoxic immunity. We highlight key methodological and biological challenges, and propose biomarker-guided, microenvironment-informed and adaptively titrated exercise interventions as a framework for advancing exercise from an adjunctive measure to a modulatory, precision immunotherapy.

Keywords:  CD8⁺ T cells; T cell dynamics; immune metabolism; immunomodulation; physical exercise

DOI:  https://doi.org/10.7150/thno.126053
bioRxiv. 2025 Oct 06. pii: 2025.10.05.680562. [Epub ahead of print]

Base-editing a single missense mutation in A20 enhances CAR-T cell efficacy.

Adam Blaisdell, Stefanie Bachl, Luis R Sandoval, Carter Ching, Christopher J Bowman, Nupura Kale, Manu Prabandham, Morgan Diolaiti, Claire Havig, Rommel Advincula, Nika Lenci, Zhongmei Li, Emily Yamashita, Charlotte H Wang, Shimin Zhang, Qi Liu, Philip Achacoso, Dorothea Stibor, Inger Øynebråten, Jin Seo, Alan Ashworth, Alexander Marson, Chun Jimmie Ye, Barbara A Malynn, Justin Eyquem, Julia Carnevale, Averil Ma.

T cell exhaustion limits the efficacy of cancer immunotherapies. Here, we performed genome-wide loss-of-function screening in repetitively stimulated human T cells and identified the mulitfunctional ubiquitin-modifying protein A20/TNFAIP3 as a major negative regulator of exhausted T cell persistence. Protein large language modeling, deep base-editing mutagenesis, and studies in immunocompetent mice with domain-specific inactivating mutations revealed A20's non-enzymatic M1 ubiquitin-binding zinc finger 7 (A20 ZF7 ) motif as critical to suppression of anti-tumor immunity. A20 ZF7 -deficient CD8 + tumor-infiltrating lymphocytes (TILs) resisted terminal exhaustion and circumvented an unappreciated mechanism restraining perforin degranulation in terminally exhausted cells. Human chimeric antigen receptor (CAR)-T cells engineered via base-editing to inactivate A20 ZF7 via a single missense mutation also resisted exhaustion, secreted more perforin and robustly suppressed cancer in vivo . These studies pinpoint A20 ZF7 as a novel T cell checkpoint and reveal precision base-editing of missense mutations as an effective approach to enhance CAR-T cell therapy.

DOI: https://doi.org/10.1101/2025.10.05.680562
Cell Rep. 2025 Dec 24. pii: S2211-1247(25)01569-4. [Epub ahead of print]45(1): 116797

Activated T cells degrade extracellular proteins to enhance effector functions.

Yunxue Yin, Xiaorong Lin, Linlin Li, Shuo Kan, Wenrong Jiang, Yuchen Han, Lixin Wang, Shiwen Wang, Jun Jin.

  Proteins are the most abundant source of amino acids in body fluids. However, the potential contribution of extracellular protein catabolism to the regulation of T cell immunity remains poorly understood. In this study, we show that endocytosed extracellular proteins function as an amino acid source in activated T cells, maintaining mTORC1 activity and sustaining cytokine production following T cell activation. Genetic ablation of Tfe3 impairs the activation-induced upregulation of lysosomal genes and disrupts extracellular protein catabolism, resulting in attenuated mTORC1 signaling and compromised anti-viral and anti-tumor T cell responses. The TFE3-protein-mTORC1 signaling axis demonstrates clinical relevance. CD8+PD-1+ tumor-infiltrating T cells from older patients with lung cancer display reduced lysosomal degradation capacity and impaired cytokine secretion compared to their middle-aged counterparts. This functional defect is rescued by treatment with Vismodegib, a TFE3-inducing drug. Our findings reveal lysosome-mediated extracellular protein catabolism as an important metabolic pathway supporting T cell immunity.

Keywords:  CP: immunology; CP: metabolism; activated T cells; amino acids; extracellular proteins; lysosomal proteolysis; mTORC1; protein degradation

DOI:  https://doi.org/10.1016/j.celrep.2025.116797
Biogerontology. 2025 Dec 22. 27(1): 27

CD47 signaling in aging and age-related diseases: mechanisms, challenges, and therapeutic opportunities.

Arsene Mutombo Menga, Xin Hong, Lei Zhu.

  Aging is marked by progressive dysfunction in cellular maintenance pathways, including mitochondrial impairment, reduced autophagic capacity, and accumulation of senescent cells, which contribute to chronic low-grade inflammation. The transmembrane protein CD47 best known for delivering a "don't eat me" signal through SIRPα is increasingly recognized as an important modulator of several aging-related processes. Its upregulation in aged or inflamed tissues can inhibit the clearance of damaged or senescent cells, reinforce inflammatory signaling through pathways such as NF-κB, and influence metabolic and autophagy-related regulation in a context-dependent manner. This review synthesizes current evidence identifying CD47 as an integrative node that intersects with multiple hallmarks of aging. We examine its roles across cardiovascular, neurodegenerative, and metabolic pathologies, and evaluate the emerging therapeutic landscape targeting the CD47-SIRPα axis. Although CD47 blockade has shown promise in enhancing immune clearance and improving tissue homeostasis, clinical translation remains challenged by on-target toxicities such as anemia and by age-dependent variability in immune responsiveness. Targeting CD47 therefore represents a mechanistically grounded but inherently complex strategy for mitigating age-related functional decline.

Keywords:  Age-related diseases; Aging; CD47; Phagocytosis; Senescence

DOI:  https://doi.org/10.1007/s10522-025-10370-4
Theranostics. 2026 ;16(5): 2576-2597

RNA Modifications in T cell Immunity: Mechanisms, Disease Relevance, and Therapeutic Potential.

Xinyuan Zhao, Meiyan Zou, Weiyao Feng, Nina Li, Xu Chen, Pei Lin, Zihao Zhou, Yunfan Lin, Li Cui.

  RNA modifications constitute a versatile and dynamic layer of post-transcriptional regulation that enables T lymphocytes to fine-tune gene expression programs in response to developmental, environmental, and pathogenic cues. Chemical marks such as N6-methyladenosine (m6A), 5-methylcytosine (m5C), and pseudouridine (Ψ) shape transcript stability, splicing, localization, and translation through coordinated actions of writer, reader, and eraser proteins. Emerging evidence reveals that these pathways orchestrate T cell lineage specification, activation thresholds, effector-memory balance, and immune tolerance, while their dysregulation contributes to infection, autoimmunity, malignancy, and graft rejection. Integrating findings across m6A and other epitranscriptomic marks-including m5C, Ψ, N7-methylguanosine (m7G), N1-methyladenosine (m1A), N4-acetylcytidine (ac4C), and N6-2'-O-methyladenosine (m6Am) -this review delineates how distinct RNA modifications converge on shared molecular circuits controlling transcriptional, metabolic, and signaling networks in T cell immunity. Aberrant modification patterns reshape cytokine profiles, mitochondrial metabolism, and antigen-driven responses, thereby influencing disease trajectories across diverse pathological contexts. Collectively, these insights establish RNA modification as a central regulatory axis linking transcriptomic plasticity to immune function and therapeutic responsiveness. We further highlight unresolved challenges-such as defining spatiotemporal modification landscapes and achieving selective pharmacological modulation-and propose integrative multi-omics and in vivo perturbation approaches to translate epitranscriptomic mechanisms into targeted immunotherapies.

Keywords:  RNA modifications; T cell immunity; epitranscriptomics; immune regulation; therapeutic potential

DOI:  https://doi.org/10.7150/thno.124482
Front Immunol. 2025 ;16 1701505

Emerging roles for methionine metabolism in immune cell fate and function.

Shaojuan Liu, Xiaotian Tang, Min Huang, Jianian Tang, Yiwen Yang.

  Metabolic reprogramming is a critical characteristic essential for the activation of immune cells. The altered amino acid metabolism, particularly changes in methionine metabolism, holds significant importance in directing the fate and function of diverse immune cells. Here we summarize the main transport system and metabolic pathway of methionine in immune cells, and the well-established and novel research findings of methionine metabolism-dependent modulation on major immune cell lineages and cancer cells are provided afterward. Unraveling the potential regulatory mechanism of methionine metabolism reprogramming in immune cells provides the new strategies for the therapy of autoimmune diseases and cancers.

Keywords:  autoimmunity; cancer; immune cells; methionine metabolism; reprogramming

DOI:  https://doi.org/10.3389/fimmu.2025.1701505
J Immunother Cancer. 2025 Dec 21. pii: e010312. [Epub ahead of print]13(12):

AMPK agonism optimizes the in vivo activation and antileukemic efficacy of chimeric antigen receptor T cells.

Erica Braverman, Mengtao Qin, Elisabet Ampudia-Mesias, Herbert Tres Schuler, Harrison Brown, Lukas Murdych, Ann Titus, Allison MacLean, Bhavya Kanagala, Christopher Wittmann, Archana Ramgopal, Felicia Kemp, Steven J Mullet, Aaron Yang, Amanda C Poholek, Stacy Gelhaus, Craig Byersdorfer.

   BACKGROUND: Chimeric antigen receptor (CAR) T cells have achieved remarkable clinical success. However, up to 50% of patients with CAR T-cell treated leukemia relapse and long-term survivor data indicate that CAR T cell persistence is key to enforcing extended, relapse-free survival. Unfortunately, ex vivo expansion protocols often drive metabolic and functional exhaustion, reducing in vivo efficacy. Preclinical models have demonstrated that redirecting metabolism can improve in vivo T-cell function. Here, we hypothesized that exposure to an agonist targeting AMP-activated protein kinase (AMPK) would create CAR T cells capable of increased in vivo function and enhanced leukemia clearance.
METHODS: CAR T cells were generated from healthy human donor T cells via lentiviral transduction, followed by exposure to either Compound 991 or dimethyl sulfoxide (DMSO) for 96 hours. During and after agonist treatment, T cells were harvested for metabolic and functional assessments. To test in vivo efficacy, immunodeficient mice were injected with luciferase+NALM6 leukemia cells, and 1 week later with 991- versus DMSO-expanded CAR T cells. Leukemia burden and antileukemia efficacy were assessed via radiance imaging and overall survival.
RESULTS: Compound 991 treatment activated AMPK without limiting cellular expansion, and increased both mitochondrial density and handling of reactive oxygen species. Mechanistically, 991 treatment mimicked nutrient starvation, with increased autophagy and generation of mitochondrially protective metabolites. Importantly, receipt of 991-exposed CAR Ts significantly improved in vivo leukemia clearance and prolonged recipient survival, likely as a result of elevated activation and increased CD4+T cell yields at early times post-injection.
DISCUSSION: Ex vivo expansion is necessary to generate sufficient cell numbers for in vivo administration, but sustained activation and differentiation often negatively impact in vivo persistence and function. Here, we demonstrate that promoting AMPK activity during in vitro CAR T expansion metabolically reprograms cells without limiting T cell yield, increases early activation following in vivo transfer, and ultimately enhances anti-leukemia efficacy. Importantly, Compound 991 treatment achieves these results without further modifying the expansion media, changing the CAR T construct, or genetically altering the cells. Together, these data highlight AMPK agonism as a potent and readily translatable approach to improve the metabolic profile and in vivo efficacy of adoptively transferred T cells.

Keywords:  Adoptive cell therapy - ACT; Immunotherapy; Leukemia; T cell

DOI:  https://doi.org/10.1136/jitc-2024-010312
Protein Cell. 2025 Dec 24. pii: pwaf110. [Epub ahead of print]

Lipid-Gated "Phosphorylation Code" for TCR Graded Signaling and T-cell exhaustion.

Hui Chen, Jizhong Lou, Wei Chen.

The TCR/CD3s complex translates antigenic cues into graded immune responses. Xu and colleagues (Molecular Cell, 2025) revealed a lipid-electrostatic mechanism that governs sequential phosphorylation of the CD3ζ chain. Using NMR in a membrane-mimetic system, they uncovered a gradient of membrane insertion across its ITAMs, establishing a structural basis for tunable signaling. Under chronic stimulation, ATP depletion preferentially impairs distal ITAM phosphorylation, revealing an intrinsic energy-sensitive pathway driving T cell exhaustion. These findings provide a compelling model for TCR regulation and suggest strategies to enhance immunotherapy via CD3ζ engineering or metabolic restoration.

DOI: https://doi.org/10.1093/procel/pwaf110
Alzheimers Dement. 2025 Dec;21 Suppl 7 e108845

Developing Topics.

Jia Min Tan, Jia Hui Wong, Gurveen Kaur Sandhu, Fatin Zahra Zailan, Jacklyn Leonardo, Xin Ying Sim, Nagaendran Kandiah, Anna M Barron.

BACKGROUND: Interest in the adaptive immune system in AD has been growing recently and it has been shown that CD8+ T cells accumulate in the AD brain, possibly exacerbating neurodegeneration. It is not clear if intrinsic differences in CD8+ T cells in AD patients predispose them to accumulate in the brain. While phenotypic differences in peripheral T cells in AD have been characterised by others, differences in cellular metabolism remains understudied. Given that cellular metabolism can drive immune function, we tested if differences in cellular metabolism can be observed in peripheral T cells in early stages of cognitive impairment.
METHOD: PBMCs were collected from participants aged 60-80 in the Biomarker and Cognition Study during their follow up visit. The following groups were examined: Amyloid+ MCI, Amyloid- MCI and Amyloid- cognitively normal (CN). Amyloid status was determined based on plasma Aβ42:Aβ40 ratio measured on the Simoa platform, which was also used to measure plasma GFAP, NfL, and pTau181. CD8+ T cells were negatively isolated from PBMCs using magnetic cell separation and activated with anti-CD3 and anti-CD28 antibodies. Label-free imaging of cellular NAD(P)H and FAD if hwas used to determine relative levels of glucose catabolism and oxidative phosphorylation. Mitochondria function was assessed using the Seahorse Mitostress assay. Correlation between CD8+ metabolism measures and plasma biomarker concentrations was measured using partial Spearman's correlation, adjusting for age and sex.
RESULT: Preliminary results indicate that NAD(P)H levels were significantly higher in Amyloid+ MCI compared to Amyloid- CN individuals. A positive correlation between NAD(P)H levels in CD8+ T cells and plasma Aβ42 and Aβ40 concentrations was also observed, whereas the correlation with FAD and plasma GFAP was negative.
CONCLUSION: Differences in NAD(P)H, a marker of glucose catabolism, can be observed in peripheral T cells in early cognitive impairment. CD8+ cellular metabolism appear to correlate with plasma biomarkers of neurodegeneration and AD, setting the stage for further investigation into the implications on CD8+ function and effect of metabolism-modifying drugs such as metformin on peripheral CD8+ T cells and AD progression.

DOI: https://doi.org/10.1002/alz70861_108845
Immunology. 2025 Dec 25.

Metabolic Reprogramming of Adaptive Immunity Induced by Viral Infections.

Guoshuai Tong, Jingwen Dai, Qianqian Liu, Xu Gao, Su Li, Hua-Ji Qiu.

  Metabolic reprogramming induced by viral infections plays a key role in shaping the efficacy and durability of the host's adaptive immune response. Notably, metabolic reprogramming not only directly governs the differentiation fates of functional subgroups, such as Th1, Th2, Th17, Treg and cytotoxic T cells, but also contributes to supportive immune responses and T-cell exhaustion mediated by metabolic disorders in the context of acute and chronic infections, respectively. Moreover, the metabolic reprogramming of B cells precisely regulates their germinal centre response, plasma cell differentiation and antibody production, thereby modulating the intensity and quality of humoral immunity. Beyond these direct effects, viruses indirectly impair the functionality of T and B cells by altering the metabolic status of innate immune cells such as dendritic cells and macrophages. This review summarises the recent advances of regulatory mechanisms regarding metabolic characteristics of T cells and B cells at various statuses, including rest, activation, differentiation and memory, and discusses immune intervention strategies targeting glycolysis, glutamine and lipid metabolism, and outlines future research directions and clinical translation potential of metabolic reprogramming. A comprehensive understanding of virus-mediated metabolic reprogramming will provide an important theoretical basis for the development of new antiviral therapies and immunotherapy strategies.

Keywords:  adaptive immunity; immune regulation; immunotherapy; metabolic reprogramming; viral infections

DOI:  https://doi.org/10.1111/imm.70089
Alzheimers Dement. 2025 Dec;21 Suppl 1 e107352

Basic Science and Pathogenesis.

Dallin Dressman, Edric D Winford, Badri N Vardarajan, Maedot Yidenk, Ryan Talcoff, Jessica Mazen, Elizabeth M Bradshaw, Jennifer J Manly, Adam Brickman, Wassim Elyaman.

BACKGROUND: The immune response to aging and Alzheimer's disease (AD) can be protective against disease in some individuals, and dysregulated and damaging in others. Factors like genetics, socioeconomic status, race, and ethnicity can affect individual risk of AD. Profiling immune phenotypes correlated with aspects of biological and cognitive aging may identify sources of variation in AD risk, and highlight immune processes that can be pharmacologically targeted in individuals at higher risk of AD.
METHODS: We performed single-cell RNA, T, and B cell receptor sequencing of >439,000 circulating immune cells from 205 participants ages 29-81 (mean 54.7±12.5) in the Offspring Study of Racial and Ethnic Disparities in Alzheimer's Disease, with plasma proteomics data from 86 of the sequencing participants. We correlated immune cell type proportions, T cell clonal expansion, and cell type-specific gene expression with cognitive scores and mean cortical thickness in brain areas associated with AD, controlling for participant age, sex, and self-reported race and ethnicity.
RESULTS: Cortical thickness correlated with several immune cell phenotypes. Within the CD8+ T cell pool, proportions of naïve and mucosal-associated invariant T (MAIT) cells were higher with higher cortical thickness (naïve: r = 0.23, p = 0.0065, MAIT: r = 0.24, p = 0.0042), while proportions of effector memory cells were lower (r = -0.26, p = 0.0027). Higher cortical thickness was also associated with lower T cell clonal expansion, and with lower expression in several T cell subtypes of genes in biological pathways such as antigen presentation, cytotoxicity, and T cell immunity. Higher total cognitive score also correlated with lower expression of genes related to cytotoxicity, antigen presentation, and antimicrobial defense in gamma-delta T cells.
CONCLUSIONS: In a multi-ethnic cohort of middle-aged adults, we showed that higher naïve CD8+ T cell proportions and reduced expression of cytotoxicity-related genes across T cell subtypes are associated with higher cortical thickness in AD-relevant brain regions, even after adjusting for age. This finding suggests that therapeutic approaches to maintain the naïve T cell pool and target T cell cytotoxicity and clonal expansion may help protect against atrophy in AD-related brain regions and boost cognition in older adults.

DOI: https://doi.org/10.1002/alz70855_107352
Int Immunopharmacol. 2025 Dec 24. pii: S1567-5769(25)02089-2. [Epub ahead of print]170 116100

T-cell apoptosis is more susceptible to overactivated neutrophils delivered-NETs-MPO/NE complex.

Cheng Lu, Lifei Shao, Heyue Li, Xi Gao, Yiwen Mei, Bingwei Sun.

  Sepsis, characterized by infection-induced systemic inflammatory response, involves polymorphonuclear leukocytes (PMNs or Neutrophils)-T cell dysregulation. However, the precise mechanisms of PMN-driven T cell apoptosis via neutrophil extracellular traps (NETs) and their protease cargo (myeloperoxidase [MPO], neutrophil elastase [NE]), along with potential mitochondrial transfer-mediated protection, remain unclear. Using PMA-activated PMNs in coculture systems, we assessed NETs formation, T cell apoptosis/proliferation/exhaustion, DNA damage, and mitochondrial function through flow cytometry, electron microscopy, immunofluorescence, and molecular assays, with validation in LPS-challenged mice. Key findings:1) Phorbol 12-myristate 13-acetate(PMA)-activated PMNs released NETs-MPO/NE complexes that directly trapped T cells, inducing apoptosis.2) Nuclear-translocated MPO/NE triggered DNA double-strand breaks and mitochondrial membrane permeabilization, activating intrinsic apoptosis.3) MPO/NE inhibitors or NETs degradation by DNase I significantly reduced apoptosis.4) Mitochondrial transfer from resting PMNs partially restored T cell bioenergetics and attenuated apoptosis. Conclusion: NETs-derived MPO/NE promote T cell apoptosis via nuclear DNA damage and mitochondrial dysfunction, while NETs clearance, protease inhibition, or mitochondrial transfer offer therapeutic potential.

Keywords:  Apoptosis; Mitochondrial transfer; NETs-MPO/NE complexes; Neutrophil; T cell

DOI:  https://doi.org/10.1016/j.intimp.2025.116100
bioRxiv. 2025 Dec 18. pii: 2025.12.16.694726. [Epub ahead of print]

Prolonged Loss of Oxidative Phosphorylation and Mitochondrial Mass Characterize CD66b + Leukocytes from Patients with Sepsis.

Christine Rodhouse, Evan L Barrios, Leilani Zeumer-Spataro, Leandro Balzano-Nogueira, Ruoxuan Wu, Xuanxuan Yu, Guimei Tian, Jason O Brant, Marie-Pierre L Gauthier, Jing Chen, Miguel Hernandez-Rios, Valerie E Polcz, Whitman Wiggins, Angel M Charles, Marvin L Dirain, Ricardo Ungaro, Jaimar Rincon, Tyler Loftus, Feifei Xiao, Guoshuai Cai, Lyle L Moldawer, Robert Maile, Michael P Kladde, Philip A Efron, Clayton E Mathews.

Introduction: Sepsis leads to expansion of myeloid-derived suppressor cells (MDSC) and their subtypes. These normally transitory MDSCs suppress T cell activation and alter T cell cytokine production while simultaneously promulgating systemic low-grade inflammation. Immune metabolism can shape cell responses, regulate immune suppression, and enhance effector activity. Although MDSC metabolism has been extensively studied in cancer, the metabolic phenotype of this heterogeneous population in sepsis remains unclear. Our goal was to assess metabolic flux in blood MDSCs during and after sepsis and to stratify these patients' clinical features and outcome with differences in metabolic flux that may guide treatment decisions.
Methods: Peripheral blood mononuclear cells (PBMC) from healthy subjects and sepsis patients at 4 days, 2-3 weeks, and 6 months underwent CD66b + or CD3 + enrichment, followed by assessment of metabolic flux, flow cytometry, mRNA sequencing, and chromatin accessibility.
Results: Mitochondrial basal oxygen consumption rates (OCR) and maximal oxygen consumption rates (SRC, spare respiratory capacity) were decreased in MDSC from septic patients at 4 days after infection and persisted for up to 6 months after sepsis onset. Sepsis was not associated with differences in glycolysis. In contrast, oxidative metabolism in CD3 + T cells was similar between sepsis patients and healthy subjects. Reduced MDSC oxidative metabolism was linked to adverse clinical outcomes. The decline in oxygen consumption from MDSCs in septic patients was also associated with significant reductions in MDSC mitochondrial content. Transcriptomic analysis of CD66b + cells isolated from PBMC of healthy participants and patients with sepsis at 4 days, 2-3 weeks, and 6 months revealed 19 differentially expressed genes and three long non-coding RNAs as potentially responsible for this decline in mitochondrial mass. Specifically, NR4A3 , NR4A2, and TAMLIN/NR4A1 expression, all critical for mitochondrial biogenesis, were persistently decreased with reduced chromatin accessibility indicative of gene silencing.
Discussion: After sepsis, blood CD66b + cells present with reduced mitochondrial mass and oxidative metabolism that continue at least 6 months after sepsis. These changes in mitochondrial function result from a reduced content of these organelles. We have also identified gene silencing, reduced gene expression of key transcription factors that regulate mitochondrial biogenesis, as well as increased long non-coding RNA as potential drivers of this unique metabolic phenotype. These results highlight the potential benefit of targeting metabolism in sepsis to promote immune homeostasis and recovery.

DOI: https://doi.org/10.64898/2025.12.16.694726
bioRxiv. 2025 Dec 10. pii: 2025.12.07.692875. [Epub ahead of print]

Precise Control of Switchable Chimeric Antigen Receptor T Cells Allows Enhanced Safety and Less T Cell Exhaustion.

Zihan Anna Zhang, Logan Herring, Thuzar Hla Shwe, Yue Hu, Xiaotong Song, Wenyue Cao, Wenshe Ray Liu.

Chimeric antigen receptor (CAR)-T cell therapies have achieved remarkable success in treating hematologic malignancies, yet their clinical utility remains limited by safety concerns, poor persistence, and T-cell exhaustion driven by continuous receptor signaling. Although switchable CAR systems offer external control, most existing designs are irreversible, binary, or compromising CAR-T potency. Here, we introduce a chemically switchable CAR platform that enables graded, reversible regulation of CAR-T activity while retaining full therapeutic capacity. Using engineered CAR-T cells, we evaluate drug-controlled activation, cytotoxicity, and cytokine release against CD19⁺ tumor cells and screened clinically approved NS3/4A inhibitors to identify optimal small-molecule controllers. Compared with conventional CAR-T cells, switchable CAR-T cells exhibited minimal background activity in the OFF state, preventing antigen-driven activation and cytokine release in the absence of drug. Upon drug addition, CAR expression was rapidly restored, with full-length CAR detectable within 1 hour and ∼80% of maximal expression achieved by 4 hours. Reversible suppression of CAR expression protected normal CD19⁺ B cells once malignant cells were eliminated, addressing the clinical challenge of persistent CD19 CAR-T activity that can lead to B-cell aplasia, hypogammaglobulinemia, and recurrent infections. Furthermore, switchable CAR-T cells displayed reduced exhaustion, enhanced persistence, stable CAR expression, and preferential central memory differentiation following tumor clearance. Together, these findings establish the switchable CAR-T system as a next-generation, reversible, and clinically compatible CAR-T platform.
Key Points: Optimized switchable CAR enables precise control of functional CAR expression, T-cell activation, cytokine release, and cytotoxicity.External regulation of CAR-T cells enhances safety and promotes sustained persistence in chronic stimulation models.

DOI: https://doi.org/10.64898/2025.12.07.692875
Front Microbiol. 2025 ;16 1704491

Spatial microbiome-metabolic crosstalk drives CD8+ T-cell exhaustion through the butyrate-HDAC axis in colorectal cancer.

Xiaoyang Chen, Yinxu Zhang, Guangyu Zhang, Dai Wang, Linhua Dou, Yuxi Wang, Zining Huang, Xiaomei Liu.

   Background: The spatial organization of intratumoral microbiota and its metabolic impact on immunotherapy response in colorectal cancer (CRC) is unclear, limiting targeted interventions.
Methods: We integrated single-cell RNA-seq, spatial transcriptomics, and microbial multi-omics from a discovery cohort of 23 treatment-naïve CRC patients. Findings were validated in an independent validation cohort from The Cancer Genome Atlas (TCGA-CRC, n = 159).
Results: Spatial depletion of Streptococcus and Acetivibrio in tumor niches disrupts butyrate-histone deacetylase (HDAC) signaling, leading to programmed cell death 1 (PDCD1) hyperacetylation and CD8+ T-cell exhaustion. The Colorectal Cancer Microbiome Score (CMS) may serve as a predictive biomarker for immunotherapy response and HDAC inhibitor-based combination therapy. We developed the CMS, a spatial biomarker that stratifies patients by microbial-metabolic dysfunction, predicting immunotherapy resistance (e.g., higher tumor immune dysfunction and exclusion (TIDE) scores; p < 0.01) and guiding combinatorial HDAC inhibition for CMS-defined subgroups. In silico fecal microbiota transplantation (FMT) validated CMS as an actionable target for microbiota modulation. Butyrate supplementation in vitro restored HDAC activity and reduced PD-1 expression on CD8+ T cells, validating the proposed mechanism.
Conclusion: Our study unveils a spatially defined, microbiome-driven metabolic niche that epigenetically programs CD8+ T-cell exhaustion via the butyrate-HDAC axis, revealing a targetable mechanism to overcome immunotherapy resistance in CRC.

Keywords:  CD8+ T-cell exhaustion; HDAC inhibition; butyrate metabolism; colorectal cancer; microbiome-metabolic-immune crosstalk; spatial microbiome

DOI:  https://doi.org/10.3389/fmicb.2025.1704491
J Biochem. 2025 Dec 24. pii: mvaf081. [Epub ahead of print]

Aging-Induced Dysfunction of Adipose Tissue and Skeletal Muscle and its link to Insulin Resistance.

Masaji Sakaguchi.

  The extension of the human lifespan has increased the incidence of age-related metabolic disorders, such as type 2 diabetes and sarcopenia, which markedly impair quality of life and reduce life expectancy in older adults. Aging and insulin resistance synergistically compromise the functional integrity of the adipose and skeletal muscles. During aging, the adipose tissue exhibits impaired progenitor differentiation, chronic inflammation, fibrotic remodeling, and loss of thermogenic capacity. Skeletal muscles also exhibit changes, including satellite cell decline, mitochondrial dysfunction, defective protein turnover, and progressive sarcopenia. These changes diminish tissue plasticity and endocrine function and exacerbate insulin resistance through disrupted intracellular signaling and accumulation of metabolic burden. Notably, the deterioration of adipose and muscle tissue functions is interconnected, further exacerbating systemic metabolic dysfunction. Recent studies have contributed to elucidating the physiopathological causes and mechanisms of age-dependent cellular and molecular alterations in adipose and muscle tissues. This review summarizes the current insights into the cellular and molecular mechanisms underlying age-related alterations in adipose and muscle tissues and discusses emerging therapeutic strategies, including lifestyle interventions, pharmacological agents, approaches targeting senescent cells, and inter-organ communication that aim to preserve metabolic health in aging populations.

Keywords:  aging; diabetes; insulin resistance; obesity; sarcopenia

DOI:  https://doi.org/10.1093/jb/mvaf081