bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2025–03–23
ten papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. The epigenetic landscape of fate decisions in T cells.
  2. Blocking lactate: kick T cells when they are down.
  3. Bioengineering the metabolic network of CAR T cells with GLP-1 and Urolithin A increases persistence and long-term anti-tumor activity.
  4. T Cell Exhaustion in Allergic Diseases and Allergen Immunotherapy: A Novel Biomarker?
  5. Crohn's Disease-associated variant in laccase domain containing 1 (LACC1) modulates T cell gene expression, metabolism and T cell function.
  6. Mitochondrial reactive oxygen species regulate acetyl-CoA flux between cytokine production and fatty acid synthesis in effector T cells.
  7. Aspirin helps T cells to stop cancer spread.
  8. VDAC2 loss elicits tumour destruction and inflammation for cancer therapy.
  9. CD38-mediated metabolic reprogramming promotes the stability and suppressive function of regulatory T cells in tumor.
  10. Metabolic mechanisms of immunotherapy resistance.
  1. Nat Immunol. 2025 Mar 19.
    The epigenetic landscape of fate decisions in T cells.
    Atishay Jay, Carlos M Pondevida, Golnaz Vahedi.
      Specialized T cell subsets mediate adaptive immunity in response to cytokine signaling and specific transcription factor activity. The epigenetic landscape of T cells has an important role in facilitating and establishing T cell fate decisions. Here, we review the interplay between transcription factors, histone modifications, DNA methylation and three-dimensional chromatin organization to define key elements of the epigenetic landscape in T cells. We introduce key technologies in the areas of sequencing, microscopy and proteomics that have enabled the multi-scale profiling of the epigenetic landscape. We highlight the dramatic changes of the epigenetic landscape as multipotent progenitor cells commit to the T cell lineage during development and discuss the epigenetic changes that favor the emergence of CD4+ and CD8+ T cells. Finally, we discuss the inheritance of epigenetic marks and its potential effects on immune responses as well as therapeutic strategies with potential for epigenetic regulation.
    DOI:  https://doi.org/10.1038/s41590-025-02113-x
  2. Immunometabolism (Cobham). 2025 Apr;7(2): e00059
    Blocking lactate: kick T cells when they are down.
    Veronika Horkova, Bart Everts, Dirk Brenner.
      In the last couple of decades, cancer research has been shifting its focus to the immune system. Cancer cells, with their ability to adapt and evade immune responses, seem to accelerate the evolutionary pressure that has been put on our immune system during evolution. We thus try to aid these natural selection processes and assist our immune system to combat cancer. Here, we are discussing a study by Greg Delgoffe and colleagues that was published in Nature Immunology in December 2024, exploring a new approach to bring the dysfunctional immune cells back to life by blocking their lactate uptake.
    Keywords:  MCT11; T cell exhaustion; anti-tumor immunity; hypoxia; immune checkpoint blockade; lactate; metabolism
    DOI:  https://doi.org/10.1097/IN9.0000000000000059
  3. Cell Rep Med. 2025 Mar 18. pii: S2666-3791(25)00094-1. [Epub ahead of print]6(3): 102021
    Bioengineering the metabolic network of CAR T cells with GLP-1 and Urolithin A increases persistence and long-term anti-tumor activity.
    Areej Akhtar, Md Shakir, Mohammad Sufyan Ansari, Divya, Md Imam Faizan, Varnit Chauhan, Aashi Singh, Ruquaiya Alam, Iqbal Azmi, Sheetal Sharma, Mehak Pracha, Insha Mohi Uddin, Uzma Bashir, Syeda Najidah Shahni, Rituparna Chaudhuri, Sarah Albogami, Rik Ganguly, Shakti Sagar, Vijay Pal Singh, Gaurav Kharya, Amit Kumar Srivastava, Ulaganathan Mabalirajan, Soumya Sinha Roy, Irfan Rahman, Tanveer Ahmad.
      Constant tumor antigen exposure disrupts chimeric antigen receptor (CAR) T cell metabolism, limiting their persistence and anti-tumor efficacy. To address this, we develop metabolically reprogrammed CAR (MCAR) T cells with enhanced autophagy and mitophagy. A compound screening identifies a synergy between GLP-1R agonist (semaglutide [SG]) and Urolithin A (UrA), which activate autophagy through mTOR (mechanistic target of rapamycin) inhibition and mitophagy via Atg4b activation, maintaining mitochondrial metabolism in CAR T cells (MCAR T-1). These changes increase CD8+ T memory cells (Tm), enhancing persistence and anti-tumor activity in vitro and in xenograft models. GLP-1R knockdown in CAR T cells diminishes autophagy/mitophagy induction, confirming its critical role. We further engineer GLP-1-secreting cells (MCAR T-2), which exhibited sustained memory, stemness, and long-term persistence, even under tumor re-challenge. MCAR T-2 cells also reduce cytokine release syndrome (CRS) risks while demonstrating potent anti-tumor effects. This strategy highlights the potential of metabolic reprogramming via targeting autophagy/mitophagy pathways to improve CAR T cell therapy outcomes, ensuring durability and efficacy.
    Keywords:  CAR T cells; GLP-1 peptide; T cell persistence; Urolithin A; anti-tumor activity; autophagy; metabolism; mitochondrial health; mitophagy
    DOI:  https://doi.org/10.1016/j.xcrm.2025.102021
  4. Curr Allergy Asthma Rep. 2025 Mar 17. 25(1): 18
    T Cell Exhaustion in Allergic Diseases and Allergen Immunotherapy: A Novel Biomarker?
    Qingxiu Xu, Le Li, Rongfei Zhu.
       PURPOSE OF REVIEW: This review explores the emerging role of T cell exhaustion in allergic diseases and allergen immunotherapy (AIT). It aims to synthesize current knowledge on the mechanisms of T cell exhaustion, evaluate its potential involvement in allergic inflammation, and assess its implications as a novel biomarker for predicting and monitoring AIT efficacy.
    RECENT FINDINGS: Recent studies highlight that T cell exhaustion, characterized by co-expression of inhibitory receptors (e.g., PD-1, CTLA-4, TIM-3), diminished cytokine production, and altered transcriptional profiles, may suppress type 2 inflammation in allergic diseases. In allergic asthma, exhausted CD4 + T cells exhibit upregulated inhibitory receptors, correlating with reduced IgE levels and airway hyperreactivity. During AIT, prolonged high-dose allergen exposure drives allergen-specific Th2 and T follicular helper (Tfh) cell exhaustion, potentially contributing to immune tolerance. Notably, clinical improvements in AIT correlate with depletion of allergen-specific Th2 cells and persistent expression of exhaustion markers (e.g., PD-1, CTLA-4) during maintenance phases. Blockade of inhibitory receptors (e.g., PD-1) enhances T cell activation, underscoring their dual regulatory role in allergy. T cell exhaustion represents a double-edged sword in allergy: it may dampen pathological inflammation in allergic diseases while serving as a mechanism for AIT-induced tolerance. The co-expression of inhibitory receptors on allergen-specific T cells emerges as a promising biomarker for AIT efficacy. Future research should clarify the transcriptional and metabolic drivers of exhaustion in allergy, validate its role across diverse allergic conditions, and optimize strategies to harness T cell exhaustion for durable immune tolerance. These insights could revolutionize therapeutic approaches and biomarker development in allergy management.
    Keywords:  Allergen immunotherapy; Allergic disease; Effector function; Inhibitory receptor; T cell exhaustion
    DOI:  https://doi.org/10.1007/s11882-025-01199-5
  5. Nat Commun. 2025 Mar 15. 16(1): 2577
    Crohn's Disease-associated variant in laccase domain containing 1 (LACC1) modulates T cell gene expression, metabolism and T cell function.
    Yingcong Li, Gabriel Ascui, Martina Dicker, Thomas Riffelmacher, Vivek Chandra, Benjamin Schmiedel, Ting-Fang Chou, Pandurangan Vijayanand, Mitchell Kronenberg.
      Genome wide association studies (GWAS) identify many risks for Crohn's disease (CD), including a site near the metabolism gene laccase domain containing 1 (LACC1). We previously found this site near LACC1 was associated with decreased LACC1 expression in T lymphocytes, yet the mechanism affecting gene expression and its links to T cell function and inflammatory disease were unknown. Here we identify variants in the promoter region that influence transcription of LACC1. Direct association of disease-risk variants with lower LACC1 pre-mRNA in human CD4+ T cells is confirmed by comparing transcripts from each allele from donors heterozygous for the LACC1 CD-risk allele. Using gene editing, we validate the function of this promoter region in LACC1 expression in T cells. Human CD4+ T cells with LACC1 gene knockdown show altered metabolism, including reduced oxygen consumption rate, and reduced in vitro regulatory T cell differentiation. Therefore, our study provides a mechanism linking these specific LACC1 variants to colitis by attributing promoter region variants to changes in T cell metabolism and function.
    DOI:  https://doi.org/10.1038/s41467-025-57744-3
  6. Cell Rep. 2025 Mar 13. pii: S2211-1247(25)00201-3. [Epub ahead of print]44(3): 115430
    Mitochondrial reactive oxygen species regulate acetyl-CoA flux between cytokine production and fatty acid synthesis in effector T cells.
    Beibei Wu, Jin Seok Woo, Spyridon Hasiakos, Calvin Pan, Shawn Cokus, Cristiane Benincá, Linsey Stiles, Zuoming Sun, Matteo Pellegrini, Orian S Shirihai, Aldon J Lusis, Sonal Srikanth, Yousang Gwack.
      Genetic and environmental factors shape an individual's susceptibility to autoimmunity. To identify genetic variations regulating effector T cell functions, we used a forward genetics screen of inbred mouse strains and uncovered genomic loci linked to cytokine expression. Among the candidate genes, we characterized a mitochondrial inner membrane protein, TMEM11, as an important determinant of Th1 responses. Loss of TMEM11 selectively impairs Th1 cell functions, reducing autoimmune symptoms in mice. Mechanistically, Tmem11-/- Th1 cells exhibit altered cristae architecture, impaired respiration, and increased mitochondrial reactive oxygen species (mtROS) production. Elevated mtROS hindered histone acetylation while promoting neutral lipid accumulation. Further experiments using genetic, biochemical, and pharmacological tools revealed that mtROS regulate acetyl-CoA flux between histone acetylation and fatty acid synthesis. Our findings highlight the role of mitochondrial cristae integrity in directing metabolic pathways that influence chromatin modifications and lipid biosynthesis in Th1 cells, providing new insights into immune cell metabolism.
    Keywords:  CP: Immunology; CP: Metabolism; EAE; MICOS complex; Th1 cells; cytokine production; histone acetylation; mitochondria; mitochondrial cristae architecture; neutral lipids; reactive oxygen species
    DOI:  https://doi.org/10.1016/j.celrep.2025.115430
  7. Nat Rev Immunol. 2025 Mar 17.
    Aspirin helps T cells to stop cancer spread.
    Yvonne Bordon.
      
    DOI:  https://doi.org/10.1038/s41577-025-01160-7
  8. Nature. 2025 Mar 19.
    VDAC2 loss elicits tumour destruction and inflammation for cancer therapy.
    Sujing Yuan, Renqiang Sun, Hao Shi, Nicole M Chapman, Haoran Hu, Cliff Guy, Sherri Rankin, Anil Kc, Gustavo Palacios, Xiaoxi Meng, Xiang Sun, Peipei Zhou, Xiaoyang Yang, Stephen Gottschalk, Hongbo Chi.
      Tumour cells often evade immune pressure exerted by CD8+ T cells or immunotherapies through mechanisms that are largely unclear1,2. Here, using complementary in vivo and in vitro CRISPR-Cas9 genetic screens to target metabolic factors, we established voltage-dependent anion channel 2 (VDAC2) as an immune signal-dependent checkpoint that curtails interferon-γ (IFNγ)-mediated tumour destruction and inflammatory reprogramming of the tumour microenvironment. Targeting VDAC2 in tumour cells enabled IFNγ-induced cell death and cGAS-STING activation, and markedly improved anti-tumour effects and immunotherapeutic responses. Using a genome-scale genetic interaction screen, we identified BAK as the mediator of VDAC2-deficiency-induced effects. Mechanistically, IFNγ stimulation increased BIM, BID and BAK expression, with VDAC2 deficiency eliciting uncontrolled IFNγ-induced BAK activation and mitochondrial damage. Consequently, mitochondrial DNA was aberrantly released into the cytosol and triggered robust activation of cGAS-STING signalling and type I IFN response. Importantly, co-deletion of STING signalling components dampened the therapeutic effects of VDAC2 depletion in tumour cells, suggesting that targeting VDAC2 integrates CD8+ T cell- and IFNγ-mediated adaptive immunity with a tumour-intrinsic innate immune-like response. Together, our findings reveal VDAC2 as a dual-action target to overcome tumour immune evasion and establish the importance of coordinately destructing and inflaming tumours to enable efficacious cancer immunotherapy.
    DOI:  https://doi.org/10.1038/s41586-025-08732-6
  9. Sci Adv. 2025 Mar 21. 11(12): eadt2117
    CD38-mediated metabolic reprogramming promotes the stability and suppressive function of regulatory T cells in tumor.
    Ishita Sarkar, Debashree Basak, Puspendu Ghosh, Anupam Gautam, Arpita Bhoumik, Praveen Singh, Anwesha Kar, Shaun Mahanti, Snehanshu Chowdhury, Lagnajita Chakraborty, Soumya Mondal, Ramanuj Mukherjee, Shikhar Mehrotra, Saikat Majumder, Shantanu Sengupta, Sandip Paul, Shilpak Chatterjee.
      In the tumor microenvironment (TME), regulatory T cells (Tregs) adapt their metabolism to thrive in low-glucose, high-lactate conditions, but the mechanisms remain unclear. Our study identifies CD38 as a key regulator of this adaptation by depleting nicotinamide adenine dinucleotide (oxidized form) (NAD+), redirecting lactate-derived pyruvate toward phosphoenolpyruvate and bypassing the tricarboxylic acid (TCA) cycle. This prevents accumulation of α-ketoglutarate, which destabilizes Tregs by inducing hypermethylation at the Foxp3 locus. Restoring NAD+ with nicotinamide mononucleotide reverses this adaptation, pushing Tregs back to the TCA cycle and reducing their suppressive function. In YUMM1.7 melanoma-bearing mice, small-molecule CD38 inhibition selectively destabilizes intratumoral Tregs, sparking robust antitumor immunity. These findings reveal that targeting the CD38-NAD+ axis disrupts Tregs metabolic adaptation and offers a strategy to enhance antitumor responses.
    DOI:  https://doi.org/10.1126/sciadv.adt2117
  10. Explor Target Antitumor Ther. 2025 ;6 1002297
    Metabolic mechanisms of immunotherapy resistance.
    Luis Cabezón-Gutiérrez, Magda Palka-Kotlowska, Sara Custodio-Cabello, Beatriz Chacón-Ovejero, Vilma Pacheco-Barcia.
      Immunotherapy has revolutionized cancer treatment, yet its efficacy is frequently compromised by metabolic mechanisms that drive resistance. Understanding how tumor metabolism shapes the immune microenvironment is essential for developing effective therapeutic strategies. This review examines key metabolic pathways influencing immunotherapy resistance, including glucose, lipid, and amino acid metabolism. We discuss their impact on immune cell function and tumor progression, highlighting emerging therapeutic strategies to counteract these effects. Tumor cells undergo metabolic reprogramming to sustain proliferation, altering the availability of essential nutrients and generating toxic byproducts that impair cytotoxic T lymphocytes (CTLs) and natural killer (NK) cell activity. The accumulation of lactate, deregulated lipid metabolism, and amino acid depletion contribute to an immunosuppressive tumor microenvironment (TME). Targeting metabolic pathways, such as inhibiting glycolysis, modulating lipid metabolism, and restoring amino acid balance, has shown promise in enhancing immunotherapy response. Addressing metabolic barriers is crucial to overcoming immunotherapy resistance. Integrating metabolic-targeted therapies with immune checkpoint inhibitors may improve clinical outcomes. Future research should focus on personalized strategies to optimize metabolic interventions and enhance antitumor immunity.
    Keywords:  Immune resistance; cancer; metabolism; tumor microenvironment
    DOI:  https://doi.org/10.37349/etat.2025.1002297
This page is being maintained by Thomas Krichel. It was last updated on 2025‒03‒23 at 6:14.