bims-imseme 2025-06-08 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2025–06–08
27 papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Lactate dehydrogenase B facilitates disulfidptosis and exhaustion of tumour-infiltrating CD8+ T cells.
Deciphering the deterministic role of TCR signaling in T cell fate determination.
The STING-activating nanofactory relieves T cell exhaustion in Mn-based tumor immunotherapy by regulating mitochondrial dysfunction.
HDAC1 controls the generation and maintenance of effector-like CD8+ T cells during chronic viral infection.
Immunometabolism of regulatory T cells in cancer.
Splenic fibroblastic reticular cells orchestrate dendritic cell maturation and facilitate CD8+ T cell priming and protective memory.
In vivo labeling reveals that degranulation is increased under supraphysiological TCR stimulation, but not infection, in CD8+ T cells from old mice.
SIRT4 Controls Macrophage Function and Wound Healing through Control of Protein Itaconylation in Mice.
TIM3-blockade synergizes with IL2 in alleviating intra-tumoral CD8+T cell exhaustion.
Cancer-fighting CAR T cells show promising results for hard-to-treat tumours.
An Il12 mRNA-LNP adjuvant enhances mRNA vaccine-induced CD8 T cell responses.
Inhibition of Cholesterol Synthesis in T Cells Protects the Liver Against Steatosis, Inflammation, and Oxidative Stress in Metabolic Dysfunction-Associated Steatohepatitis.
Editing epigenetic age.
Unraveling the interplay between sleep, redox metabolism, and aging: implications for brain health and longevity.
CAR T cells affect cognition.
Mechanisms and implications of vascular-homing CD8 T cells in atherosclerosis.
Targeting Regnase-1 unleashes CAR T cell antitumor activity for osteosarcoma and creates a proinflammatory tumor microenvironment.
Membrane-IL12 adjuvant mRNA vaccine polarizes pre-effector T cells for optimized tumor control.
KMT2D coordinates antiviral CD4+ T cell responses through opposing effects on T follicular helper and cytotoxic gene expression.
Spatiotemporal Charging Single-Atom Nanozymes Activated Pyroptosis for Antitumor Immunotherapy via Bioorthogonal Disruption of Succination and Reinvigorating T Lymphocytes.
Targeting intramyocellular lipids to improve aging muscle function.
Revolutionising cancer intervention: the repercussions of CAR-T cell therapy on modern oncology practices.
Multi-engineered T cell vaccine boosting TCR-T cell therapy enhances anti-tumor function and eradicates heterogeneous solid tumors.
RUNX1/SLAMF3 Axis Drives Immunosuppression to Contribute to Colorectal Cancer Liver Metastasis by Blocking Phagocytosis and Depleting C1QC+ Tumor-Associated Macrophages.
Cysteine depletion triggers adipose tissue thermogenesis and weight loss.
Disrupted priming within draining lymph nodes drives immune quiescence in gastric cancer.
IFN-γ-resistant CD28 CAR T cells demonstrate increased survival, efficacy, and durability in multiple murine tumor models.

Nat Cell Biol. 2025 Jun 03.

Lactate dehydrogenase B facilitates disulfidptosis and exhaustion of tumour-infiltrating CD8+ T cells.

Jie Wan, Jian-Hong Shi, Min Shi, Haiyan Huang, Zhen Zhang, Wenyan Li, Chenyue Guo, Rujuan Bao, Xiaoyan Yu, Qiaoqiao Han, Xian Du, Song Li, Youqiong Ye, Xingang Cui, Xia Li, Jing-Hua Li, Qiang Zou.

The aberrant accumulation of intracellular disulfides promotes cancer cell disulfidptosis; however, how disulfide stress influences tumour-infiltrating CD8+ T cell function remains unknown. Here we demonstrate that lactate dehydrogenase B (LDHB) facilitates intratumoural CD8+ T cell disulfidptosis and exhaustion, leading to impaired antitumour immunity. SLC7A11-mediated cystine uptake by CD8+ T cells induces disulfidptosis, which plays critical roles in the development of exhausted CD8+ T cells. LDHB restricts glucose-6-phosphate dehydrogenase (G6PD) activity in exhausted CD8+ T cells by interacting with G6PD, causing NADPH depletion and consequently triggering disulfidptosis. Accordingly, the loss of LDHB in T cells prevents disulfidptosis-dependent CD8+ T cell exhaustion and improves antitumour immunity. Mechanistically, STAT3 directs LDHB expression to limit G6PD activity and mediate disulfidptosis in exhausted CD8+ T cells. Our results highlight the distinct roles of disulfidptosis and ferroptosis in driving CD8+ T cell exhaustion and suggest a potential therapeutic strategy to target LDHB in cancer immunotherapy.

DOI: https://doi.org/10.1038/s41556-025-01673-2
Front Immunol. 2025 ;16 1562248

Deciphering the deterministic role of TCR signaling in T cell fate determination.

Zhen Qin, Tao Xu.

  T cell receptor (TCR) signaling, also known as signal 1, plays a crucial role in the activation and proliferation of T cells. The question of whether TCR signaling exerts a deterministic role in T cell fate determination is an area of active investigation. It has been particularly challenging to address this question due to the complexities associated with genetic manipulation of TCR signaling components, which often disrupts thymic T cell development or impairs T cell activation upon TCR engagement. Recent study demonstrates that the TCR-Lck/Fyn axis directly induces STAT3 phosphorylation and synergizes with pro-inflammatory cytokines to optimize STAT3 phosphorylation during Th17 cell differentiation. Additionally, the TCR-Lck/Fyn-AKT/mTOR axis negatively regulates Treg cell differentiation. In CD8+ T cells, persistent high-affinity antigen stimulation drives differentiation along the exhaustion pathway, while acute infection or intermediate antigen levels promote differentiation into effector and memory T cells, although the underlying mechanism remains to be fully elucidated. Collectively, these studies provide compelling evidence that TCR signaling has a deterministic impact on T cell fate. This review summarizes recent advances in understanding how TCR signaling shapes T cell fate determination.

Keywords:  T cell differentiation; T cell exhaustion; T cell fate; TCR signal strength; TCR signaling; Tpex; immunometabolism; memory T cells

DOI:  https://doi.org/10.3389/fimmu.2025.1562248
J Nanobiotechnology. 2025 May 31. 23(1): 403

The STING-activating nanofactory relieves T cell exhaustion in Mn-based tumor immunotherapy by regulating mitochondrial dysfunction.

Nana Chen, Yushan Yang, Limin Fan, Yanni Cai, Weimin Yin, Zichen Yang, Yuge Zhao, Shiyu Chen, Hui Zhi, Liangyi Xue, Xiaoyou Zhang, Lulu An, Yongyong Li, Tianbin Ren.

  Manganese-based STING-activating tumor immunotherapy faces limitations due to T cell exhaustion. Mitochondrial dysfunction is a key factor contributing to T cell exhaustion. Modulating mitochondrial function during manganese-based immunotherapy offers a promising strategy to reverse T cell exhaustion. Spermidine (SPD) enhances mitochondrial function in T cells, making the co-delivery of Mn and SPD a potential therapeutic approach. However, intravenous co-delivery is hindered by the rapid formation of MnO(OH)₂ precipitates. In this study, liposomes were employed as nano-reactors to facilitate the reaction between pre-loaded Mn²⁺ and O₂ in the presence of SPD, forming MnO(OH)₂ precipitates within the liposomes. These liposomes function as nanofactories, further processing MnO(OH)₂ under the regulation of the tumor microenvironment (TME) and delivering Mn, SPD, and O₂. Beyond activating the STING pathway in dendritic cells, L@Mn@SPD alleviates TME hypoxia and effectively reverses CD8⁺ T cell exhaustion. In vivo, L@Mn@SPD achieved a 2.44-fold increase in tumor suppression compared to MnCl₂, along with a 47% rise in CD8⁺ T cell infiltration, a 62.1% reduction in PD-1 expression, and a 110% increase in IFN-γ secretion. This STING-activating nanofactory provides a promising strategy to enhance manganese-based tumor immunotherapy by addressing mitochondrial dysfunction in exhausted T cells.

Keywords:  Liposome; Mitochondrial dysfunction; Mn-based tumor immunotherapy; STING pathway; T cell exhaustion

DOI:  https://doi.org/10.1186/s12951-025-03469-w
J Exp Med. 2025 Aug 04. pii: e20240829. [Epub ahead of print]222(8):

HDAC1 controls the generation and maintenance of effector-like CD8+ T cells during chronic viral infection.

Ramona Rica, Monika Waldherr, Emi Miyakoda, Ana Patricia Kutschat, Marlene Schülein, Jing Zhang, Ricardo Alfredo Orbegozo-Medina, Lisa Sandner, Valentina Stolz, Darina Waltenberger, Thomas Krausgruber, Christoph Bock, Nicole Boucheron, Davide Seruggia, Wilfried Ellmeier, Shinya Sakaguchi.

CD8+ T cell exhaustion is a complex process involving the differentiation of persistently activated CD8+ T cells into functionally distinct cell subsets. Here, we investigated the role of the key epigenetic regulator histone deacetylase 1 (HDAC1) in the differentiation of exhausted T (Tex) cells during chronic viral infection. We uncovered that HDAC1 controls the generation and maintenance of effector-like CX3CR1+ Tex cells in a CD8+ T cell-intrinsic manner. Deletion of HDAC1 led to expansion of an alternative Tex subset characterized by high expression of T cell exhaustion markers, and this was accompanied by elevated viremia. HDAC1 bound to and facilitated an open chromatin state of effector-like signature gene loci in progenitor Tex cells, thereby priming cell fate specification toward the CX3CR1+ Tex subset. Our study uncovers a selective role for HDAC1 in CX3CR1+ Tex subset differentiation, which is essential for controlling viral load during chronic infection.

DOI: https://doi.org/10.1084/jem.20240829
Oncogene. 2025 Jun 04.

Immunometabolism of regulatory T cells in cancer.

Jordy Saravia, Hongbo Chi.

Regulatory T (Treg) cells play critical roles in maintaining immune tolerance and tissue homeostasis, but impede anti-tumor immunity. Recent work has established how Treg cells metabolically adapt within the tumor microenvironment (TME), and these adaptations frequently provide a functional advantage over effector T cells. Further, enhanced Treg cell function in the TME may contribute to the limited efficacy of current immunotherapies, especially immune checkpoint blockade (ICB). Here, we review recent progress in understanding mechanisms of Treg cell heterogeneity and function in tumors, with a particular focus on cellular metabolism as an underlying factor by which Treg cells are uniquely poised to thrive in the TME and contribute to tumorigenesis. We describe how cellular metabolism and nutrient or metabolic communication shape Treg cell lineage identity and function in the TME. We also discuss the interplay between ICB and Treg cell metabolism and function, and highlight current strategies targeting Treg cell metabolism specifically in the TME. Understanding metabolic control of intratumoral Treg cells provides excellent opportunities to uncover new or combination therapies for cancer.

DOI: https://doi.org/10.1038/s41388-025-03458-1
Sci Adv. 2025 Jun 06. 11(23): eadt5939

Splenic fibroblastic reticular cells orchestrate dendritic cell maturation and facilitate CD8+ T cell priming and protective memory.

Yannick O Alexandre, Nikita Potemkin, Dominik Schienstock, Baptiste Duchamp, Annika Poch, Susan N Christo, Shihan Li, Lei Qin, Lynette Beattie, Daniel T Utzschneider, Masahiro Ono, Jan Schröder, Laura K Mackay, Scott N Mueller.

Fibroblastic reticular cells (FRCs) are specialized fibroblasts that construct secondary lymphoid organs where they provide crucial signals for immune cell homeostasis and migration. While splenic FRCs are thought to support antiviral T cell responses, their role remains unclear. Here, we found that ablation of splenic FRCs impaired virus-specific CD8+ T cell responses during lymphocytic choriomeningitis virus (LCMV) infection. Immunofluorescence imaging revealed that FRCs promote CD8+ T cell clustering with type 1 conventional dendritic cells (cDC1) in the T cell zone before migration to the infected marginal zone. Without FRCs, T cells instead clustered with cDC1 and virus-infected cells in the marginal zone, leading to suboptimal priming. Mechanistically, FRCs coordinated early viral replication and the inflammatory milieu for optimal DC activation, and an intact FRC network was crucial for generating effector T cells and maintaining protective memory T cells. Thus, splenic FRCs provide essential lymphoid niches for antiviral T cell responses.

DOI: https://doi.org/10.1126/sciadv.adt5939
Geroscience. 2025 Jun 06.

In vivo labeling reveals that degranulation is increased under supraphysiological TCR stimulation, but not infection, in CD8+ T cells from old mice.

Korbyn J V Dahlquist, Emma M Dehm, Declan M Smith, Erin D Lucas, Mark Pierson, Sara E Hamilton, Christina D Camell.

  CD8+ T cells exhibit distinct changes with aging, including a diminished naïve cell pool, an expansion of memory and exhausted cells, and altered effector molecule production, altogether leading to increased susceptibility to infection. They have reduced cytotoxicity in vivo, but increased granule content and faster cytotoxic kinetics to target cells in vitro. Whether CD8+ T cells from old mice degranulate when activated in vivo, within the aged environment, is unknown. This study investigates in vitro and in vivo degranulation of CD8+ T cells from young and old mice during supraphysiological aCD3 stimulation and two types of infection. Actively degranulating CD8+ CD44+ T cells were identified by positive labeling after a two-hour exposure to granule-specific fluorescent antibodies (CD107a and CD107b). Surprisingly, CD8+ T cells from old mice challenged with supraphysiological TCR-specific stimulation exhibited higher levels of degranulation as compared to their young counterparts. This effect is more prominent in vitro and can be partially explained by the age-specific increase in CD8+ CD44+ CD62L- cells. However, during microbial exposure or LCMV Armstrong infection, we show that CD8+ CD44+ and antigen-specific T cells from old mice have reduced degranulation, consistent with the diminished cytotoxic capacity. These data highlight the preserved intrinsic cytotoxic capacity of memory CD8+ T cells from old mice and suggest that the aged microenvironment and type of stimulation are contributing factors to the lower degranulation and cytotoxic capacity of these cells. This provides insight into the potential of increasing T cell activation to improve vaccine approaches in the elderly.

Keywords:  Aging; CD8+ T cells; Cytotoxicity; Degranulation; Infection

DOI:  https://doi.org/10.1007/s11357-025-01723-5
bioRxiv. 2025 May 13. pii: 2025.05.12.653532. [Epub ahead of print]

SIRT4 Controls Macrophage Function and Wound Healing through Control of Protein Itaconylation in Mice.

Kristin A Anderson, Beverly deSouza, Pol Castellano-Escuder, Zhihong Lin, Olga R Ilkayeva, Michael J Muehlbauer, Paul A Grimsrud, Matthew D Hirschey.

Proper regulation of inflammatory responses is essential for organismal health. Dysregulation can lead to accelerated development of the diseases of aging and the aging process itself. Here, we identify a novel enzymatic activity of the mitochondrial sirtuin SIRT4 as a lysine deitaconylase that regulates macrophage inflammatory responses. Itaconate is a metabolite abundantly produced in activated macrophages. We find it forms a protein modification called lysine itaconylation. Using biochemical and proteomics approaches, we demonstrate that SIRT4 efficiently removes this modification from target proteins both in vitro and in vivo . In macrophages, elevated protein itaconylation increases upon LPS stimulation, coinciding with elevated SIRT4 expression. SIRT4-deficient macrophages exhibit significantly increased IL-1β production in response to LPS stimulation. This phenotype is intrinsic to macrophages, as demonstrated by both lentiviral over-expression and acute SIRT4 knockdown models. Mechanistically, we identify key enzymes in branched-chain amino acid (BCAA) metabolism as targets of hyperitaconylation in SIRT4-deficient macrophages. The BCKDH complex component dihydrolipoamide branched chain transacylase E2 (DBT) is hyperitaconylated and has reduced BCKDH activity in SIRT4KO macrophages. Physiologically, SIRT4-deficient mice exhibit significantly delayed wound healing, demonstrating a consequence of dysregulated macrophage function. Our data reveal a novel protein modification pathway in immune cells and establish SIRT4 as a critical regulator at the intersection of metabolism and inflammation. These findings have implications for understanding immune dysregulation in aging and metabolic disease.

DOI: https://doi.org/10.1101/2025.05.12.653532
Nat Commun. 2025 Jun 03. 16(1): 5130

TIM3-blockade synergizes with IL2 in alleviating intra-tumoral CD8+T cell exhaustion.

Xuhao Zhang, Yu Gao, Huiping Liao, Wenyan Wang, Zaili Yang, Weian Cao, Ge Li, Jing Wen, Gencheng Han, Yang-Xin Fu.

TIM3, a T-cell inhibitory receptor, is expressed on exhausted T cells in the TME. Progressive loss of IL2-secretion is an early sign of diminished effector function in TILs, which raises the possibility of IL2 loss driving exhaustion of TILs. We show that endogenous IL-2 is required for the antitumor effect of anti-TIM3. Selective delivery of IL-2 to TIM3high TILs via an engineered anti-TIM3-Pro-IL2 fusion enhances anti-TIM3 efficacy, while reducing IL2 toxicity. IL2 activity is inhibited at the acidic pH of the TME, thus an IL2 mutein (IL2V2) with sustained activity at low pH is integrated into the construct. Mechanistically, TIM3-ProIL2V2 not only reactivates TIM3+ TILs but also facilitates the activation and expansion of TIM3- TILs, which in turn provide a sustained source of effector T cells. TIM3-ProIL2V2 is efficient in multiple tumor models, including tumors in humanized mice. TIM3-ProIL2V2 has the potential to overcome anti-PD-1/L1 resistance in cold cancers.

DOI: https://doi.org/10.1038/s41467-025-60463-4
Nature. 2025 Jun 02.

Cancer-fighting CAR T cells show promising results for hard-to-treat tumours.

Rachel Fieldhouse.



Keywords:  Cancer; Immunology

DOI:  https://doi.org/10.1038/d41586-025-01722-8
Sci Immunol. 2025 Jun 06. 10(108): eads1328

An Il12 mRNA-LNP adjuvant enhances mRNA vaccine-induced CD8 T cell responses.

Emily A Aunins, Anthony T Phan, Mohamad-Gabriel Alameh, Garima Dwivedi, Elisa Cruz-Morales, David A Christian, Ying Tam, Molly E Bunkofske, Anabel Zabala Peñafiel, Keenan M O'Dea, Maria Merolle, Colleen Furey, Phillip Scott, Robert H Vonderheide, Scott E Hensley, Ross M Kedl, Drew Weissman, Christopher A Hunter.

Optimizing vaccine design to induce CD8 T cell responses has been challenging, but lipid nanoparticle (LNP)-encapsulated mRNA vaccines effectively generate CD8 T cell memory. Interleukin-12 (IL-12) supports CD8 T cell expansion and acquisition of effector function, but the role of IL-12 in the generation of CD8 T responses to mRNA vaccination is unclear. Here, we determine that endogenous IL-12 is not required for CD8 T cell responses to mRNA-LNP vaccination. We assessed the adjuvant activity of an mRNA-LNP encapsulating a codon-optimized mRNA that encodes both subunits of IL-12 (LNP-IL-12). Coadministration of LNP-IL-12 with ovalbumin (OVA) mRNA-LNPs enhanced CD8 T cell expansion and effector function and expanded circulating, effector, and tissue-resident memory CD8 T cells. LNP-IL-12 increased CD8 T cell responses against SARS-CoV-2 and influenza virus antigens and improved protection against Listeria monocytogenes-OVA and B16F0-OVA melanoma. Thus, modification of mRNA-LNP formulations to include a cytokine mRNA provides a strategy to enhance CD8 T cell-mediated protection.

DOI: https://doi.org/10.1126/sciimmunol.ads1328
FASEB J. 2025 Jun 15. 39(11): e70665

Inhibition of Cholesterol Synthesis in T Cells Protects the Liver Against Steatosis, Inflammation, and Oxidative Stress in Metabolic Dysfunction-Associated Steatohepatitis.

Huizhen Lin, Jingwen Qi, Siwei Lin, Mengnan Lin, Zijie Chen, Yunhui Guo, Xin Zhang, Qi-Long Wang, Ting Cai, Wei Yang, Xiaojun Zheng.

  Metabolic dysfunction-associated steatohepatitis (MASH) is a manifestation of systemic metabolic disease defined by abnormal lipid metabolism and causes liver disease. Inflammation driven by immune cells has been linked to liver damage, fibrosis, and the progression of MASH. Here, single-cell transcriptome analysis disclosed the increasing hepatic infiltration of CD8+ T cells in a murine methionine- and choline-deficient (MCD) diet-induced MASH model. Simvastatin alleviated the progression of MCD-diet-induced MASH, accompanied by the decreased infiltration of T cells. Depletion of CD8+ T cells also improved MASH progression. It is widely recognized that cholesterol plays an indispensable role in tuning the activation and function of CD8+ T cells. We found that specific inhibition of cholesterol synthesis in T cells significantly reduced MCD-induced hepatic steatosis, damage, inflammation, and concurrently lowered the accumulation of T cells and macrophages in the liver. Mechanistic studies revealed that MCD-induced hepatic oxidative stress was reduced by inhibiting T-cell cholesterol metabolism. Simvastatin ameliorated MASH in mice, at least in part through inhibiting the infiltration and effector function of CD8+ T cells. Collectively, our findings provide compelling evidence that pharmacological modulation of T-cell cholesterol metabolism may represent a promising therapeutic approach in the treatment of MASH.

Keywords:  T cells; cholesterol; metabolic dysfunction‐associated steatohepatitis; oxidative stress; simvastatin

DOI:  https://doi.org/10.1096/fj.202500115R
Nat Aging. 2025 Jun 02.

Editing epigenetic age.

Bastiaan T Heijmans.

DOI: https://doi.org/10.1038/s43587-025-00893-3
Front Aging. 2025 ;6 1605070

Unraveling the interplay between sleep, redox metabolism, and aging: implications for brain health and longevity.

Fayaz A Mir, Arianna R S Lark, Christa J Nehs.

  The relationship between sleep and metabolism has emerged as a critical factor in aging and age-related diseases, including Alzheimer's disease and dementia. Mitochondrial oxidative phosphorylation, essential for neuronal energy production, also generates reactive oxygen species (ROS), which increase with age and contribute to oxidative stress. Sleep plays a vital role in modulating redox balance, facilitating the clearance of free radicals, and supporting mitochondrial function. Disruptions in sleep are closely linked to redox imbalances, and emerging evidence suggests that pharmacological interventions, such as dual orexin receptor antagonists and antioxidant-based therapies, may help restore redox homeostasis. Furthermore, antioxidant-rich diets and supplements have shown promise in improving both sleep quality and metabolic health in aging populations. Neurons, with their high energy demands, are particularly vulnerable to oxidative damage, making redox regulation crucial in maintaining brain integrity. This review explores the bidirectional relationship between sleep and redox metabolism through five key areas: (1) sleep's role in free radical regulation, (2) ROS as mediators of age-related sleep disturbances, (3) feedback loops between impaired sleep and brain metabolism, (4) sleep, redox, and aging in peripheral systems, and (5) therapeutic strategies to restore redox balance and improve aging outcomes. Understanding these mechanisms may provide new targets for interventions aimed at mitigating age-associated diseases.

Keywords:  antioxidants; ketones; metabolic; mitochondria; oxidative stress; sleep

DOI:  https://doi.org/10.3389/fragi.2025.1605070
Nat Immunol. 2025 Jun;26(6): 807

CAR T cells affect cognition.

Paula Jauregui.

DOI: https://doi.org/10.1038/s41590-025-02188-6
NPJ Cardiovasc Health. 2025 ;2(1): 19

Mechanisms and implications of vascular-homing CD8 T cells in atherosclerosis.

Xi Su, Katelyn A O'Hare, Michael L Freeman.

  CD8 T cells likely contribute to atherosclerosis. Here, we review the relationship of vascular-homing CD8 T cells to atherosclerotic cardiovascular disease, with discussions of atherogenic and atheroprotective CD8 T cell subsets, encompassing their origin, activation, antigen-specificity, trafficking, and functionality. Furthermore, we explore factors that promote CD8 T cell vascular-homing phenotypes, such as infections and inflammation, and describe innovative therapeutic strategies targeting vascular-homing CD8 T cells in people with atherosclerosis.

Keywords:  Atherosclerosis; Immunology

DOI:  https://doi.org/10.1038/s44325-025-00056-8
bioRxiv. 2025 May 23. pii: 2025.05.20.650777. [Epub ahead of print]

Targeting Regnase-1 unleashes CAR T cell antitumor activity for osteosarcoma and creates a proinflammatory tumor microenvironment.

Adeleye O Adeshakin, Hao Shi, S Scott Perry, Heather Sheppard, Phuong Nguyen, Xiang Sun, Peipei Zhou, Jean-Yves Métais, Trevor Cunningham, K C Anil, Liqing Tian, Vivek Peche, Mollie S Prater, Deanna M Langfitt, Shondra M Pruett-Miller, Jason T Yustein, Giedre Krenciute, Christopher DeRenzo, Hongbo Chi, Stephen Gottschalk.

Negative regulators of T cell function represent promising targets to enhance the intrinsic antitumor activity of CAR T cells against solid tumors. However, the endogenous immune ecosystem in solid tumors often represents an immunosuppressive therapeutic barrier to CAR T cell therapy, and it is currently unknown whether deletion of negative regulators in CAR T cells reshapes the endogenous immune landscape. To address this knowledge gap, we developed CAR T cells targeting B7-H3 in immune-competent osteosarcoma models and evaluated the intrinsic and extrinsic effects of deleting a potent negative regulator called Regnase-1 (Reg-1). Deletion of Reg-1 not only improved the effector function of B7-H3-CAR T cells but also endowed them with the ability to create a proinflammatory landscape characterized by an influx of IFNγ-producing endogenous T cells and NK cells and a reduction of inhibitory myeloid cells, including M2 macrophages. Thus, deleting negative regulators in CAR T cells enforces a non-cell-autonomous state by creating a proinflammatory tumor microenvironment.

DOI: https://doi.org/10.1101/2025.05.20.650777
J Exp Med. 2025 Sep 01. pii: e20241454. [Epub ahead of print]222(9):

Membrane-IL12 adjuvant mRNA vaccine polarizes pre-effector T cells for optimized tumor control.

Kun Peng, Xiaoxue Zhao, Hongjian Li, Yang-Xin Fu, Yong Liang.

Conventional mRNA cancer vaccines can expand the quantity of tumor-specific CD8 T cells, but their effector function might be compromised. Specific cytokine signaling may enhance T cell differentiation for better tumor killing. We screened various cytokines and identified IL-12 as a potent adjuvant for mRNA vaccines, though with significant systemic toxicity. To balance efficacy and toxicity, we developed a membrane-tethered IL-12 (mtIL12) adjuvant mRNA vaccine. This design restricts mtIL12 expression to the surface of antigen-presenting cells, thereby selectively activating antigen-specific T cells without affecting bystander T or NK cells. mtIL12 adjuvant mRNA vaccination induced a unique pre-effector T cell subset that gives rise to highly responsive effector T cells, resulting in superior anti-tumor activity. Moreover, this approach overcame immune checkpoint therapy resistance and prevented cancer metastasis. Our study highlights that next-generation mRNA vaccines encoding membrane-tethered cytokine adjuvants can generate potent effector T cells, offering effective tumor control with reduced toxicity.

DOI: https://doi.org/10.1084/jem.20241454
Cell Rep. 2025 Jun 02. pii: S2211-1247(25)00546-7. [Epub ahead of print]44(6): 115775

KMT2D coordinates antiviral CD4+ T cell responses through opposing effects on T follicular helper and cytotoxic gene expression.

Jonathan A Cohen, Ashlyn A Buzzelli, Gabrielle Quickstad, Lixin Yang, Ichiro Misumi, Karl B Shpargel, Jason K Whitmire.

  T follicular helper (TFH) cells are essential for protective antibody responses. Histone modifications direct TFH development and function; however, the role of specific chromatin modifiers in this process is not well understood. Lysine methyltransferase 2D (KMT2D) is a histone methyltransferase that acts at H3K4 to promote gene expression. Herein, we examined the contribution of KMT2D to T cell responses during acute lymphocytic choriomeningitis virus infection. Mice lacking KMT2D in T cells generated sufficient antiviral CD8+ T cell responses to resolve infection. However, these mice formed fewer TFH cells and had diminished germinal center and antibody responses. Mechanistically, KMT2D sustained TFH responses in part by promoting Thpok and Il21 expression through H3K4Me1 deposition at gene enhancers. Consistent with loss of THPOK, KMT2D-deficient CD4+ T cells acquired a cytotoxic CD4+ T (CD4CTL) cell phenotype involving elevated expression of RUNX3, EOMES, and cytolytic molecules. Our findings show KMT2D balances TFH development and humoral immunity over CD4CTL cells.

Keywords:  CD4(+) T cells; CD8(+) T cells; CP: Genomics; CP: Immunology; KMT2D; LCMV; T follicular helper cells; Th1 cells; antiviral T cells; cytolytic CD4(+) T cells; epigenetics; mouse

DOI:  https://doi.org/10.1016/j.celrep.2025.115775
Adv Mater. 2025 Jun 04. e2502940

Spatiotemporal Charging Single-Atom Nanozymes Activated Pyroptosis for Antitumor Immunotherapy via Bioorthogonal Disruption of Succination and Reinvigorating T Lymphocytes.

Rui Niu, Bin Zhang, Yang Liu, Bo Xu, Ruiping Deng, Shuyan Song, Kai Liu, Yinghui Wang, Hongjie Zhang.

  Pyroptosis can trigger strong immunogenic cell death (ICD) of tumor cells for antitumor immunotherapy. However, metabolic disorders of fumarate in the tumor microenvironment (TME) can significantly reduce the pyroptosis rate and render T lymphocytes dysfunctional. Here, the ultrasound (US)-driven piezoelectric charges assisted Fe-based SAzyme (BFTM) with co-loaded triphenylphosphonium (TPP) and methyl (Z)-4-(chloro(2-phenylhydrazono)methyl)benzoate (MMB, a bioorthogonal reagent of fumarate) for activating pyroptosis and regulating fumarate metabolism is developed. Positive and negative charges generated by barium titanate (BTO) regulate the electron cloud density of single-Fe atom, endowing the BFTM with efficient reactive oxygen species (ROS) production ability for triggering caspase-1 related gasdermin D (GSDMD) mediated pyroptosis. Meanwhile, the consumption of intracellular fumarate through bioorthogonal reaction not only prevented the succinate of cysteines in GSDMD, causing it to be activated and oligomerized by caspase-1 to enhance pyroptosis but also restored the phosphorylation of ZAP70 to normalize the T cell receptor (TCR) signaling pathways for reinvigorating CD8+ T cells. In short, US-driven BFTM as a pyroptosis initiator and metabolism immune activator significantly enhances antitumor immunotherapy effects via ROS storms, fumarate depletion, triggering pyroptosis, and reinvigorating T lymphocytes.

Keywords:  antitumor immunotherapy; fumarate metabolism; pyroptosis; reactive oxygen species; single‐atom nanozyme

DOI:  https://doi.org/10.1002/adma.202502940
Lipids Health Dis. 2025 May 31. 24(1): 197

Targeting intramyocellular lipids to improve aging muscle function.

David W Russ, Ravikumar Manickam, Srinivas M Tipparaju.

  Decline of skeletal muscle function in old age is a significant contributor to reduced quality of life, risk of injury, comorbidity and disability and even mortality. While this loss of muscle function has traditionally been attributed to sarcopenia (loss of muscle mass), it is now generally appreciated that factors other than mass play a significant role in age-related muscle weakness. One such factor gaining increased attention is the ectopic accumulation of lipids in skeletal muscle, in particular, intramyocellular lipids (IMCLs). It has been appreciated for some time that metabolic flexibility of several tissues/organs declines with age and may be related to accumulation of IMCLs in a "vicious cycle" whereby blunted metabolic flexibility promotes accumulation of IMCLs, which leases to lipotoxicity, which can then further impair metabolic flexibility. The standard interventions for addressing lipid accumulation and muscle weakness remain diet (caloric restriction) and exercise. However, long-term compliance with both interventions in older adults is low, and in the case of caloric restriction, may be inappropriate for many older adults. Accordingly, it is important, from a public health standpoint, to pursue potential pharmacological strategies for improving muscle function. Because of the success of incretin-analog drugs in addressing obesity, these medications may potentially reduce IMCLs in aging muscles and thus improve metabolic flexibility and improve muscle health. A contrasting potential pharmacological strategy for addressing these issues might be to enhance energy provision to stimulate metabolism by increasing NAD + availability, which is known to decline with age and has been linked to reduced metabolic flexibility. In this narrative review, we present information related to IMCL accumulation and metabolic flexibility in old age and how the two major lifestyle interventions, caloric restriction and exercise, can affect these factors. Finally, we discuss the potential benefits and risks of select pharmacologic interventions in older adults.

Keywords:  Aging; Lipotoxicity; Sarcopenia

DOI:  https://doi.org/10.1186/s12944-025-02622-6
Med Oncol. 2025 May 31. 42(7): 228

Revolutionising cancer intervention: the repercussions of CAR-T cell therapy on modern oncology practices.

Hossam Kamli, Najeeb Ullah Khan.

  Chimeric Antigen Receptor T-cell (CAR-T) therapy represents a groundbreaking advance in oncology, leveraging patient-specific immune cells to target malignant tumours precisely. By equipping T cells with synthetic receptors, CAR-T therapy achieves remarkable antitumor effects and offers hope for durable cancer control. However, several limitations persist, including antigen scarcity, immunosuppressive tumour microenvironments, and T-cell exhaustion. CRISPR-Cas9 gene editing has enhanced CAR-T potency by knocking out immune checkpoints (PD-1, CTLA-4) and improving persistence, while RNA interference (RNAi) silences immune-evasion genes (e.g. SOCS1). Nanozyme-based delivery systems enable precise CRISPR-Cas9 delivery (> 70% editing efficiency) and tumour targeting, overcoming instability and off-target effects. Innovations like SUPRA CARs, armoured CAR-T cells (e.g. IL-12/IL-21-secreting TRUCKs), and dual checkpoint inhibition synergize to reprogram the tumour microenvironment, reducing relapse by 40% in trials. Despite progress, high costs, manufacturing hurdles, and ethical concerns (e.g. germline editing risks) remain critical barriers. Emerging solutions include universal off-the-shelf CAR-Ts, hybrid nano-CRISPR systems, and AI-driven design, paving the way for scalable, personalised immunotherapy. This review highlights breakthroughs in CRISPR, RNAi, and nanotechnology, underscoring CAR-T therapy's transformative potential while addressing translational challenges for broader clinical adoption.

Keywords:  CAR-T therapy; CRISPR-Cas9 in oncology; Cancer immunotherapy; Genetic engineering; Nanozymes in cancer; Tumour microenvironment

DOI:  https://doi.org/10.1007/s12032-025-02783-5
Mol Ther. 2025 May 30. pii: S1525-0016(25)00408-3. [Epub ahead of print]

Multi-engineered T cell vaccine boosting TCR-T cell therapy enhances anti-tumor function and eradicates heterogeneous solid tumors.

Xuan Che, Shen Zheng, Yuan Sun, Xiya Wang, Pengchong Zhang, Jixiang Cao, Yun Bai.

T cell receptor (TCR) engineered T cell therapy holds great promise for treating solid tumors, but the overall clinical efficacy remains limited. The vital challenge lies in the loss of TCR-targeted antigens and poor T cell persistence. Here, we demonstrate a novel approach to enhance TCR-T cell therapy and reject antigen heterogeneous tumors through a multi-engineered T cell vaccine (Multi-Tvac). Multi-Tvac is composed of a TCR-targeted cognate peptide, tumor neoantigens, and a LAG-3Ig adjuvant signal, which significantly boosts dendritic cell (DC) maturation, enhances TCR-T cell anti-tumor function, and alleviates exhaustion phenotype. When combined with TCR-T cell therapy, Multi-Tvac induced long-lasting responses in established solid tumors resistant to TCR-T cell monotherapy. Notably, Multi-Tvac prevented antigen-loss tumor escape and achieved complete responses in an antigen-heterogeneous solid tumor model. Mechanistically, Multi-Tvac enhanced antigen presentation in secondary lymphoid organs (SLOs), orchestrating a strong endogenous immune response that primes T cells. As a proof-of-concept, our study extended T cell engineering beyond TCR-directed killing, which could perform as a therapeutic vaccination platform to empower TCR-T cells with new capabilities and overcome major barriers in the clinical treatment of solid tumors.

DOI: https://doi.org/10.1016/j.ymthe.2025.05.036
Adv Sci (Weinh). 2025 May 31. e06641

RUNX1/SLAMF3 Axis Drives Immunosuppression to Contribute to Colorectal Cancer Liver Metastasis by Blocking Phagocytosis and Depleting C1QC+ Tumor-Associated Macrophages.

Yinheng Luo, Xiaoli Jin, Lan Huang, Dejia Zeng, Nan Zhang, Shiyu Tang, Shu Luo, Samina Ejaz Syed, Ruiwu Dai, Qiu Li, Shufang Liang.

  Colorectal cancer liver metastasis (CRLM) is a leading cause of death in colorectal cancer (CRC) patients and is characterized by an immunosuppressive tumor microenvironment (TME). This study employs mouse in vivo selection to isolate highly metastatic CRLM derivatives for profiling their transcriptomic, proteomic, and metabolomic alterations associated with CRLM. Notably, the expression of SLAMF3 is significantly upregulated in CRLM derivatives and its knockdown effectively suppresses CRLM in mice. RUNX1 transcriptionally upregulates SLAMF3 expression and combined targeting of the RUNX1/SLAMF3 axis synergistically suppresses liver metastasis in mice. In parallel, SLAMF3 suppresses macrophage-mediated phagocytosis of CRC cells through the SHP-1/2/mTORC1 pathway. Conversely, SLAMF3 knockdown promotes M1 polarization in liver metastases and activates the CCL signaling pathway between macrophages and CD8+ T cells. It also reduces the exhausted CD8+ T cells in liver metastases and the expression of inhibitory receptors PD-1 and TIM-3, thus alleviating the immunosuppressive TME. Clinically, activation of the RUNX1/SLAMF3 axis is closely associated with CRLM progression and correlates with a reduced proportion of clinically beneficial C1QC⁺ tumor-associated macrophages (TAMs). Collectively, these findings identify the RUNX1/SLAMF3 axis as a key driver of immunosuppressive TME remodeling and CRLM progression, highlighting its potential as a promising therapeutic target for CRLM.

Keywords:  SLAMF3; T cell exhaustion; colorectal cancer liver metastasis; tumor immune microenvironment; tumor‐associated macrophages

DOI:  https://doi.org/10.1002/advs.202506641
Nat Metab. 2025 Jun 03.

Cysteine depletion triggers adipose tissue thermogenesis and weight loss.

Aileen H Lee, Lucie Orliaguet, Yun-Hee Youm, Rae Maeda, Tamara Dlugos, Yuanjiu Lei, Daniel Coman, Irina Shchukina, Prabhakar Sairam Andhey, Steven R Smith, Eric Ravussin, Krisztian Stadler, Bandy Chen, Maxim N Artyomov, Fahmeed Hyder, Tamas L Horvath, Marc Schneeberger, Yuki Sugiura, Vishwa Deep Dixit.

Caloric restriction and methionine restriction-driven enhanced lifespan and healthspan induces 'browning' of white adipose tissue, a metabolic response that increases heat production to defend core body temperature. However, how specific dietary amino acids control adipose thermogenesis is unknown. Here, we identified that weight loss induced by caloric restriction in humans reduces thiol-containing sulfur amino acid cysteine in white adipose tissue. Systemic cysteine depletion in mice causes lethal weight loss with increased fat utilization and browning of adipocytes that is rescued upon restoration of cysteine in diet. Mechanistically, cysteine-restriction-induced adipose browning and weight loss requires sympathetic nervous system-derived noradrenaline signalling via β3-adrenergic-receptors that is independent of FGF21 and UCP1. In obese mice, cysteine deprivation induced rapid adipose browning, increased energy expenditure leading to 30% weight loss and reversed metabolic inflammation. These findings establish that cysteine is essential for organismal metabolism as removal of cysteine in the host triggers adipose browning and rapid weight loss.

DOI: https://doi.org/10.1038/s42255-025-01297-8
bioRxiv. 2025 May 17. pii: 2025.05.05.651897. [Epub ahead of print]

Disrupted priming within draining lymph nodes drives immune quiescence in gastric cancer.

Sohrab Salehi, Emily E Stroobant, Hannah Lees, Ya-Hui Lin, Shoji Shimada, Miseker Abate, Matthew J Zatzman, Nicholas Ceglia, Samuel S Freeman, Monika Laszkowska, Steven Maron, Andrew McPherson, Nicole Rusk, Eliyahu Havasov, Harrison Drebin, Ping Gu, Laura H Tang, Yelena Y Janjigian, Ruslan Soldatov, Ronan Chaligne, Sohrab P Shah, Vivian E Strong, Santosha A Vardhana.

The gastric mucosa is characterized by continuous innate immune surveillance and inflammatory signaling, yet a high proportion of gastric carcinomas (GCs) are recalcitrant to immune-directed therapies. The mechanisms by which GCs evade adaptive immune surveillance within the highly antigenic microenvironment of the gastric mucosa remains unknown. To address this, we collected patient-matched tumor tissue, distant normal tissue, metastasis, and draining lymph nodes to generate a large-scale single-cell immune profiling dataset from 64 patients (n=179 samples, >150,000 cells). From single cell analysis, we identified two distinct sources of impaired tumor surveillance within tumor draining lymph nodes. First, we observed that a significant fraction of tumor draining lymph nodes had undergone cytokine-driven reprogramming, leading to reduced dendritic cell homing and limited T cell priming. Second, T cells undergoing successful activation exhibited limited expansion and constrained differentiation, marked by expression of the quiescence-associated transcription factor Kruppel-like Factor 2 ( KLF2 ). Overexpression of KLF2 in primary T cells limited both their differentiation and cytotoxic capacity. These findings implicate both impaired T cell priming and KLF2 -dependent T cell quiescence in limiting T cell immunity in gastric adenocarcinoma. We suggest these findings represent an emerging model for immune silencing in tumors developing from tissues with chronic inflammation.

DOI: https://doi.org/10.1101/2025.05.05.651897
Sci Transl Med. 2025 Jun 04. 17(801): eadp8166

IFN-γ-resistant CD28 CAR T cells demonstrate increased survival, efficacy, and durability in multiple murine tumor models.

Stefanie R Bailey, Hana N Takei, Giulia Escobar, Michael C Kann, Amanda A Bouffard, Tamina Kienka, Valentina M Supper, Alexander Armstrong, Diego Salas-Benito, Merle K Phillips, Filippo Birocchi, Sonika Vatsa, Harrison Silva, Irene Scarfò, Marc Wehrli, Korneel Grauwet, Eli P Darnell, Charlotte E Graham, Mark B Leick, Felix Korell, Trisha R Berger, Marcela V Maus.

Interferon-γ (IFN-γ) plays complex and, sometimes, contradictory roles in cancer, which can affect patient responses to treatments such as immunotherapies. We recently demonstrated that IFN-γ production by chimeric antigen receptor (CAR) T cells is not required for efficacy in hematologic tumor models, whereas IFN-γ receptor (IFN-γR) signaling in solid tumor cells facilitates CAR T cell adhesion and antigen-specific cytotoxicity. Here, we show that IFN-γ induces apoptosis of CAR T cells bearing a CD28 intracellular signaling domain, which can be reduced through targeting of IFN-γ or IFN-γR. In hematologic malignancies, knockout of IFN-γR (IFN-γRKO) in CAR T cells increased their persistence without compromising efficacy. In xenograft and syngeneic solid tumor models, IFN-γR knockout CAR T cells displayed more potent tumor control, prolonged survival, and improved T cell memory that conferred protection from tumor rechallenge. RNA sequencing of tumor-infiltrating IFN-γRKO CAR T cells derived from tumor-bearing mice revealed increased cell death in tumor cells. Collectively, these data show that inhibition of IFN-γ signaling can increase the expansion and antitumor activity of CD28-based CAR T cells in liquid and solid tumors.

DOI: https://doi.org/10.1126/scitranslmed.adp8166