bims-imseme 2025-05-04 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2025–05–04
twenty papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Gut T cell plasticity generates pathogenic TFH cells that promote systemic autoimmunity.
Impact of mitochondrial metabolism on T-cell dysfunction in chronic lymphocytic leukemia.
Metal-modulated T cell antitumor immunity and emerging metalloimmunotherapy.
CD8+ T Cell Subsets as Biomarkers for Predicting Checkpoint Therapy Outcomes in Cancer Immunotherapy.
Correspondence to editorial "Targeting CD36 to reinvigorate CD8+ T Cells in early-stage hepatocellular carcinoma".
Taurine-driven restoration of metabolic and redox balance in postovulatory aging porcine oocytes: A metabolomic perspective.
miR-143-3p Promotes TSCM Differentiation and Inhibits Progressive T Cell Differentiation via Inhibiting ABL2 and PAG1.
Intracellular metabolic gradients dictate dependence on exogenous pyruvate.
Blockade of TIGAR prevents CD8+ T cell dysfunction and elicits anti-AML immunity.
T-cell phenotype and clonality changes in myeloma patients with short OS.
Regulation of the CD8⁺ T Cell and PDL1/PD1 Axis in Gastric Cancer: Unraveling the Molecular Landscape.
Age reprogramming: Innovations and ethical considerations for prolonged longevity (Review).
CAR Binders Affect CAR T-cell Tonic Signaling, Durability, and Sensitivity to Target.
Single-cell transcriptomic analysis reveals gut microbiota-immunotherapy synergy through modulating tumor microenvironment.
Targeting HMGB2 acts as dual immunomodulator by bolstering CD8+ T cell function and inhibiting tumor growth in hepatocellular carcinoma.
Nicotinic acid riboside maintains NAD+ homeostasis and ameliorates aging-associated NAD+ decline.
KLRG1 identifies regulatory T cells with mitochondrial alterations that accumulate with aging.
The effect of enhanced glycolysis on cardiac aging.
Reprogramming the breast tumor immune microenvironment: cold-to-hot transition for enhanced immunotherapy.
Cytosolic NADK is conditionally essential for folate-dependent nucleotide synthesis.

Nat Immunol. 2025 May;26(5): 657-658

Gut T cell plasticity generates pathogenic TFH cells that promote systemic autoimmunity.

DOI: https://doi.org/10.1038/s41590-025-02147-1
Front Cell Dev Biol. 2025 ;13 1577081

Impact of mitochondrial metabolism on T-cell dysfunction in chronic lymphocytic leukemia.

Wael Gamal, Melanie Mediavilla-Varela, Vishaal Kunta, Eva Sahakian, Javier Pinilla-Ibarz.

  T cells play a central role in anti-tumor immunity, yet their function is often compromised within the immunosuppressive tumor microenvironment, leading to cancer progression and resistance to immunotherapies. T-cell activation and differentiation require dynamic metabolic shifts, with mitochondrial metabolism playing a crucial role in sustaining their function. Research in cancer immunometabolism has revealed key mitochondrial abnormalities in tumor-infiltrating lymphocytes, including reduced mitochondrial capacity, depolarization, structural defects, and elevated reactive oxygen species. While these mitochondrial disruptions are well-characterized in solid tumors and linked to T-cell exhaustion, their impact on T-cell immunity in lymphoproliferative disorders remains underexplored. Chronic lymphocytic leukemia (CLL), the most prevalent chronic adult leukemia, is marked by profound T-cell dysfunction that limits the success of adoptive cell therapies. Emerging studies are shedding light on the role of mitochondrial disturbances in CLL-related T-cell dysfunction, but significant knowledge gaps remain. This review explores mitochondrial metabolism in T-cell exhaustion, emphasizing recent findings in CLL. We also discuss therapeutic strategies to restore T-cell mitochondrial function and identify key research gaps.

Keywords:  CAR T cell; CLL (chronic lymphocytic leukemia); T-cell exhaustion; adoptive cell immunotherapy; cancer; metabolism; mitochondria

DOI:  https://doi.org/10.3389/fcell.2025.1577081
Cancer Metastasis Rev. 2025 Apr 29. 44(2): 49

Metal-modulated T cell antitumor immunity and emerging metalloimmunotherapy.

Peiyun Liao, Ying Zhou, Yingqi Qiu, Rong Hu, Hongyan Li, Hongzhe Sun, Yuhua Li.

  In recent years, increasing evidence has shown that metals play important roles in both innate and adaptive immunity. An emerging concept of metalloimmunotherapy has been proposed, which may accelerate the development of immunotherapy for cancers. Here, we discuss how metals affect T cell function through different signaling pathways. Metals impact the fate of T cells, including their activation, proliferation, cytotoxicity, and differentiation. Most importantly, metals also participate in mitochondrial operation by regulating energy production and reactive oxygen species homeostasis in T cells. We also identified the metal-based mutual effects between tumor cells and T cells in the tumor microenvironment. Overall, the antitumor effect of T cells can be improved by targeting metal metabolism and metalloimmunotherapy, which will be a step forward in the treatment of cancers.

Keywords:  Immunomodulation; Metal ion; Metalloimmunotherapy; T cell; Tumor microenvironment

DOI:  https://doi.org/10.1007/s10555-025-10266-2
Biomedicines. 2025 Apr 09. pii: 930. [Epub ahead of print]13(4):

CD8+ T Cell Subsets as Biomarkers for Predicting Checkpoint Therapy Outcomes in Cancer Immunotherapy.

Rosaely Casalegno Garduño, Alf Spitschak, Tim Pannek, Brigitte M Pützer.

  The advent of immune checkpoint blockade (ICB) has transformed cancer immunotherapy, enabling remarkable long-term outcomes and improved survival, particularly with ICB combination treatments. However, clinical benefits remain confined to a subset of patients, and life-threatening immune-related adverse effects pose a significant challenge. This limited efficacy is attributed to cancer heterogeneity, which is mediated by ligand-receptor interactions, exosomes, secreted factors, and key transcription factors. Oncogenic regulators like E2F1 and MYC drive metastatic tumor environments and intertwine with immunoregulatory pathways, impairing T cell function and reducing immunotherapy effectiveness. To address these challenges, FDA-approved biomarkers, such as tumor mutational burden (TMB) and programmed cell death-ligand 1 (PD-L1) expression, help to identify patients most likely to benefit from ICB. Yet, current biomarkers have limitations, making treatment decisions difficult. Recently, T cells-the primary target of ICB-have emerged as promising biomarkers. This review explores the relationship between cancer drivers and immune response, and emphasizes the role of CD8+ T cells in predicting and monitoring ICB efficacy. Tumor-infiltrating CD8+ T cells correlate with positive clinical outcomes in many cancers, yet obtaining tumor tissue remains complex, limiting its practical use. Conversely, circulating T cell subsets are more accessible and have shown promise as predictive biomarkers. Specifically, memory and progenitor exhausted T cells are associated with favorable immunotherapy responses, while terminally exhausted T cells negatively correlate with ICB efficacy. Ultimately, combining biomarkers enhances predictive accuracy, as demonstrated by integrating TMB/PD-L1 expression with CD8+ T cell frequency. Computational models incorporating cancer and immune signatures could further refine patient stratification, advancing personalized immunotherapy.

Keywords:  CD8+ T cell subsets; ICB; NSCLC; TILs; biomarker; cancer immunotherapy; melanoma

DOI:  https://doi.org/10.3390/biomedicines13040930
Clin Mol Hepatol. 2025 Apr 28.

Correspondence to editorial "Targeting CD36 to reinvigorate CD8+ T Cells in early-stage hepatocellular carcinoma".

Yifei Qin, Peng Lin, Huijie Bian, Zhi-Nan Chen, Jiao Wu.



Keywords:  CD36; CD8+ T dysfunction; Ferroptosis; Hepatocellular carcinoma; Iron accumulation; Lipid peroxidation

DOI:  https://doi.org/10.3350/cmh.2025.0402
Free Radic Biol Med. 2025 Apr 25. pii: S0891-5849(25)00252-7. [Epub ahead of print]235 137-149

Taurine-driven restoration of metabolic and redox balance in postovulatory aging porcine oocytes: A metabolomic perspective.

Zihao Zhang, Feixue Wang, Wenjun Zeng, Zhaokang Cui, Qian Gao, Bingqian Liu, Najun Huang, Xiaofan Sun, Na Li, Bo Xiong, Yilong Miao.

  Oocyte quality is closely linked to metabolic integrity, and age-related metabolic dysregulation is a key factor contributing to oocyte aging. In this study, we utilized non-targeted metabolomics to explore the impact of taurine supplementation on the metabolic profile of postovulatory aging (POA) porcine oocytes. Our analysis revealed that taurine supplementation significantly altered the metabolic landscape, restoring key metabolic pathways associated with energy production, amino acid metabolism, and oxidative stress regulation. Notably, taurine supplementation enhanced mitochondrial function, increased ATP synthesis, and improved the redox balance by upregulating reduced glutathione (GSH) levels and reducing oxidative damage. Metabolomics data also indicated a restoration of critical metabolic intermediates, including those involved in the glutathione synthesis pathway and amino acid metabolism. These findings suggest that taurine can modulate oocyte metabolism, improve cellular energy status, and mitigate oxidative stress, thereby enhancing oocyte quality at the metabolic level.

Keywords:  Metabolomics; Oxidative stress; POA; Porcine oocyte; Taurine

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.04.042
Genes (Basel). 2025 Apr 19. pii: 466. [Epub ahead of print]16(4):

miR-143-3p Promotes TSCM Differentiation and Inhibits Progressive T Cell Differentiation via Inhibiting ABL2 and PAG1.

Wenkai Shi, Jieming Hu, Hongqiong Wang, Huishan Zhong, Wenfeng Zhang, Jinquan Wang, Hongwei Shao, Han Shen, Huaben Bo, Changli Tao, Fenglin Wu.

   BACKGROUND: Adoptive cell therapy (ACT), including CAR-T and TCR-T therapies, shows promise for cancer treatment, depending on infused T cell expansion, persistence and activity. We previously characterized four T-cell subsets (TN, TSCM, TCM and TEM) and their miRNA profiles.
OBJECTIVES: This study investigates miR-143-3p's role in T cell differentiation.
METHODS: Using qPCR, we analyzed miR-143-3p expression. Target genes were validated by dual-luciferase assays. Functional assays assessed differentiation markers, proliferation, apoptosis and cytokine secretion.
RESULTS: miR-143-3p was upregulated in early-differentiated TSCM but downregulated during progression. We confirmed ABL2 and PAG1 as direct targets suppressed by miR-143-3p. Overexpression increased early markers (LEF1, CCR7 and CD62L) while decreasing late markers (EOMES, KLRG1 and CD45RO). It also enhanced proliferation, reduced apoptosis and suppressed cytokine secretion.
CONCLUSIONS: miR-143-3p promotes TSCM differentiation and inhibits progressive differentiation by targeting ABL2/PAG1, suggesting new ACT optimization strategies.

Keywords:  T cell; microRNA; progressive differentiation

DOI:  https://doi.org/10.3390/genes16040466
Nat Metab. 2025 Apr 28.

Intracellular metabolic gradients dictate dependence on exogenous pyruvate.

Benjamin T Jackson, Angela M Montero, Sangita Chakraborty, Julia S Brunner, Paige K Arnold, Anna E Bridgeman, Pavlina K Todorova, Katrina I Paras, Lydia W S Finley.

During developmental transitions, cells frequently remodel metabolic networks, including changing reliance on metabolites such as glucose and glutamine to fuel intracellular metabolic pathways. Here we used embryonic stem (ES) cells as a model system to understand how changes in intracellular metabolic networks that characterize cell state transitions affect reliance on exogenous nutrients. We find that ES cells in the naive ground state of pluripotency increase uptake and reliance on exogenous pyruvate through the monocarboxylate transporter MCT1. Naive ES cells, but not their more committed counterparts, rely on exogenous pyruvate even when other sources of pyruvate (glucose, lactate) are abundant. Pyruvate dependence in naive ES cells is a consequence of their elevated mitochondrial pyruvate consumption at the expense of cytosolic NAD+ regeneration. Indeed, across a range of cell types, increased mitochondrial pyruvate consumption is sufficient to drive demand for extracellular pyruvate. Accordingly, restoring cytosolic NAD+ regeneration allows naive ES cells to tolerate pyruvate depletion in diverse nutrient microenvironments. Together, these data demonstrate that intracellular metabolic gradients dictate uptake and reliance on exogenous pyruvate and highlight mitochondrial pyruvate metabolism as a metabolic vulnerability of naive ES cells.

DOI: https://doi.org/10.1038/s42255-025-01289-8
Cancer Immunol Immunother. 2025 Apr 26. 74(6): 183

Blockade of TIGAR prevents CD8+ T cell dysfunction and elicits anti-AML immunity.

Jialin Cui, Wenjie Liu, Shiyang Zhong, Yiran Fang, Pei Xu, Cheng Xu, Rong Wang, Xingfei Hu, Wanting Zhou, Kening Li, Ming Hong, Sixuan Qian, Qian Sun.

  Acute myeloid leukemia (AML) cells and activated T cells rely on aerobic glycolysis for energy metabolism. The TP53-induced glycolysis and apoptosis regulator (TIGAR) inhibits glycolysis and protects AML cells from apoptosis. Preliminary studies suggest that combining TIGAR inhibition with the glycolysis inhibitor 2-deoxy-D-glucose (2-DG) may offer a therapeutic strategy for AML. However, it remains unclear whether silencing TIGAR can enhance T cell function and thereby improve AML prognosis. This study aims to investigate whether TIGAR silencing in host can eliminate AML cells and rejuvenate dysfunctional T cells with mouse models. TIGAR knockout mice on the C57BL/6J background were generated and AML mouse models were established through intravenous injection of C1498 cells. We found that TIGAR depletion enhanced CD8+ T cell counts and raised CD4/CD8 ratio, downregulating CD44 and immune checkpoints CTLA-4, LAG-3, PD-1 on cell surface of CD8+ T cells. TIGAR depletion boosted cytokine secretion (IFN-γ, perforin, granzyme B, TNF-α) by CD8+ T cells and IL-2, TNF-α by CD4+ T cells, improving cytotoxicity against AML cells, proliferation, and reducing apoptosis. TIGAR suppression in host with 2-DG prolonged AML mouse survival, decreased tumor burden, and leukemic infiltration. TIGAR suppression restored thymic T cell development and peripheral immune balance. Single-cell RNA sequencing analysis also revealed that high TIGAR expression influences the glycolysis pathway, and correlates with markers of T cell exhaustion. This study indicates that blocking TIGAR prevents CD8+ T cell dysfunction and induces anti-AML immunity.

Keywords:  Acute myeloid leukemia; Knockout mice; Single-cell RNA sequencing; T-lymphocytes; TP53-induced glycolysis and apoptosis regulator

DOI:  https://doi.org/10.1007/s00262-025-04042-y
JCI Insight. 2025 Apr 22. pii: e181096. [Epub ahead of print]

T-cell phenotype and clonality changes in myeloma patients with short OS.

Alenka Djarmila Behsen, Esten Nymoen Vandsemb, Tobias Schmidt Slørdahl, Karen Dybkær, Maja Zimmer Jakobsen, Muhammad Kashif, Johan Lund, Vincent Luong, Astrid Marta Olsnes, Anders Waage, Anne Marit Sponaas, Kristine Misund.

  Overall survival (OS) in multiple myeloma (MM) varies between a couple of months to more than 20 years, influenced by tumor characteristics, the tumor microenvironment (TME), and patient factors such as age and frailty. We analyzed sequential BM samples from 45 MM patients with OS < 3 years versus > 8 years using mass cytometry and bulk TCRβ sequencing. Patients with long OS demonstrated stability in the TME and T cell environments, while those with short OS had significant changes at relapse, including fewer T cells, increased Treg cells, and more activated and exhausted CD8 T cells. Notably, higher PD-1 expression in CD8 T cells at diagnosis correlated with short OS. Additionally, short-OS patients exhibited a more monoclonal T cell environment at relapse, with abundance of hyperexpanded clones. These findings reveal distinct immune cell differences between patients with short and long OS.

Keywords:  Cancer; Hematology; Immunology; Oncology; T cell receptor; T cells

DOI:  https://doi.org/10.1172/jci.insight.181096
Crit Rev Oncol Hematol. 2025 Apr 28. pii: S1040-8428(25)00138-6. [Epub ahead of print] 104750

Regulation of the CD8⁺ T Cell and PDL1/PD1 Axis in Gastric Cancer: Unraveling the Molecular Landscape.

Xin Yong, Dong Mu, Hua Ni, Xue Wang, Tongqin Zhang, Xing Chang, Sheng He, Dejiang Zhou.

  Gastric cancer (GC) remains a significant global health burden, mainly due to immune evasion mechanisms within its complex tumor microenvironment (TME). The interaction between CD8⁺ T cells and the PD1/PDL1 axis is central to these mechanisms. CD8⁺ T cells, key players in antitumor immunity, often exhibit impaired functionality in the GC TME, primarily due to PD1-mediated inhibitory signaling induced by PDL1 expressed on tumor and immune cells. Recent findings have elucidated intricate molecular interactions governing PD1 expression on CD8⁺ T cells and the modulation of PDL1 on tumor cells and immune cells by diverse signals such as cytokines, metabolic factors, and noncoding RNAs. While high PD1 expression typically indicates CD8⁺ T cell exhaustion and poor clinical outcomes, recent studies highlight scenarios where elevated PD1 levels correlate with preserved or enhanced T cell cytotoxic activity, suggesting nuanced regulatory pathways. Therapeutic strategies that disrupt PD1/PDL1 interactions, through checkpoint inhibitors or pharmacological modulation, have demonstrated potential in reactivating antitumor responses. However, resistance mechanisms, including altered antigen presentation, metabolic reprogramming, and immunosuppressive cell infiltration, continue to limit efficacy. Emerging combination therapies, biomarker-driven patient stratification, and novel targets like noncoding RNAs and exosomal PDL1 represent promising avenues to enhance treatment effectiveness. This review synthesizes current insights into the molecular regulation of CD8⁺ T cell functionality and the PD1/PDL1 axis, highlighting potential therapeutic strategies to restore antitumor immunity and improve patient outcomes in gastric cancer.

Keywords:  CD8⁺ T cells; Gastric cancer; PD1/PDL1 axis; immune checkpoint inhibitors; tumor microenvironment

DOI:  https://doi.org/10.1016/j.critrevonc.2025.104750
Biomed Rep. 2025 Jun;22(6): 96

Age reprogramming: Innovations and ethical considerations for prolonged longevity (Review).

Timur Saliev, Prim B Singh.

  Age reprogramming and cellular rejuvenation therapies are revolutionizing the approach to aging and age-related diseases. These ground-breaking interventions target fundamental biological processes, including genomic instability, telomere attrition, and mitochondrial dysfunction, to restore cellular function and delay the onset of degenerative conditions. Emerging strategies such as epigenetic reprogramming, gene editing, stem cell therapy, and senolytic drugs show immense promise in extending health spans and potentially reversing aspects of aging. Despite marked progress in preclinical studies and early-stage clinical trials, translating these therapies into practical healthcare solutions presents significant challenges. Key issues include ensuring safety, optimizing delivery mechanisms, overcoming regulatory barriers, and addressing high costs. Moreover, ethical and economic considerations, such as equitable access and societal impacts, must be carefully addressed to prevent widening health disparities. The present review examines the current state of cellular rejuvenation research, highlighting both scientific advancements and the complex challenges associated with these therapies. With interdisciplinary collaboration, robust ethical frameworks, and scalable technological innovations, these therapies have the potential to transform healthcare. By shifting the focus from disease management to proactive health preservation, they offer a future where aging becomes a manageable and equitable process.

Keywords:  CRISPR; age reprogramming; epigenetic; ethics; gene editing; rejuvenation; senolytics; stem cell therapy

DOI:  https://doi.org/10.3892/br.2025.1974
Cancer Immunol Res. 2025 Apr 29. OF1-OF14

CAR Binders Affect CAR T-cell Tonic Signaling, Durability, and Sensitivity to Target.

Divanshu Shukla, Khatuna Gabunia, Shannon E McGettigan, Prachi R Patel, Shannon Christensen, Ting-Jia Fan, Decheng Song, Yanping Luo, Yanling Wang, Huaishan Wang, Regina M Young, Carl H June, John Scholler, James L Riley.

Patients can develop human anti-mouse immune responses against CD19-specific chimeric antigen receptor (CAR) T cells due to the use of a murine CD19-specific single-chain variable fragment to redirect T cells. We screened a yeast display library to identify an array of fully human CD19 single-chain variable fragment binders and performed a series of studies to select the most promising fully human CAR. We observed significant differences in the ability of CARs employing these CD19 binders to be expressed on the cell surface, induce tonic signaling, redirect T-cell function, mediate tumor killing, recognize lower levels of CD19 antigen, and maintain function upon continuous antigen exposure. From this initial analysis, CAR T cells using two binders (42 and 52) were selected for additional studies. Although CAR T cells using both binders controlled tumor growth well in vivo, we advanced a CAR construct using binder 42 for more advanced preclinical testing because of its greater similarity to binders based on the antibody FMC63, which is the murine antibody underlying four FDA-approved CD19-specific CAR T-cell therapies, and ability to robustly respond to tumors expressing lower levels of CD19. We found that this binder uniquely bound CD19 using distinct contact residues than FMC63 and with ∼40-fold lower affinity. CARs using binder 42 were non-inferior to those using the FMC63 binder in a mouse model of acute lymphoblastic leukemia, indicating that CAR T cells using binder 42 should be considered for clinical use.

DOI: https://doi.org/10.1158/2326-6066.CIR-24-1347
Signal Transduct Target Ther. 2025 May 02. 10(1): 140

Single-cell transcriptomic analysis reveals gut microbiota-immunotherapy synergy through modulating tumor microenvironment.

Minyuan Cao, Yun Deng, Qing Hao, Huayun Yan, Quan-Lin Wang, Chunyan Dong, Jing Wu, Yajiao He, Li-Bin Huang, Xuyang Xia, Yongchao Gao, Hai-Ning Chen, Wei-Han Zhang, Yan-Jing Zhang, Xiaozhen Zhuo, Lunzhi Dai, Hongbo Hu, Yong Peng, Feng Zhang, Zhaoqian Liu, Weihua Huang, Huiyuan Zhang, Li Yang, Yang Shu, Wei Zhang, Yan Zhang, Heng Xu.

The gut microbiota crucially regulates the efficacy of immune checkpoint inhibitor (ICI) based immunotherapy, but the underlying mechanisms remain unclear at the single-cell resolution. Using single-cell RNA sequencing and subsequent validations, we investigate gut microbiota-ICI synergy by profiling the tumor microenvironment (TME) and elucidating critical cellular interactions in mouse models. Our findings reveal that intact gut microbiota combined with ICIs may synergistically increase the proportions of CD8+, CD4+, and γδ T cells, reduce glycolysis metabolism, and reverse exhausted CD8+ T cells into memory/effector CD8+ T cells, enhancing antitumor response. This synergistic effect also induces macrophage reprogramming from M2 protumor Spp1+ tumor-associated macrophages (TAMs) to Cd74+ TAMs, which act as antigen-presenting cells (APCs). These macrophage subtypes show a negative correlation within tumors, particularly during fecal microbiota transplantation. Depleting Spp1+ TAMs in Spp1 conditional knockout mice boosts ICI efficacy and T cell infiltration, regardless of gut microbiota status, suggesting a potential upstream role of the gut microbiota and highlighting the crucial negative impact of Spp1+ TAMs during macrophage reprogramming on immunotherapy outcomes. Mechanistically, we propose a γδ T cell-APC-CD8+ T cell axis, where gut microbiota and ICIs enhance Cd40lg expression on γδ T cells, activating Cd40 overexpressing APCs (e.g., Cd74+ TAMs) through CD40-CD40L-related NF-κB signaling and boosting CD8+ T cell responses via CD86-CD28 interactions. These findings highlight the potential importance of γδ T cells and SPP1-related macrophage reprogramming in activating CD8+ T cells, as well as the synergistic effect of gut microbiota and ICIs in immunotherapy through modulating the TME.

DOI: https://doi.org/10.1038/s41392-025-02226-7
Sci Adv. 2025 May 02. 11(18): eads8597

Targeting HMGB2 acts as dual immunomodulator by bolstering CD8+ T cell function and inhibiting tumor growth in hepatocellular carcinoma.

Wei-Feng Qu, Gui-Qi Zhu, Rui Yang, Tian-Hao Chu, Zhi-Qi Guan, Run Huang, Meng-Xin Tian, Xi-Fei Jiang, Chen-Yang Tao, Yuan Fang, Jun Gao, Xiao-Ling Wu, Jia-Feng Chen, Qian-Fu Zhao, Yi Wang, Yi-Chao Bu, Jian Zhou, Jia Fan, Wei-Ren Liu, Zheng Tang, Ying-Hong Shi.

T cell exhaustion is a critical obstacle for durable treatment response in hepatocellular carcinoma (HCC). Developing drugs that control tumor growth and simultaneously bolster immune function is of great significance. Although high-mobility group box 2 (HMGB2) has been reported to be crucial to HCC prognosis, its role in the tumor microenvironment remains unclear. Here, we found HMGB2+ CD8+ T cells as being associated with immune exhaustion and resistance to anti-PD-1 treatment through single-cell RNA sequencing. Mechanistically, HMGB2 impaired the oxidative phosphorylation in CD8+ T cells and inactivated the interferon-γ response in tumor cells, reducing the antitumor effector function. Tannic acid, a specific inhibitor of HMGB2, synergized with PD-1 antibody to attenuate tumor growth and reverse T cell exhaustion. Our findings highlight the unique role of HMGB2 as an immune exhaustion associated molecule. Targeting HMGB2 on both CD8+ T cells and tumor cells contributed to promising treatment strategies for HCC.

DOI: https://doi.org/10.1126/sciadv.ads8597
Cell Metab. 2025 Apr 25. pii: S1550-4131(25)00217-7. [Epub ahead of print]

Nicotinic acid riboside maintains NAD+ homeostasis and ameliorates aging-associated NAD+ decline.

Won-Suk Song, Xiyu Shen, Kang Du, Cuauhtemoc B Ramirez, Sang Hee Park, Yang Cao, Johnny Le, Hosung Bae, Joohwan Kim, Yujin Chun, Nikki Joyce Khong, Marie Kim, Sunhee Jung, Wonsuk Choi, Miranda L Lopez, Zaid Said, Zehan Song, Sang-Guk Lee, Dequina Nicholas, Yo Sasaki, Jeffrey Milbrandt, David K Imagawa, Dorota Skowronska-Krawczyk, Danica Chen, Gina Lee, Cholsoon Jang, Qin Yang.

  Liver-derived circulating nicotinamide from nicotinamide adenine dinucleotide (NAD+) catabolism primarily feeds systemic organs for NAD+ synthesis. We surprisingly found that, despite blunted hepatic NAD+ and nicotinamide production in liver-specific nicotinamide nucleotide adenylyltransferase 1 (NMNAT1) deletion mice (liver-specific knockout [LKO]), circulating nicotinamide and extra-hepatic organs' NAD+ are unaffected. Metabolomics reveals a massive accumulation of a novel molecule in the LKO liver, which we identify as nicotinic acid riboside (NaR). We further demonstrate cytosolic 5'-nucleotidase II (NT5C2) as the NaR-producing enzyme. The liver releases NaR to the bloodstream, and kidneys take up NaR to synthesize NAD+ through nicotinamide riboside kinase 1 (NRK1) and replenish circulating nicotinamide. Serum NaR levels decline with aging, whereas oral NaR supplementation in aged mice boosts serum nicotinamide and multi-organ NAD+, including kidneys, and reduces kidney inflammation and albuminuria. Thus, the liver-kidney axis maintains systemic NAD+ homeostasis via circulating NaR, and NaR supplement ameliorates aging-associated NAD+ decline and kidney dysfunction.

Keywords:  NAD(+); aging; kidney; liver; nicotinic acid riboside

DOI:  https://doi.org/10.1016/j.cmet.2025.04.007
Nat Aging. 2025 Apr 30.

KLRG1 identifies regulatory T cells with mitochondrial alterations that accumulate with aging.

Gonzalo Soto-Heredero, Enrique Gabandé-Rodríguez, Elisa Carrasco, José Ignacio Escrig-Larena, Manuel M Gómez de Las Heras, Sandra Delgado-Pulido, Isaac Francos-Quijorna, Eva M Blanco, Álvaro Fernández-Almeida, David Abia, María Josefa Rodríguez, Cristina M Fernández-Díaz, María Beatriz Álvarez-Flores, Ana Ramírez de Molina, Sascha Jung, Antonio Del Sol, Virginia Zorita, Fátima Sánchez-Cabo, Carlos Torroja, María Mittelbrunn.

Recent studies using single-cell RNA sequencing technology have uncovered several subpopulations of CD4+ T cells that accumulate with aging. These age-associated T cells are emerging as relevant players in the onset of inflammaging and tissue senescence. Here, based on information provided by single-cell RNA sequencing data, we present a flow cytometry panel that allows the identification of age-associated T cell subsets in systematic larger analysis in mice. We use this panel to evaluate at the single-cell level mitochondrial and senescence marks in the different age-associated CD4+ T cell subpopulations. Our analysis identifies a subpopulation of regulatory T (Treg) cells that is characterized by the extracellular expression of the co-inhibitory molecule killer cell lectin-like receptor subfamily G member 1 (KLRG1) and accumulates with aging in humans and mice. KLRG1-expressing Treg cells display senescence features such as mitochondrial alterations, increased expression of cell-cycle regulators and genomic DNA damage. Functionally, KLRG1+ Treg cells show a reduced suppressive activity in vivo accompanied by a pro-inflammatory phenotype.

DOI: https://doi.org/10.1038/s43587-025-00855-9
Geroscience. 2025 May 01.

The effect of enhanced glycolysis on cardiac aging.

Anna Faakye, Kylene M Harold, Satoshi Matsuzaki, Atul Pranay, Maria F Mendez Garcia, Brooke L Loveland, Sandra N Rigsby, Frederick F Peelor, Craig Eyster, Benjamin F Miller, Timothy M Griffin, Michael Kinter, Ying Ann Chiao, Kenneth M Humphries.

  Cardiac aging is associated with metabolic changes, including an increased reliance on glycolysis, and an increased susceptibility to cardiovascular diseases. This study explores the relationship between enhanced cardiac glycolysis and aging using the GlycoHi mouse model, characterized by constitutively elevated glycolysis. We compared cardiac function, metabolism, mitochondrial performance, and hallmarks of aging between aged (21 and 24 months) GlycoHi and wild-type (WT) mice across sexes. Our findings reveal modest reductions in cardiac function in aged GlycoHi mice compared to WT mice, with sex-specific differences in heart size and collagen concentration. Female GlycoHi hearts exhibited hypertrophy without fibrosis, while males showed elevated collagen levels. Whole-body metabolic assessments revealed similar energy expenditure and respiratory patterns across genotypes, with females displaying less circadian-associated variation in metabolism. Mitochondrial analyses showed that aged GlycoHi hearts maintained metabolic adaptations favoring glycolysis but did not exhibit significant bioenergetic dysfunction or oxidative stress. Pyruvate dehydrogenase activity, initially elevated in younger GlycoHi hearts, normalized to WT levels with age. Proteomic and metabolomic analyses highlighted distinct profiles between genotypes, with GlycoHi hearts exhibiting increased glycolytic enzyme levels and reduced abundance of fatty acid oxidation proteins. Despite these differences, indicators of oxidative stress, proteostasis, and cellular senescence were comparable between genotypes, suggesting no acceleration of aging-related dysfunction. This study demonstrates that increased cardiac glycolysis alone does not suffice to drive accelerated cardiac aging. Instead, metabolic and functional changes in aged GlycoHi hearts reflect adaptations rather than pathological declines, providing insights into potential metabolic targets for interventions against cardiac aging.

Keywords:  Cardiac aging; Glycolysis; Mitochondria; Oxidative stress; Proteostasis

DOI:  https://doi.org/10.1007/s11357-025-01656-z
J Exp Clin Cancer Res. 2025 Apr 25. 44(1): 131

Reprogramming the breast tumor immune microenvironment: cold-to-hot transition for enhanced immunotherapy.

Saber Imani, Reyhaneh Farghadani, Ghazaal Roozitalab, Mazaher Maghsoudloo, Mahdieh Emadi, Atefeh Moradi, Behnaz Abedi, Parham Jabbarzadeh Kaboli.

  This review discusses reprogramming the breast tumor immune microenvironment from an immunosuppressive cold state to an immunologically active hot state. A complex interplay is revealed, in which the accumulation of metabolic byproducts-such as lactate, reactive oxygen species (ROS), and ammonia-is shown to impair T-cell function and promote tumor immune escape. It is demonstrated that the tumor microenvironment (TME) is dominated by immunosuppressive cytokines, including interleukin-10 (IL-10), transforming growth factorβ (TGFβ), and IL-35. Notably, IL-35 is produced by regulatory T cells and breast cancer cells. The conversion of conventional T cells into IL-35-producing induced regulatory T cells, along with the inhibition of pro-inflammatory cytokine secretion, contributes to the suppression of anti-tumor immunity. It is further demonstrated that key immune checkpoint molecules-such as PD-1, PDL1, CTLA-4, TIM-3, LAG-3, and TIGIT-are upregulated within the TME, leading to Tcell exhaustion and diminished immune responses. The blockade of these checkpoints is shown to restore T-cell functionality and is proposed as a strategy to convert cold tumors into hot ones with robust effector cell infiltration. The therapeutic potential of chimeric antigen receptor (CAR)T cell therapy is also explored, and targeting specific tumor-associated antigens, such as glycoproteins and receptor tyrosine kinases, is highlighted. It is suggested that CART cell efficacy can be enhanced by combining these cells with immune checkpoint inhibitors and other immunomodulatory agents, thereby overcoming the barriers imposed by the immunosuppressive TME. Moreover, the role of the microbiome in regulating estrogen metabolism and systemic inflammation is reviewed. Alterations in the gut microbiota are shown to affect the TME, and microbiome-based interventions are proposed as an additional means to facilitate the cold-to-hot transition. It is concluded that by targeting the metabolic and immunological pathways that underpin immune suppression-through combination strategies involving checkpoint blockade, CART cell therapies, and microbiome modulation-the conversion of the breast TME from cold to hot can be achieved. This reprogramming is anticipated to enhance immune cell infiltration and function, thereby improving the overall efficacy of immunotherapies and leading to better clinical outcomes for breast cancer patients.

Keywords:  Breast cancer; Cancer vaccine; Cold tumor; Hot tumor; Immune checkpoint; Immunotherapy

DOI:  https://doi.org/10.1186/s13046-025-03394-8
Nat Metab. 2025 May 02.

Cytosolic NADK is conditionally essential for folate-dependent nucleotide synthesis.

Kyle M Flickinger, Carlos A Mellado Fritz, Kimberly S Huggler, Gina M Wade, Gavin R Chang, Kathryn C Fox, Judith A Simcox, Jason R Cantor.

Nicotinamide adenine dinucleotide kinase (NADK) catalyses the phosphorylation of NAD+ to produce NAD phosphate, the oxidized form of NADPH, a cofactor that serves a critical role in driving reductive metabolism. Cancer cells co-express two distinct NAD kinases that differ by localization (NADK, cytosol; NADK2, mitochondria). CRISPR screens performed across hundreds of cancer cell lines indicate that both are dispensable for growth in conventional culture media. By contrast, NADK deletion impaired cell growth in human plasma-like medium. Here we trace this conditional NADK dependence to the availability of folic acid. NADPH is the preferred cofactor of dihydrofolate reductase (DHFR), the enzyme that mediates metabolic activation of folic acid. We find that NADK is required for enabling cytosolic NADPH-driven DHFR activity sufficient to maintain folate-dependent nucleotide synthesis under low folic acid conditions. Our results reveal a basis for conditional NADK essentiality and suggest that folate availability determines whether DHFR activity can be sustained by alternative electron donors such as NADH.

DOI: https://doi.org/10.1038/s42255-025-01272-3