bims-imseme 2025-05-18 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2025–05–18
twenty-two papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Malonate promotes CD8+ T cell memory formation via protein malonylation.
GFI1-driven transcriptional and epigenetic programs maintain CD8+ T cell stemness and persistence.
PIM kinase control of CD8 T cell protein synthesis and cell trafficking.
Aging immunity: unraveling the complex nexus of diet, gut microbiome, and immune function.
STAT5 and STAT3 balance shapes dendritic cell function and tumour immunity.
Gfi1 controls the formation of effector-like CD8+ T cells during chronic infection and cancer.
Tissue-specific effects of bacterial PncA overexpression on NAD+ metabolism and aging in mice: implications for tissue-specific aging interventions.
The interplay of cellular senescence and reprogramming shapes the biological landscape of aging and cancer revealing novel therapeutic avenues.
Mitochondria regulate MR1 protein expression and produce self-metabolites that activate MR1-restricted T cells.
Mechanostimulatory Platform for Improved CAR T Cell Immunotherapy.
Sickle cell disease induces chromatin introversion and ferroptosis in CD8+ T cells to suppress anti-tumor immunity.
Targeting of COPⅠ elicits CD8+ T cell-mediated anti-tumor immunity and suppresses growth of intrahepatic cholangiocarcinoma.
Advances in T Cell-Based Cancer Immunotherapy: From Fundamental Mechanisms to Clinical Prospects.
The NF-κB signaling network in the life of T cells.
Inhibition of ENT1 relieves intracellular adenosine-mediated T cell suppression in cancer.
Mitochondrial HSP90 paralog TRAP1 deletion drives glutamine addiction in tumor cells via destablization of the Cys/Glu antiporter SLC7A11/xCT.
Characterization of the aryl hydrocarbon receptor as a potential candidate to improve cancer T cell therapies.
Metabolic reprogramming of interleukin-17-producing γδ T cells promotes ACC1-mediated de novo lipogenesis under psoriatic conditions.
CD8+ T cells in breast cancer tumors and draining lymph nodes: PD-1 levels, effector functions and prognostic relevance.
Lag3 and PD-1 pathways preferentially regulate NFAT-dependent TCR signalling programmes during early CD4+ T cell activation.
TIGIT deficiency promotes autoreactive CD4+ T-cell responses through a metabolic‒epigenetic mechanism in autoimmune myositis.
Age-associated changes in the heart: implications for COVID-19 therapies.

Cell Mol Immunol. 2025 May 14.

Malonate promotes CD8+ T cell memory formation via protein malonylation.

Qianqian Duan, Jiajia Wang, Liang Sun, Zihan Chen, Wenhui Li, Xiaowei Liu, Aijun Zhang, Yong Liu, Lianjun Zhang.

  Protein malonylation represents a recently identified posttranslational modification whose role in CD8+ T cell differentiation and functionality remains incompletely understood. In this study, we demonstrate that enhancing protein malonylation through sodium malonate (SM) treatment promotes CD8+ T cell memory formation in response to bacterial infection, subsequently potentiating recall responses. Comparative metabolomic analysis between SM-treated and control CD8+ T cells revealed significant metabolic alterations associated with protein malonylation. We present the first comprehensive proteomic analysis of lysine malonylation in murine CD8+ T cells, identifying 77 malonylation sites across 64 proteins involved in diverse cellular processes, particularly metabolic pathways. Malonylation of STAT6 was confirmed via the use of a specific chemical probe. Notably, we established that malonylation at the lysine 374 site of STAT6 results in increased TCF1 expression, due to alleviated transcriptional repression of TCF1 by STAT6. Collectively, our findings provide compelling evidence that protein malonylation plays a significant role in regulating CD8+ T cell memory formation.

Keywords:  CD8+ T cell; Malonylation; TCF1; memory differentiation

DOI:  https://doi.org/10.1038/s41423-025-01294-7
Nat Immunol. 2025 May 15.

GFI1-driven transcriptional and epigenetic programs maintain CD8+ T cell stemness and persistence.

M Zeeshan Chaudhry, Evelyn Chen, Hiu On Man, Aneesha Jones, Renae Denman, Huiyang Yu, Qiutong Huang, Adrian Ilich, Jaring Schreuder, Severine Navarro, Zewen K Tuong, Gabrielle T Belz.

Long-lived memory CD8+ T cells are essential for the control of persistent viral infections. The mechanisms that preserve memory cells are poorly understood. Fate mapping of the transcriptional repressor GFI1 identified that GFI1 was differentially regulated in virus-specific CD8+ T cells and was selectively expressed in stem cell memory and central memory cells. Deletion of GFI1 led to reduced proliferation and progressive loss of memory T cells, which in turn resulted in failure to maintain antigen-specific CD8+ T cell populations following infection with chronic lymphocytic choriomeningitis virus or murine cytomegalovirus. Ablation of GFI1 resulted in downregulation of the transcription factors EOMES and BCL-2 in memory CD8+ T cells. Ectopic expression of EOMES rescued the expression of BCL-2, but the persistence of memory CD8+ T cells was only partially rescued. These findings highlight the critical role of GFI1 in the long-term maintenance of memory CD8+ T cells in persistent infections by sustaining their proliferative potential.

DOI: https://doi.org/10.1038/s41590-025-02151-5
Elife. 2025 May 13. pii: RP98622. [Epub ahead of print]13

PIM kinase control of CD8 T cell protein synthesis and cell trafficking.

Julia M Marchingo, Laura Spinelli, Shalini Pathak, Doreen A Cantrell.

  Integration of kinase signalling networks co-ordinates the transcriptional, translational, and metabolic changes required for T cell activation and differentiation. This study explores the role of the Serine/Threonine kinases PIM1 and PIM2 in controlling mouse CD8 T lymphocyte antigen receptor-mediated activation and differentiation in response to the cytokines Interleukin-2 (IL-2) or IL-15. We show that the PIM kinases are dispensable for antigen-receptor and IL-15 controlled differentiation programs, but that they play a selective role in IL-2 regulated CD8 T cell fate. One key insight was that PIM kinases controlled the migratory capabilities of effector CD8 T cells, with Pim1/Pim2-deficient CD8 T cells unable to fully switch off the naive T cell chemokine and adhesion receptor program during effector differentiation. PIM kinases were also needed for IL-2 to sustain high expression of the glucose transporters SLC2A1 and SLC2A3 and to maintain activity of the nutrient-sensing kinase mTORc1. Strikingly, PIM kinases did not have a dominant impact on IL-2-driven transcriptional programs but rather selectively modulated protein synthesis to shape cytotoxic T cell proteomes. This study reveals a selective role of PIM kinases in IL-2 control of CD8 T cells and highlights how regulated changes in protein synthesis can impact T cell phenotypes.

Keywords:  IL-15; IL-2; PIM kinase; T cell; immunology; inflammation; mouse; protein translation; proteomics

DOI:  https://doi.org/10.7554/eLife.98622
Immunometabolism (Cobham). 2025 Apr;7(2): e00061

Aging immunity: unraveling the complex nexus of diet, gut microbiome, and immune function.

Khatereh Babakhani, Amanda L Kucinskas, Xiangcang Ye, Erin D Giles, Yuxiang Sun.

  Aging is associated with immune senescence and gut dysbiosis, both of which are heavily influenced by the diet. In this review, we summarize current knowledge regarding the impact of diets high in fiber, protein, or fat, as well as different dietary components (tryptophan, omega-3 fatty acids, and galacto-oligosaccharides) on the immune system and the gut microbiome in aging. Additionally, this review discusses how aging alters tryptophan metabolism, contributing to changes in immune function and the gut microbiome. Understanding the relationship between diet, the gut microbiome, and immune function in the context of aging is critical to formulate sound dietary recommendations for older individuals, and these personalized nutritional practices will ultimately improve the health and longevity of the elderly.

Keywords:  aging; diet; fat; fiber; galacto-oligosaccharides; gut microbiome; high-fat diet; high-fiber diet; high-protein diet; immune system; omega-3 fatty acids; protein; tryptophan

DOI:  https://doi.org/10.1097/IN9.0000000000000061
Nature. 2025 May 14.

STAT5 and STAT3 balance shapes dendritic cell function and tumour immunity.

Jiajia Zhou, Kole Tison, Haibin Zhou, Longchuan Bai, Ranjan Kumar Acharyya, Donna McEachern, Hoda Metwally, Yu Wang, Michael Pitter, Jae Eun Choi, Linda Vatan, Peng Liao, Jiali Yu, Heng Lin, Long Jiang, Shuang Wei, Xue Gao, Sara Grove, Abhijit Parolia, Marcin Cieslik, Ilona Kryczek, Michael D Green, Jian-Xin Lin, Arul M Chinnaiyan, Warren J Leonard, Shaomeng Wang, Weiping Zou.

Immune checkpoint blockade (ICB) has transformed cancer therapy1,2. The efficacy of immunotherapy depends on dendritic cell-mediated tumour antigen presentation, T cell priming and activation3,4. However, the relationship between the key transcription factors in dendritic cells and ICB efficacy remains unknown. Here we found that ICB reprograms the interplay between the STAT3 and STAT5 transcriptional pathways in dendritic cells, thereby activating T cell immunity and enabling ICB efficacy. Mechanistically, STAT3 restrained the JAK2 and STAT5 transcriptional pathway, determining the fate of dendritic cell function. As STAT3 is often activated in the tumour microenvironment5, we developed two distinct PROTAC (proteolysis-targeting chimera) degraders of STAT3, SD-36 and SD-2301. STAT3 degraders effectively degraded STAT3 in dendritic cells and reprogrammed the dendritic cell-transcriptional network towards immunogenicity. Furthermore, STAT3 degrader monotherapy was efficacious in treatment of advanced tumours and ICB-resistant tumours without toxicity in mice. Thus, the crosstalk between STAT3 and STAT5 transcriptional pathways determines the dendritic cell phenotype in the tumour microenvironment and STAT3 degraders hold promise for cancer immunotherapy.

DOI: https://doi.org/10.1038/s41586-025-09000-3
Nat Commun. 2025 May 15. 16(1): 4542

Gfi1 controls the formation of effector-like CD8+ T cells during chronic infection and cancer.

Oluwagbemiga A Ojo, Hongxing Shen, Jennifer T Ingram, James A Bonner, Robert S Welner, Georges Lacaud, Allan J Zajac, Lewis Z Shi.

During chronic infection and tumor progression, CD8+ T cells lose their effector functions and become exhausted. These exhausted CD8+ T cells are heterogeneous and comprised of progenitors that give rise to effector-like or terminally-exhausted cells. The precise cues and mechanisms directing subset formation are incompletely understood. Here, we show that growth factor independent-1 (Gfi1) is dynamically regulated in exhausted CD8+ T cells. During chronic LCMV Clone 13 infection, a previously under-described Ly108+CX3CR1+ subset expresses low levels of Gfi1 while other established subsets have high expression. Ly108+CX3CR1+ cells possess distinct chromatin profiles and represent a transitory subset that develops to effector-like and terminally-exhausted cells, a process dependent on Gfi1. Similarly, Gfi1 in tumor-infiltrating CD8+ T cells is required for the formation of terminally differentiated cells and endogenous as well as anti-CTLA-induced anti-tumor responses. Taken together, Gfi1 is a key regulator of the subset formation of exhausted CD8+ T cells.

DOI: https://doi.org/10.1038/s41467-025-59784-1
Front Aging. 2025 ;6 1546017

Tissue-specific effects of bacterial PncA overexpression on NAD+ metabolism and aging in mice: implications for tissue-specific aging interventions.

Fengjiao Huo, Meili Zhao, Yue Liu, Shuyao Lv, Shengyu Feng, Liuling Guo, Nan Wang, Shuaishuai Zhang, Qing Liu, Taotao Mi, Hao Wang, Jian-Kang Zhu, Hailiang Liu.

   Background: As a critical molecule in biological systems, nicotinamide adenine dinucleotide (NAD+) influences the aging of mammals. Therefore, regulation of NAD+ synthesis and degradation may slow aging and mitigate related diseases.
Results: This study investigated how mammalian tissues rely on different NAD+ synthesis pathways and prefer specific NAD+ precursors. Overexpressing the bacterial nicotinamidase PncA in mice increased NAD+ levels in the liver and kidneys but decreased levels in the heart and hippocampus. In aged mice (25 months old), this overexpression delayed aging indicators by boosting NAD+ levels in the liver and kidneys, indicating potential for PncA to improve age-related decline in these tissues. However, in younger mice (4 months old), PncA overexpression accelerates the senescence of cardiac cells, resulting in a reduction of NAD + levels, increased aging markers, and cognitive decline. These disparate results underscore the necessity of a nuanced, tissue-specific perspective when contemplating the use of NAD+ precursor supplementation as a means of addressing aging.
Conclusion: Our study highlights the complexity of NAD+ metabolism and its effects on aging in various tissues. It suggests personalized interventions for aging and age-related diseases by showing how different tissues respond to NAD+ precursor manipulation, emphasizing the importance of targeted strategies for optimal therapeutic results with minimal side effects.

Keywords:  aging; nicotinamide; nicotinamide adenine dinucleotide; nicotinic acid; pncA

DOI:  https://doi.org/10.3389/fragi.2025.1546017
Front Cell Dev Biol. 2025 ;13 1593096

The interplay of cellular senescence and reprogramming shapes the biological landscape of aging and cancer revealing novel therapeutic avenues.

Fuan Ding, Ying Yu, Jiangqi Zhao, Shibo Wei, Yan Zhang, Jung Ho Han, Zhuo Li, Hong-Bo Jiang, Dongryeol Ryu, Minkyoung Cho, Sung-Jin Bae, Wonyoung Park, Ki-Tae Ha, Bo Gao.

  Cellular senescence and cellular reprogramming represent two fundamentally intertwined processes that profoundly influence aging and cancer. This paper explores how the permanent cell-cycle arrest of senescent cells and the identity-resetting capacity of reprogramming jointly shape biological outcomes in later life and tumor development. We synthesize recent findings to show that senescent cells, while halting the proliferation of damaged cells, can paradoxically promote tissue dysfunction and malignancy via their secretory phenotype. Conversely, induced reprogramming of somatic cells-exemplified by Yamanaka factors-resets cellular age and epigenetic marks, offering a potential to rejuvenate aged cells. Key findings highlight shared mechanisms (e.g., DNA damage responses and epigenetic remodeling) and bidirectional crosstalk between these processes: senescence signals can facilitate neighboring cell plasticity, whereas reprogramming attempts can trigger intrinsic senescence programs as a barrier. In aging tissues, transient (partial) reprogramming has been shown to erase senescence markers and restore cell function without inducing tumorigenesis, underlining a novel strategy to combat age-related degeneration. In cancer, we discuss how therapy-induced senescence of tumor cells may induce stem-cell-like traits in some cells and drive relapse, revealing a delicate balance between tumor suppression and tumor promotion. Understanding the interplay between senescence and reprogramming is crucial for developing innovative therapies. By targeting the senescence-reprogramming axis-for instance, via senolytic drugs, SASP inhibitors, or safe reprogramming techniques-there is significant therapeutic potential to ameliorate aging-related diseases and improve cancer treatment. Our findings underscore that carefully modulating cellular senescence and rejuvenation processes could pave the way for novel regenerative and anti-cancer strategies.

Keywords:  aging; cancer; cellular senescence; reprogramming; tumor progression

DOI:  https://doi.org/10.3389/fcell.2025.1593096
Proc Natl Acad Sci U S A. 2025 May 20. 122(20): e2418525122

Mitochondria regulate MR1 protein expression and produce self-metabolites that activate MR1-restricted T cells.

Gennaro Prota, Giuliano Berloffa, Wael Awad, Alessandro Vacchini, Andrew Chancellor, Verena Schaefer, Daniel Constantin, Dene R Littler, Rodrigo Colombo, Vladimir Nosi, Lucia Mori, Jamie Rossjohn, Gennaro De Libero.

  Mitochondria coordinate several metabolic pathways, producing metabolites that influence the immune response in various ways. It remains unclear whether mitochondria impact antigen presentation by the MHC-class-I-related antigen-presenting molecule, MR1, which presents small molecules to MR1-restricted T-lymphocytes. Here, we demonstrate that mitochondrial complex III and the enzyme dihydroorotate dehydrogenase are essential for the cell-surface expression of MR1 and for generating uridine- and thymidine-related compounds that bind to MR1 and are produced upon oxidation by reactive oxygen species. One mitochondria-derived immunogenic formylated metabolite we identified is 5-formyl-deoxyuridine (5-FdU). Structural studies indicate that 5-FdU binds in the A'-antigen-binding pocket of MR1, positioning the deoxyribose toward the surface of MR1 for TCR interaction. 5-FdU stimulates specific T cells and detects circulating T cells when loaded onto MR1-tetramers. 5-FdU-reactive cells resemble adaptive T cells and express the phenotypes of naïve, memory, and effector cells, indicating prior in vivo stimulation. These findings suggest that mitochondria may play a role in MR1-mediated immune surveillance.

Keywords:  MR1; T cells; antigen presentation; formylated metabolite; mitochondria

DOI:  https://doi.org/10.1073/pnas.2418525122
Adv Mater. 2025 May 09. e2412482

Mechanostimulatory Platform for Improved CAR T Cell Immunotherapy.

Abed Al-Kader Yassin, Carlos Ureña Martin, Guillaume Le Saux, Ashish Pandey, Sivan Tzadka, Esti Toledo, Jatin Jawhir Pandit, Tomer Sherf, Idan Nusbaum, Baisali Bhattachrya, Rajashri Banerji, Yariv Greenshpan, Muhammad Abu Abu Ahmad, Olga Radinsky, Menachem Sklartz, Roi Gazit, Moshe Elkabets, Sabah Ghassemi, Ofir Cohen, Mark Schvartzman, Angel Porgador.

  Chimeric Antigen Receptor T (CAR T) cell immunotherapy has revolutionized cancer treatment, yet it is hindered by rapid T-cell exhaustion caused by uncontrolled activation during CAR generation. Leveraging insights into T-cell mechanosensing, a novel mechanostimulatory platform is engineered for T-cell activation based on an antigen-carrying surface with controlled elasticity and nanotopography. The platform is designed to optimize and balance T-cell exhaustion, proliferation, and CAR expression. It enhances the differentiation of T cells into the central memory subset, which is crucial for the persistence of CAR T cell therapy's anticancer effects. The platform produces CAR T cells with higher antitumor efficacy, as validated through ex vivo experiments, and with higher in vivo persistence and ability to suppress tumor proliferation, as compared to CAR T cells generated by standard protocols. RNA-seq analysis confirmed an increased transcriptional signature of central memory T cells. Furthermore, this platform completely eliminates T-cell toxicity associated with the non-viral transfection process typically observed with standard activation methods. This platform presents a promising pathway for improving the efficiency and safety of CAR T cell therapy.

Keywords:  CAR T cells; biomaterials; immunotherapy; mechanosensing

DOI:  https://doi.org/10.1002/adma.202412482
Immunity. 2025 May 08. pii: S1074-7613(25)00183-9. [Epub ahead of print]

Sickle cell disease induces chromatin introversion and ferroptosis in CD8+ T cells to suppress anti-tumor immunity.

Zilong Zhao, Benxia Hu, Yalan Deng, Melinda Soeung, Jun Yao, Lanxin Bei, Yaohua Zhang, Pengju Gong, Lisa A Huang, Zhou Jiang, Jian Gao, Shuang Peng, Tina K Nguyen, Menuka Karki, Bora Lim, Cassian Yee, Jared K Burks, Qing Zhang, Li Ma, Jianjun Gao, Nizar M Tannir, Leng Han, Dihua Yu, Linghua Wang, Michael A Curran, Maria A Gubbiotti, Giannicola Genovese, Boyi Gan, Wenbo Li, Pavlos Msaouel, Liuqing Yang, Chunru Lin.

  Understanding how genetic disorders affect CD8+ T cells in the tumor microenvironment is key to improving cancer immunotherapy. Individuals with sickle cell disease (SCD), the most prevalent inherited blood disorder, have a higher risk of developing certain cancers than the general population, but the mechanisms driving this increased risk remain unclear. Our study revealed that SCD altered CD8+ T cell 3D genome architecture, triggering ferroptosis and weakening anti-tumor immunity, thereby promoting tumor growth. Using murine and humanized SCD models, we found that disrupted chromosomal interactions in CD8+ T cells reduced the expression of anti-ferroptotic genes, including SLC7A11 and hydrogen sulfide (H2S) biogenesis genes, thereby increasing susceptibility to ferroptosis. Therapeutic restoration of H2S concentration in SCD mice rescued SLC7A11 expression, mitigated ferroptosis, and enhanced immune and anti-tumor responses. These findings highlight the impact of inherited disorders on cancer immunity and suggest precision immunotherapy strategies for affected individuals.

Keywords:  CD8(+) T cells; H(2)S; Hi-C; SLC7A11; SMARCB1; ferroptosis; genomic architecture alteration; immune checkpoint inhibitors; renal medullary carcinoma; sickle cell disease

DOI:  https://doi.org/10.1016/j.immuni.2025.04.020
Cancer Lett. 2025 May 08. pii: S0304-3835(25)00352-0. [Epub ahead of print]626 217786

Targeting of COPⅠ elicits CD8+ T cell-mediated anti-tumor immunity and suppresses growth of intrahepatic cholangiocarcinoma.

Zehong Chen, Guiqin Xu, Chen Xu, Yun Liu, Zhaojuan Yang, Lvzhu Xiang, You Zuo, Ningqian Zheng, Zhiqian Ye, Wangjie Xu, Yingbin Liu, Yongzhong Liu, Li Zhang.

  Intrahepatic cholangiocarcinoma (iCCA) possesses the immunosuppressive tumor microenvironment (TME) that limits the effectiveness of immunotherapy. Genetic alterations of the coat protein complex Ⅰ (COPⅠ) lead to STING activation and inflammatory immune response. This study aims to address whether targeting COPⅠ can be exploited as a strategy to elicit immune response and inhibit iCCA progression. Here, we demonstrated that the COPⅠ subunits were highly expressed in human and mouse iCCA tissues. Genetic and pharmacological inhibition of COPⅠ suppressed growth of the mouse autochthonous iCCAs driven by activated oncogenes. Disruption of COPⅠ increased T cell presence in tumor environment and elicited anti-tumor T cell response through activating STING-type-I interferon (IFN-I) pathway. Neutralizing CD8+ T cell or STING deletion efficiently counteracted the suppression of iCCA growth by targeting COPⅠ. In addition, the Wnt/β-catenin signaling was dramatically attenuated in tumor cells by STING activation in the context of COPⅠ disruption. Notably, targeting COPⅠ markedly potentiates the therapeutic efficacy of anti-PD-1 in suppressing iCCA growth. In conclusion, our study reveals that targeting COPⅠ effectively suppresses tumor growth by enhancing T cell presence and function in mouse iCCA. STING activation by COPⅠ inhibition dedicates the T cell control of iCCA growth. COPⅠ is a potential target for iCCA treatment.

Keywords:  COPⅠ; Interferon; Sting; Transposon; Tumor environments

DOI:  https://doi.org/10.1016/j.canlet.2025.217786
Mol Pharm. 2025 May 13.

Advances in T Cell-Based Cancer Immunotherapy: From Fundamental Mechanisms to Clinical Prospects.

Kaili Zhang, Yi Zhang, Pan Xiang, Yi Wang, Yifan Li, Shuze Jiang, Yuxuan Zhang, Min Chen, Weijun Su, Xiaoling Li, Shuai Li.

  T cells and their T cell receptors (TCRs) play crucial roles in the adaptive immune system's response against pathogens and tumors. However, immunosenescence, characterized by declining T cell function and quantity with age, significantly impairs antitumor immunity. Recent years have witnessed remarkable progress in T cell-based cancer treatments, driven by a deeper understanding of T cell biology and innovative screening technologies. This review comprehensively examines T cell maturation mechanisms, T cell-mediated antitumor responses, and the implications of thymic involution on T cell diversity and cancer prognosis. We discuss recent advances in adoptive T cell therapies, including tumor-infiltrating lymphocyte (TIL) therapy, engineered T cell receptor (TCR-T) therapy, and chimeric antigen receptor T cell (CAR-T) therapy. Notably, we highlight emerging DNA-encoded library technologies in mammalian cells for high-throughput screening of TCR-antigen interactions, which are revolutionizing the discovery of novel tumor antigens and optimization of TCR affinity. The review also explores strategies to overcome challenges in the solid tumor microenvironment and emerging approaches to enhance the efficacy of T cell therapy. As our understanding of T cell biology deepens and screening technologies advances, T cell-based immunotherapies show increasing promise for delivering durable clinical benefits to a broader patient population.

Keywords:  Adoptive T cell therapy; Cancer immunoediting; DNA-encoded libraries; T cell-based immunotherapy; TCR engineering

DOI:  https://doi.org/10.1021/acs.molpharmaceut.4c01502
Front Immunol. 2025 ;16 1559494

The NF-κB signaling network in the life of T cells.

Mark A Daniels, Emma Teixeiro.

  NF-κB is a crucial transcription factor in lymphocyte signaling. It is activated by environmental cues that drive lymphocyte differentiation to combat infections and cancer. As a key player in inflammation, NF-κB also significantly impacts autoimmunity and transplant rejection, making it an important therapeutic target. While the signaling molecules regulating this pathway are well-studied, the effect of changes in NF-κB signaling levels on T lymphocyte differentiation, fate, and function is not fully understood. Advances in computational biology and new NF-κB-inducible animal models are beginning to clarify these questions. In this review, we highlight recent findings related to T cells, focusing on how environmental cues affecting NF-κB signaling levels determine T cell fate and function.

Keywords:  NF-kB; T cell; differentiation; network; signaling

DOI:  https://doi.org/10.3389/fimmu.2025.1559494
Nat Immunol. 2025 May 12.

Inhibition of ENT1 relieves intracellular adenosine-mediated T cell suppression in cancer.

Theodore J Sanders, Christopher S Nabel, Margreet Brouwer, Annelise L Hermant, Lucas Chaible, Jean-Philippe Deglasse, Nicolas Rosewick, Angélique Pabois, Wilfried Cathou, Aurore Smets, Michael Deligny, João Marchante, Quentin Dubray, Marie-Claire Letellier, Chiara Martinoli, Reece Marillier, Olivier De Henau, Yvonne McGrath, Matthew G Vander Heiden, Erica Houthuys.

The benefit of immune checkpoint blockade for cancer therapy is limited to subsets of patients because of factors including the accumulation of immunosuppressive metabolites, such as adenosine, within tumors. Pharmacological inhibition of adenosine generation and signaling is an active area of clinical investigation, but only limited clinical benefit has been reported. Here, we show that adenosine suppresses anti-cancer T cell responses following uptake into activated T cells by equilibrative nucleoside transporter 1 (ENT1) and inhibition of de novo pyrimidine nucleotide synthesis. We identify EOS301984 as a potent ENT1 antagonist that restores pyrimidine levels in activated T cells in adenosine-rich environments, resulting in enhanced tumor cell killing by memory T cells and increased ex vivo expansion of functional human tumor-infiltrating lymphocytes. A combination of EOS301984 with anti-PD-1 led to synergistic control of tumor growth in a humanized mouse model of triple-negative breast cancer. ENT1 inhibition, therefore, augments anti-cancer immune responses through the restoration of pyrimidine nucleotide synthesis in T cells suppressed by adenosine.

DOI: https://doi.org/10.1038/s41590-025-02153-3
Mol Cancer Res. 2025 May 16.

Mitochondrial HSP90 paralog TRAP1 deletion drives glutamine addiction in tumor cells via destablization of the Cys/Glu antiporter SLC7A11/xCT.

Abhinav Joshi, Li Dai, Marisa Maisiak, Sunmin Lee, Elizabeth Lopez, Takeshi Ito, Len Neckers.

TRAP1, the mitochondrial isoform of HSP90, has emerged as a key regulator of cancer cell metabolism, yet the mechanisms by which it rewires nutrient utilization remain poorly understood. We previously reported that TRAP1 loss increases glutamine dependency of mitochondrial respiration following glucose withdrawal. Here, we investigate how TRAP1 deletion impacts glucose metabolism and the mechanisms enabling glutamine retention to support mitochondrial respiration via reductive carboxylation and the oxidative TCA cycle. TRAP1 knockout (KO) in bladder and prostate cancer cells recapitulates the carbon source-specific metabolic rewiring previously observed. Stable isotope tracing reveals that although glucose oxidation remains functional, TRAP1 KO reduces overall glucose uptake and its contribution to glycolysis and the pentose phosphate pathway. This effect is consistent across multiple cell lines. Concurrently, TRAP1-deficient cells exhibit increased glutamine retention and reliance, potentially due to downregulation of the cystine/glutamate antiporter SLC7A11/xCT. Supporting this, xCT overexpression reduces glutamine-dependent respiration in TRAP1 KO cells. qPCR and proteasome inhibition assays suggest xCT is regulated post-translationally via protein stability. Notably, xCT suppression does not trigger ferroptosis, indicating a selective adaptation rather than induction of cell death. Together, our findings suggest that TRAP1 loss decreases glucose uptake while preserving its metabolic fate, promoting glutamine conservation through xCT downregulation to maintain mitochondrial respiration without inducing ferroptosis. Implications: These results reveal a TRAP1-dependent mechanism of metabolic rewiring in cancer cells and identify xCT-mediated glutamine conservation as a key adaptive response, underscoring TRAP1 as a potential metabolic vulnerability and therapeutic target in tumors with altered nutrient utilization.

DOI: https://doi.org/10.1158/1541-7786.MCR-24-0194
Cancer Immunol Immunother. 2025 May 13. 74(7): 200

Characterization of the aryl hydrocarbon receptor as a potential candidate to improve cancer T cell therapies.

Valentine De Castro, Oumaïma Abdellaoui, Barbara Dehecq, Babacar Ndao, Patricia Mercier-Letondal, Alexandra Dauvé, Francine Garnache-Ottou, Olivier Adotévi, Romain Loyon, Yann Godet.

  The efficacy of T-cell-based cancer therapies can be limited by the tumor microenvironment which can lead to T cell dysfunction. Multiple studies, particularly in murine models, have demonstrated the capacity of the aryl hydrocarbon receptor (AHR) to negatively regulate antitumor T cell functions. AHR is a cytoplasmic receptor and transcription factor that was originally identified as a xenobiotic sensor, but has since been shown to play a significant role in the gene regulation of various immune cells, including T cells. Given the insights from murine studies, AHR emerges as a promising candidate to invalidate for optimizing T cell-based cancer therapies. However, the controversial role of AHR in human T cells underscores the need for a more comprehensive characterization of AHR expressing T cells. This study aims to investigate the regulatory mechanisms of AHR in human T cell biology to better understand its impact on reducing antitumor immune responses. Here, we knocked-out AHR in human T cells using CRISPR-Cas9 technology to characterize AHR's function in an in vitro chronic stimulation model. Engineered T cells exhibited enhanced effector- and memory-like profiles and expressed reduced amount of CD39 and TIGIT. AHR knockout enhanced human CAR-T cells' functionality and persistence upon tumor chronic stimulation. Collectively, these results highlight the role of AHR in human CAR-T cells efficiency.

Keywords:  AHR; CAR-T cell therapy; CRISPR-Cas9; T cell dysfunction

DOI:  https://doi.org/10.1007/s00262-025-04065-5
Nat Metab. 2025 May 13.

Metabolic reprogramming of interleukin-17-producing γδ T cells promotes ACC1-mediated de novo lipogenesis under psoriatic conditions.

Yu-San Kao, Mario Lauterbach, Aleksandra Lopez Krol, Ute Distler, Gloria Janet Godoy, Matthias Klein, Rafael Jose Argüello, Fatima Boukhallouk, Sara Vallejo Fuente, Kathrin Luise Braband, Assel Nurbekova, Monica Romero, Panagiota Mamareli, Luana Silva, Luis Eduardo Alves Damasceno, Francesca Rampoldi, Luciana Berod, Lydia Lynch, Karsten Hiller, Tim Sparwasser.

Metabolic reprogramming determines γδ T cell fate during thymic development; however, the metabolic requirements of interleukin (IL)-17A-producing γδ T cells (γδT17 cells) under psoriatic conditions are unclear. Combining high-throughput techniques, including RNA sequencing, SCENITH, proteomics and stable isotope tracing, we demonstrated that psoriatic inflammation caused γδT17 cells to switch toward aerobic glycolysis. Under psoriatic conditions, γδT17 cells upregulated ATP-citrate synthase to convert citrate to acetyl-CoA, linking carbohydrate metabolism and fatty acid synthesis (FAS). Accordingly, we used a pharmacological inhibitor, Soraphen A, which blocks acetyl-CoA carboxylase (ACC), to impair FAS in γδT17 cells, reducing their intracellular lipid stores and ability to produce IL-17A under psoriatic conditions in vitro. We pinpointed the pathogenic role of ACC1 in γδT17 cells in vivo by genetic ablation, ameliorating inflammation in a psoriatic mouse model. Furthermore, ACC inhibition limited human IL-17A-producing γδT17 cells. Targeting ACC1 to attenuate pathogenic γδT17 cell function has important implications for psoriasis management.

DOI: https://doi.org/10.1038/s42255-025-01276-z
Oncoimmunology. 2025 Dec;14(1): 2502354

CD8+ T cells in breast cancer tumors and draining lymph nodes: PD-1 levels, effector functions and prognostic relevance.

Carolina Abrate, Fernando P Canale, Sabrina N Bossio, Jimena Tosello Boari, María C Ramello, Nicolas Nuñez, Wilfrid Richer, Christine Sedlik, Jordan Denizeau, Anne Vincent-Salomon, Edith Borcoman, Andres Del Castillo, Adriana Gruppi, Eva V Acosta Rodríguez, Eliane Piaggio, Carolina L Montes.

  CD8+ T cells shape the antitumor immune response. Here, we evaluated CD8+ T cells expressing different levels of PD-1, their functional status, and distribution in different tissues of luminal breast cancer (BC) patients. We characterized the exhaustion stages of CD8+ T cells in tumors, juxtatumoral tissues (JTs), and tumor-draining lymph nodes (TDLNs). Terminal exhausted CD8+ T cells (PD-1High CD8+) were predominant in tumors and nearly absent in other tissues. However, in all tissues evaluated, most CD8+ T cells exhibited a pre-exhausted phenotype (PD-1Int CD8+) or did not express PD-1. PD-1High and PD-1Int CD8+ T cells from tumors and JTs presented central and effector memory phenotypes, while in TDLNs were primarily central memory. TCR-β sequencing revealed higher clonality among CD8+ T cells from tumor than TDLNs, with tumor-enriched clones also detected in TDLNs. Analysis of scRNA-seq datasets from tumors and JTs of colorectal and non-small cell lung cancer patients, identified a CD8+ terminal exhaustion and a CD8+ pre-exhausted signatures. High expression of exhaustion-associated genes in BC tumors correlated with improved overall survival. Overall, PD-1 expression effectively distinguishes exhaustion stages in CD8+ T cells. PD-1Int cells found in tumors, JTs, and TDLNs represent a promising therapeutic target for cancer immunotherapy.

Keywords:  Breast cancer; CD8+ T cells; PD-1; draining lymph nodes; exhaustion

DOI:  https://doi.org/10.1080/2162402X.2025.2502354
Immunother Adv. 2025 ;5(1): ltaf015

Lag3 and PD-1 pathways preferentially regulate NFAT-dependent TCR signalling programmes during early CD4+ T cell activation.

Lozan Sheriff, Alastair Copland, David A J Lecky, Reygn Done, Lorna S George, Emma K Jennings, Sophie Rouvray, Thomas A E Elliot, Elizabeth S Jinks, Lalit Pallan, David Bending.

   Introduction: Lag3 and PD-1 are immune checkpoints that regulate T cell responses and are current immunotherapy targets. Yet how they function to control early stages of CD4+ T cell activation remains unclear.
Methods: Here, we show that the PD-1 and Lag3 pathways exhibit layered control of the early CD4+ T cell activation process, with the effects of Lag3 more pronounced in the presence of PD-1 pathway co-blockade (CB). RNA sequencing revealed that CB drove an early NFAT-dependent transcriptional profile, including promotion of ICOShi T follicular helper cell differentiation.
Results: NFAT pathway inhibition abolished CB-induced upregulation of NFAT-dependent co-receptors ICOS and OX40, whilst unaffecting the NFAT-independent gene Nr4a1. Mechanistically, Lag3 and PD-1 pathways functioned additively to regulate the duration of T cell receptor signals during CD4+ T cell re-activation. Phenotypic changes in peripheral blood CD4+ T cells in humans on anti-Lag3 and anti-PD-1 combination therapy revealed upregulation of genes encoding ICOS and OX40 on distinct CD4+ T cell subsets, highlighting the potential translational relevance of our findings.
Conclusion: Our data therefore reveal that PD-1 and Lag3 pathways converge to additively regulate TCR signal duration and may preferentially control NFAT-dependent transcriptional activity during early CD4+ T cell re-activation.

Keywords:  CD4+ T cells; Lag3; NFAT; PD-1; TCR signaling; tolerance

DOI:  https://doi.org/10.1093/immadv/ltaf015
Nat Commun. 2025 May 15. 16(1): 4502

TIGIT deficiency promotes autoreactive CD4+ T-cell responses through a metabolic‒epigenetic mechanism in autoimmune myositis.

Yimei Lai, Shuang Wang, Tingting Ren, Jia Shi, Yichao Qian, Shuyi Wang, Mianjing Zhou, Ryu Watanabe, Mengyuan Li, Xinyuan Ruan, Xin Wang, Lili Zhuang, Zunfu Ke, Niansheng Yang, Yuefang Huang, Hui Zhang.

Polymyositis (PM) is a systemic autoimmune disease characterized by muscular inflammatory infiltrates and degeneration. T-cell immunoreceptor with Ig and ITIM domains (TIGIT) contributes to immune tolerance by inhibiting T cell-mediated autoimmunity. Here, we show that a reduced expression of TIGIT in CD4+ T cells from patients with PM promotes these cells' differentiation into Th1 and Th17 cells, which could be rescued by TIGIT overexpression. Knockout of TIGIT enhances muscle inflammation in a mouse model of experimental autoimmune myositis. Mechanistically, we find that TIGIT deficiency enhances CD28-mediated PI3K/AKT/mTOR co-stimulatory pathway, which promotes glucose oxidation, citrate production, and increased cytosolic acetyl-CoA levels, ultimately inducing epigenetic reprogramming via histone acetylation. Importantly, pharmacological inhibition of histone acetylation suppresses the differentiation of Th1 and Th17 cells, alleviating muscle inflammation. Thus, our findings reveal a mechanism by which TIGIT directly affects the differentiation of Th1 and Th17 T cells through metabolic‒epigenetic reprogramming, with important implications for treating systemic autoimmune diseases.

DOI: https://doi.org/10.1038/s41467-025-59786-z
Aging (Albany NY). 2025 May 13. 17

Age-associated changes in the heart: implications for COVID-19 therapies.

Colby Wood, Zach Saltera, Isaiah Garcia, Michelle Nguyen, Andres Rios, Jacqui Oropeza, Destiny Ugwa, Upasana Mukherjee, Ujala Sehar, P Hemachandra Reddy.

  Cardiac aging involves progressive structural, functional, cellular, and molecular changes that impair heart function. This review explores key mechanisms, including oxidative stress, mitochondrial dysfunction, impaired autophagy, and chronic low-grade inflammation. Excess reactive oxygen species (ROS) damage heart muscle cells, contributing to fibrosis and cellular aging. Mitochondrial dysfunction reduces energy production and increases oxidative stress, accelerating cardiac decline. Impaired autophagy limits the removal of damaged proteins and organelles, while inflammation activates signaling molecules that drive tissue remodeling. Gender differences reveal estrogen's protective role in premenopausal women, with men showing greater susceptibility to heart muscle dysfunction and injury. After menopause, women lose this hormonal protection, increasing their risk of cardiovascular conditions. Ethnic disparities, particularly among underserved minority populations, emphasize how social factors such as access to care, environment, and chronic stress contribute to worsening cardiovascular outcomes. The coronavirus disease pandemic has introduced further challenges by increasing the incidence of heart damage through inflammation, blood clots, and long-term heart failure, especially in older adults with existing metabolic conditions like diabetes and high blood pressure. The virus's interaction with receptors on heart and blood vessel cells, along with a weakened immune response in older adults, intensifies cardiac aging. Emerging therapies include delivery of therapeutic extracellular vesicles, immune cell modulation, and treatments targeting mitochondria. In addition, lifestyle strategies such as regular physical activity, nutritional improvements, and stress reduction remain vital to maintaining cardiac health. Understanding how these biological and social factors intersect is critical to developing targeted strategies that promote healthy aging of the heart.

Keywords:  COVID-19 cardiovascular complications; cardiac aging; health disparities; mitochondrial dysfunction; oxidative stress

DOI:  https://doi.org/10.18632/aging.206251