bims-imseme 2025-10-05 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2025–10–05
thirty-two papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Regulators of CD8+ T cell exhaustion.
The transcriptional repressor BLIMP1 enforces TCF-1-dependent and -independent restriction of the memory fate of CD8+ T cells.
Reprogramming T cell stemness against cancer.
Genetic perturbations link autoimmune risk variants to T cell function.
Exhaustion-Resistant CD8+ T Cells in Ankylosing Spondylitis: A Proposed Three-Axis Model.
Improving Immune Checkpoint Therapy in the Tumor Microenvironment by Targeting T Cell Metabolism.
Proteotoxic stress response drives T cell exhaustion and immune evasion.
Dietary cysteine enhances intestinal stemness via CD8+ T cell-derived IL-22.
Dietary methionine restriction primes T cell metabolism for activation and tumor inhibition and enhances the efficacy of immune checkpoint blockade.
In vivo genome-wide CRISPR screens in human T cells to enhance T cell therapy for solid tumors.
SkinspanTM: A Healthy Longevity Framework for Skin Aging: Redefining Skin Aging to Hallmarks and Longevity.
Differentiation and mitochondrial metabolic characteristics of CD8+ T cells in malignant ascites of epithelial ovarian cancer and their correlation with estrogen signaling.
Early-life thymectomy results in visceral adipose tissue inflammation and glucose intolerance.
Metabolic profiling of antigen-specific CD8+ T cells by spectral flow cytometry.
Mini review: Gene therapy targets for aging-associated diseases.
Intercellular Nanotube Mitochondrial Transplantation Strategy Mediating T Cell "Supercharging".
Steroid hormone regulation of immunometabolism and inflammation.
Targeting immunosenesence promotes clearance of senescent cells.
MEIS2 Modulates Oxidative Phosphorylation and ROS Generation to Affect CD8+ T Cell Antitumor Immunity in Prostate Cancer.
Acetyl-CoA carboxylase-1 inhibition increases regulatory T-Cell metabolism and graft-vs-host disease treatment efficacy via mitochondrial fusion.
Aging puts Leydig cells in a tough spot.
Rewiring antitumor immunity: targeting CLDN18.2 with conditional 4-1BB activation.
IL-7-mediated expansion of autologous lymphocytes increases CD8 + VLA-4 expression and accumulation in glioblastoma models.
Vascular Endothelial NAMPT-Mediated NAD+ Biosynthesis Regulates Angiogenesis and Cardiometabolic Functions in Male Mice.
BiTE-secreting T cells rationally combine with PD-1 blockade and vaccine boosting to reshape antitumor immunity in ovarian cancer.
Lactate promotes longevity through redox-driven lipid remodeling in Caenorhabditis elegans.
Single-cell transcriptomic analyses provide insights into SPP1+ TAM-mediated immune suppression and CD8+ T cell dysfunction in lung cancer.
Targeting an essential viral oncoprotein with an IL-7-enhanced mRNA vaccine induces durable immunity to Merkel cell carcinoma.
Macrophage-TREM2 promotes cardiac repair by restricting the infiltration of CD8+ T cells via CXCL16-CXCR6 axis after myocardial infarction.
Ferritinophagy Loss Drives Mitochondrial Iron Import and Colorectal Tumorigenesis.
Current strategies for armoring chimeric antigen receptor T-cells to overcome barriers of the solid tumor microenvironment.
Metabolic regulation of Th9 cell differentiation: insights for IL-9-driven diseases.

Nat Rev Immunol. 2025 Oct 01.

Regulators of CD8+ T cell exhaustion.

Qinli Sun, Chen Dong.

T cell exhaustion is an adaptive and distinct cell fate that emerges in response to persistent antigen stimulation, primarily in chronic infections and cancer. It is characterized by a progressive loss of effector functions and sustained expression of multiple inhibitory receptors. Progression to T cell exhaustion is driven by persistent antigen stimulation through the T cell receptor and is modulated by signals from co-stimulatory and inhibitory molecules as well as by microenvironmental factors such as cytokines, metabolites and neuronal factors. These extrinsic cellular factors reshape the T cell transcriptome, epigenome and metabolism towards a state of exhaustion through critical intrinsic cell regulators. In this Review, we summarize our current understanding of the regulators involved in T cell exhaustion, highlighting their roles in directing the fates and functionalities of distinct exhausted T cell subsets and how they may be harnessed for the development of improved immunotherapies against cancer and chronic infections.

DOI: https://doi.org/10.1038/s41577-025-01221-x
Immunity. 2025 Oct 02. pii: S1074-7613(25)00419-4. [Epub ahead of print]

The transcriptional repressor BLIMP1 enforces TCF-1-dependent and -independent restriction of the memory fate of CD8+ T cells.

Maegan K Murphy, Matthew McCullen, Joshua L Deffenbaugh, Andy Y Chen, Joy Pai, Bence Daniel, Amir Yousif, Saravanan Raju, Sunnie Hsiung, Zhenxiao Wang, Hazem E Ghoneim, Ansuman T Satpathy, Marco Colonna, Eugene M Oltz, Takeshi Egawa.

  During differentiation of CD8+ T cells, the transcription factors TCF-1 and Blimp1 control progenitor and terminally differentiated states, respectively. Here, we examined the hierarchy and functional consequences of cross-regulation between these factors. We identified two Blimp1-bound cis-regulatory elements, Tcf7+22kb and Tcf7+17kb, that enforced Tcf7 silencing in a context-specific manner during both acute and chronic responses. Deletion of these elements decoupled Tcf7 repression from effector differentiation but did not rewire effector T cells to a memory state or prevent the acquisition of phenotypic hallmarks of exhaustion. However, combined ablation of Prdm1 and Tcf7 preserved a memory surface phenotype despite defects in secondary expansion. Thus, the anti-proliferative and pro-differentiative effects of Blimp1 in effector or exhausted CD8+ T cells represent mechanistically distinct modules, wherein repression of Tcf7 limits proliferative capacity but not memory or progenitor specification.

Keywords:  Blimp1; T cell exhaustion; T cell memory; TCF-1; effector differentiation

DOI:  https://doi.org/10.1016/j.immuni.2025.09.008
Trends Cancer. 2025 Oct 02. pii: S2405-8033(25)00232-8. [Epub ahead of print]

Reprogramming T cell stemness against cancer.

Jiaqi Wang, Ruochen Yan, Dingjiacheng Jia, Shujie Chen.

  Stem-like CD8+ T cells - characterized by high-level expression of the transcription factor TCF-1, and known as progenitor exhausted T (Tpex) cells - have emerged as crucial mediators of durable antitumor immunity. These cells demonstrate unique self-renewal capacity, multipotency, and enhanced responsiveness to immune checkpoint blockade therapy. This review synthesizes current understanding of Tpex cell biology, including their defining characteristics, tissue distribution, and functional importance in antitumor immunity. We focus particularly on innovative approaches to preserve and enhance T cell stemness through combination therapies, cytokine signal modulation, epigenetic regulation, tumor microenvironment modification, and microbiota-based interventions. The development of these next-generation immunotherapies targeting T cell stemness represents a transformative frontier in oncology, holding significant promise for improving therapeutic outcomes in cancer patients.

Keywords:  TCF-1; cancer; gut microbiota; immune checkpoint blockade; progenitor exhausted T cells; stemness

DOI:  https://doi.org/10.1016/j.trecan.2025.09.004
Nat Genet. 2025 Sep 29.

Genetic perturbations link autoimmune risk variants to T cell function.

DOI: https://doi.org/10.1038/s41588-025-02302-2
Immunology. 2025 Oct 02.

Exhaustion-Resistant CD8+ T Cells in Ankylosing Spondylitis: A Proposed Three-Axis Model.

Xuhong Zhang, Lu Jia, Xueni Lin, Lamei Zhou.

  Ankylosing spondylitis (AS) is a chronic immune-mediated disease marked by sustained joint inflammation and aberrant bone remodelling. Although chronic antigen exposure usually enforces terminal exhaustion, emerging evidence indicates that a subset of CD8+ T cells in AS evades canonical exhaustion programmes while expressing programmed cell death protein 1 (PD-1). These exhaustion-resistant cells retain effector function and likely contribute to persistent tissue inflammation and structural damage. In this review, we dissect the cellular and molecular basis of exhaustion resistance in AS CD8+ T cells and focus on the convergence of intermittent T cell receptor (TCR) stimulation, metabolic adaptation that preserves mitochondrial fitness, and co-stimulatory inputs from interleukin-15 (IL-15) and CD28. We propose an integrated three-axis model governing CD8+ T cell fate and functional persistence in the AS context shaped by human leukocyte antigen-B27 (HLA-B27) and the gut-joint axis. Clarifying these mechanisms refines current views of T cell dysfunction in chronic inflammation and highlights therapeutic strategies aimed at reprogramming pathogenic immunity in AS.

Keywords:  CD8+ T cells; HLA‐B27; IL‐15; T‐cell exhaustionankylosing spondylitis; co‐stimulation; exhaustion resistance; gut–joint axis

DOI:  https://doi.org/10.1111/imm.70044
Endocr Metab Immune Disord Drug Targets. 2025 Sep 02.

Improving Immune Checkpoint Therapy in the Tumor Microenvironment by Targeting T Cell Metabolism.

Jun Wei, Baozhen An, Renchao Dong, Xinyi Tu, Yifei Dong, Yuang Liu, Yanqiu Liu.

  To meet the increased nutrient requirements associated with rapid cellular proliferation, tumor cells undergo metabolic reprogramming, characterized by a substantial increase in the production of energy and precursor molecules necessary for biosynthetic processes. Similarly, T cells experience metabolic reprogramming to support their proliferation and immunological functions, leading to metabolic competition with tumor cells within the tumor microenvironment (TME). This metabolic competition adversely affects T cell activation, proliferation, and immune function, primarily due to the limited availability of glucose, lipids, and amino acids. Furthermore, cytokines and immune checkpoints significantly impact T cell-mediated immunoreactivity. Modulating the metabolism of tumor cells and T cell-mediated immune evasion within the TME is of paramount importance. Notably, the metabolism of small-molecule target agents has garnered considerable attention in the context of the TME. This study aimed to examine the influence of various microenvironmental factors on T cell metabolism and explore corresponding innovative therapeutic approaches, thereby offering a comprehensive array of potential clinical strategies for cancer prevention and treatment.

Keywords:  T cell metabolism; combination therapy.; immune checkpoint; nutrient competition; tumor immunotherapy; tumor microenvironment

DOI:  https://doi.org/10.2174/0118715303400871250821103310
Nature. 2025 Oct 01.

Proteotoxic stress response drives T cell exhaustion and immune evasion.

Yi Wang, Anjun Ma, No-Joon Song, Ariana E Shannon, Yaa S Amankwah, Xingyu Chen, Weidong Wu, Ziyu Wang, Abbey A Saadey, Amir Yousif, Gautam Ghosh, Jay K Mandula, Maria Velegraki, Tong Xiao, Haitao Wen, Stanley Ching-Cheng Huang, Ruoning Wang, Christian M Beusch, Abdelhameed S Dawood, David E Gordon, Mohamed S Abdel-Hakeem, Hazem E Ghoneim, Gang Xin, Brian C Searle, Zihai Li.

Chronic infections and cancer cause T cell dysfunction known as exhaustion. This cell state is caused by persistent antigen exposure, suboptimal co-stimulation and a plethora of hostile factors that dampen protective immunity and limit the efficacy of immunotherapies1-4. The mechanisms that underlie T cell exhaustion remain poorly understood. Here we analyse the proteome of CD8+ exhausted T (Tex) cells across multiple states of exhaustion in the context of both chronic viral infections and cancer. We show that there is a non-stochastic pathway-specific discordance between mRNA and protein dynamics between T effector (Teff) and Tex cells. We identify a distinct proteotoxic stress response (PSR) in Tex cells, which we term Tex-PSR. Contrary to canonical stress responses that induce a reduction in protein synthesis5,6, Tex-PSR involves an increase in global translation activity and an upregulation of specialized chaperone proteins. Tex-PSR is further characterized by the accumulation of protein aggregates and stress granules and an increase in autophagy-dominant protein catabolism. We establish that disruption of proteostasis alone can convert Teff cells to Tex cells, and we link Tex-PSR mechanistically to persistent AKT signalling. Finally, disruption of Tex-PSR-associated chaperones in CD8+ T cells improves cancer immunotherapy in preclinical models. Moreover, a high Tex-PSR in T cells from patients with cancer confers poor responses to clinical immunotherapy. Collectively, our findings indicate that Tex-PSR is a hallmark and a mechanistic driver of T cell exhaustion, which raises the possibility of targeting proteostasis pathways as an approach for cancer immunotherapy.

DOI: https://doi.org/10.1038/s41586-025-09539-1
Nature. 2025 Oct 01.

Dietary cysteine enhances intestinal stemness via CD8+ T cell-derived IL-22.

Fangtao Chi, Qiming Zhang, Jessica E S Shay, Shixun Han, Johanna Ten Hoeve, Yin Yuan, Zhenning Yang, Heaji Shin, Samuel Block, Sumeet Solanki, Yatrik M Shah, Matthew G Vander Heiden, Judith Agudo, Ömer H Yilmaz.

A fundamental question in physiology is understanding how tissues adapt and alter their cellular composition in response to dietary cues1-8. The mammalian small intestine is maintained by rapidly renewing LGR5+ intestinal stem cells (ISCs) that respond to macronutrient changes such as fasting regimens and obesogenic diets, yet how specific amino acids control ISC function during homeostasis and injury remains unclear. Here we demonstrate that dietary cysteine, a semi-essential amino acid, enhances ISC-mediated intestinal regeneration following injury. Cysteine contributes to coenzyme A (CoA) biosynthesis in intestinal epithelial cells, which promotes expansion of intraepithelial CD8αβ+ T cells and their production of interleukin-22 (IL-22). This enhanced IL-22 signalling directly augments ISC reparative capacity after injury. The mechanistic involvement of the pathway in driving the effects of cysteine is demonstrated by several findings: CoA supplementation recapitulates cysteine effects, epithelial-specific loss of the cystine transporter SLC7A11 blocks the response, and mice with CD8αβ+ T cells lacking IL-22 or a depletion of CD8αβ+ T cells fail to show enhanced regeneration despite cysteine treatment. These findings highlight how coupled cysteine metabolism between ISCs and CD8+ T cells augments intestinal stemness, providing a dietary approach that exploits ISC and immune cell crosstalk for ameliorating intestinal damage.

DOI: https://doi.org/10.1038/s41586-025-09589-5
bioRxiv. 2025 Sep 23. pii: 2025.09.18.676961. [Epub ahead of print]

Dietary methionine restriction primes T cell metabolism for activation and tumor inhibition and enhances the efficacy of immune checkpoint blockade.

Xiaoqing Qing, Binita Chakraborty, Panpan Liu, Sandeep Artham, Patrick K Juras, Dongyin Guan, Kristen E Pauken, Ching-Yi Chang, Xia Gao.

The proliferation of many cancer cells is methionine dependent and dietary methionine restriction (MR) has shown anti-tumor effects in a wide variety of immunodeficiency preclinical models. Yet, whether MR exerts an anti-tumor effect in the presence of an immune-competent background remains inconclusive. Accumulating evidence has shown an essential role of methionine in immune cell differentiation and function. Thus, competition for methionine between tumor cells and immune cells in the tumor microenvironment may drive tumor growth and tumor response to therapy. Here, we aim to define the impact of MR on tumor growth and associated immunity. We first assessed the effect of MR in a series of immunocompetent mouse models of melanoma, colorectal cancer, breast cancer, and lung. MR led to a broad tumor inhibition effect across these models and such tumor inhibition was not sex-or genetic background-dependent but appears to be fully or partially immune-dependent. Through flow cytometry analysis, we found a consistent increase in intratumoral activated CD8 + T cells across different tumor models and depletion of CD8 + T cells partially or completely reversed MR-induced tumor inhibition in a model dependent manner. Interestingly in young healthy non-tumor-bearing mice, MR increased spleen CD3 + and CD8 + T cell populations. Metabolomics and RNAseq analysis of spleen-derived CD8 + T cells revealed significant increase in purine metabolism and amino acid metabolism and that are in line with the metabolic feature of activated T cells. Furthermore, MR improved the efficacy of anti-PD1 immune checkpoint blockade. Together, MR primes T cell metabolism for its anti-tumor effect and improves the efficacy of anti-PD1 checkpoint blockade.

DOI: https://doi.org/10.1101/2025.09.18.676961
bioRxiv. 2025 Sep 24. pii: 2025.09.23.678127. [Epub ahead of print]

In vivo genome-wide CRISPR screens in human T cells to enhance T cell therapy for solid tumors.

Qi Liu, Peixin Amy Chen, Esha Urs, Shimin Zhang, Maya M Arce, Charlotte H Wang, Zhongmei Li, Jin Seo, Nupura Kale, Taylor N LaFlam, Fanglue Peng, Eric Shifrut, Greg M Allen, Justin Eyquem, Katherine Fuh, Stacie E Dodgson, Jason G Cyster, Alexander Marson, Julia Carnevale.

Large-scale CRISPR screening in human T cells holds significant promise for identifying genetic modifications that can enhance cellular immunotherapy. However, many genetic regulators of T cell performance in solid tumors may not be readily revealed in vitro. In vivo screening in tumor-bearing mice offers greater physiological relevance, but has historically been limited by low intratumoral T cell recovery. Here, we developed a new model system that achieves significantly higher human T cell recovery from tumors, enabling genome-wide in vivo screens with small numbers of mice. Tumor-infiltrating T cells in this model exhibit hallmarks of dysfunction compared to matched splenic T cells, creating an ideal context for screening for genetic modifiers of T cell activity in the tumor microenvironment. Using this platform, we performed two genome-wide CRISPR knockout screens to identify genes regulating T cell intratumoral abundance and effector function (e.g., IFN-γ production). The intratumoral abundance screen uncovered the P2RY8-Gα13 GPCR signaling pathway as a negative regulator of human T cell infiltration into tumors. The effector function screen identified GNAS (Gαs), a central signaling mediator downstream of multiple GPCRs that sense different suppressive ligands, as a key regulator of T cell dysfunction in tumors. Targeted GNAS knockout rendered T cells resistant to multiple suppressive cues and significantly improved therapeutic performance across diverse solid tumor models. Moreover, combinatorial knockout of P2RY8 (trafficking) and GNAS (effector function) further enhanced overall tumor control, demonstrating that genetic modifications targeting distinct T cell phenotypes can be combined to improve therapeutic potency. This flexible and scalable in vivo screening platform can be adapted to diverse tumor models and pooled CRISPR libraries, enabling future discovery of genetic strategies that equip T cell therapies to overcome barriers imposed by solid tumors.

DOI: https://doi.org/10.1101/2025.09.23.678127
Mayo Clin Proc. 2025 Sep 30. pii: S0025-6196(25)00416-1. [Epub ahead of print]

SkinspanTM: A Healthy Longevity Framework for Skin Aging: Redefining Skin Aging to Hallmarks and Longevity.

Saranya P Wyles, Hasina S Maredia, Ryeim B Ansaf, Moudar R Dweydari, Ryan T Hurt, Sara L Bonnes, Sundeep Khosla, Nathan K LeBrasseur, Zoe Diana Draelos, Mark D P Davis.

Skin aging is an inherent biological component of human aging. As the global population ages, the incidence of age-related skin conditions has become increasingly prevalent. Both intrinsic and extrinsic factors, collectively known as the skin "exposome," contribute to visible and physiological changes. The skin's layers, including the epidermis, dermis, and hypodermis, function both independently and interdependently in these aging processes. Intrinsic factors such as hormonal fluctuations, genetic predispositions, and cellular senescence, defined as an irreversible cell cycle arrest, drive physiological age-related skin changes. These changes are underpinned by several interconnected hallmarks of aging, including genomic instability, telomere attrition, epigenetic alterations, and loss of proteostasis, all of which impair cell renewal and dermal structure. Stem cell exhaustion and mitochondrial dysfunction reduce the skin's capacity to regenerate and adapt to stress, whereas altered intercellular communication and chronic low-grade inflammation ("inflammaging") further accelerate aging phenotypes such as loss of elasticity, epidermal thinning, and delayed wound healing. Extrinsic factors, including ultraviolet radiation, air pollution, smoking, and poor nutrition, compound these effects by increasing oxidative stress, DNA damage, and activating senescence-associated secretory phenotypes. Lifelong sun protection, nutritious dietary habits, regular physical activity, and topical interventions such as sunscreen and moisturizers help maintain a resilient skin microenvironment. This review highlights the urgent need to recognize, prevent, and treat skin aging. Emerging therapies targeting root-cause mechanisms may revolutionize dermatologic care and extend skin healthspan - now known as skinspan.

DOI: https://doi.org/10.1016/j.mayocp.2025.07.027
Cancer Immunol Immunother. 2025 Sep 29. 74(10): 321

Differentiation and mitochondrial metabolic characteristics of CD8+ T cells in malignant ascites of epithelial ovarian cancer and their correlation with estrogen signaling.

Zouyu Jiang, Ying Zhou, Jiajuan Wu, Yu Shen, Danni Tang, Yuhong Wu, Qiuxia Qu, Juan Wang.

  The tumor microenvironment of epithelial ovarian cancer (EOC) malignant ascites remains incompletely characterized, particularly regarding CD8+ T lymphocyte differentiation and metabolic adaptations. This study investigated these characteristics and their relationship with estrogen receptor (ER) expression in 40 treatment-naïve EOC patients. Matched ascitic fluid and peripheral blood samples underwent comprehensive multicolor flow cytometric analysis to evaluate programmed death-1 (PD-1) expression, differentiation subset distribution, and mitochondrial functional parameters. CD8+ T lymphocytes demonstrated substantial enrichment among the lymphocyte population in ascitic fluid (27.9 ± 2.0%) compared to peripheral blood (13.1 ± 1.3%, p < 0.0001), accompanied by elevated PD-1 expression (62.4 ± 2.9% versus 40.9 ± 2.1%, p < 0.0001). Effector memory populations (Tem) predominated within ascites (67.9 ± 2.8%), indicating chronic antigenic exposure. Mitochondrial functional assessment revealed a distinctive metabolic phenotype: despite preserved mitochondrial mass, ascitic CD8+ T lymphocytes exhibited significantly reduced mitochondrial calcium (Rhod-2 positivity: 44.7 ± 3.8% versus 68.2 ± 4.5%, p < 0.0001) and reactive oxygen species (MitoSOX positivity: 18.7 ± 2.2% versus 28.9 ± 3.0%, p = 0.0287). Notably, ER-positive tumors (≥ 50% immunohistochemical expression) correlated with reduced frequency of CD8+ T cells among lymphocytes (22.1 ± 2.2% versus 32.5 ± 2.9%, p = 0.0040) and decreased PD-1 expression (55.7 ± 3.4% versus 74.5 ± 2.5%, p = 0.0003), while maintaining elevated mitochondrial mass (MTG positivity: 77.3 ± 2.8% versus 43.4 ± 6.9%, p < 0.0001). These findings indicate ascitic CD8+ T lymphocytes undergo metabolic reprogramming characterized by minimized mitochondrial stress, potentially representing an adaptive survival mechanism within the hostile ascitic microenvironment. The differential immune phenotypes associated with ER expression suggest distinct immune evasion strategies requiring tailored therapeutic approaches. This comprehensive characterization provides critical insights for developing personalized immunotherapeutic strategies incorporating metabolic modulation and hormone receptor status stratification.

Keywords:  CD8+ T lymphocytes; Epithelial ovarian cancer; Estrogen receptor; Mitochondrial metabolism; Programmed death-1

DOI:  https://doi.org/10.1007/s00262-025-04174-1
Immun Ageing. 2025 Oct 01. 22(1): 36

Early-life thymectomy results in visceral adipose tissue inflammation and glucose intolerance.

David J Buckley, Sogol Zahedi, Prema Velusamy, Sunita Sharma, Manoj Sabnani, Lisa C Flores, Ganga Tandukar, Yuji Ikeno, Paul J Fadel, Lisa A Lesniewski, Daniel W Trott.

  We have previously demonstrated that proinflammatory T cells in adipose tissue and the liver play a mechanistic role in glucose intolerance in old mice. Further, we and others have demonstrated that early life thymectomy results in a T cell phenotype that shares many features of classical T cell aging in an otherwise young healthy mouse. In this investigation, we sought to test the hypothesis that inducing premature T cell aging via early life thymectomy results in T cell mediated inflammation of the liver and visceral adipose tissue, as well as glucose intolerance in otherwise young mice. Mice were thymectomized at three weeks of age. At 9 months of age, thymectomized mice exhibited glucose intolerance that was independent of body mass along with greater frailty. Thymectomized mice exhibited blunted proportions of naïve and greater proportions of memory cells in the spleen, liver and perigonadal adipose tissue (pgWAT). Bulk RNAseq of the pgWAT revealed that thymectomized mice exhibited an upregulation of genes responsible for immune activation, chemokine signaling, and inflammation along with a downregulation of genes responsible for metabolic function. We also found that T cells in the pgWAT of thymectomized mice exhibited greater chemokine receptor expression as well as increased markers of histopathological inflammation that were independent of greater adipose tissue expansion. These results suggest that early life thymectomy results in T cell mediated pgWAT inflammation, systemic glucose intolerance and frailty in adult mice.

Keywords:  Aging; Glucose intolerance; Inflammation; T cell; Thymectomy

DOI:  https://doi.org/10.1186/s12979-025-00531-x
Cell Rep Methods. 2025 Sep 26. pii: S2667-2375(25)00221-8. [Epub ahead of print] 101185

Metabolic profiling of antigen-specific CD8+ T cells by spectral flow cytometry.

Nils Mülling, J Fréderique de Graaf, Graham A Heieis, Kristina Boss, Benjamin Wilde, Bart Everts, Ramon Arens.

  Cytotoxic CD8+ T cells are essential mediators of immune responses against viral infections and tumors. Upon antigen encounter, antigen-specific CD8+ T cells undergo clonal expansion and produce effector cytokines, processes that require dynamic metabolic adaptation. However, profiling antigen-specific T cells at single-cell resolution remains technically challenging. We present a spectral flow cytometry-based workflow enabling metabolic profiling of antigen-specific CD8+ T cells identified via major histocompatibility complex (MHC) class I tetramers or CD137 upregulation. The approach integrates the analysis of metabolic protein expression to infer pathway activity, uptake of fluorescent probes to measure functional metabolism and metabolite utilization, and assays evaluating cellular energy metabolism. Applied to human and mouse samples, this method defined the metabolic profiles of cytomegalovirus-, SARS-CoV-2-, and tumor-specific CD8+ T cells across distinct activation states and tissues. By detailing each component of the workflow, we provide practical guidance for applying metabolic spectral flow cytometry to dissect disease mechanisms and therapeutic responses.

Keywords:  CP: immunology; CP: metabolism; T cell; antigen-specific; metabolism; spectral flow cytometry

DOI:  https://doi.org/10.1016/j.crmeth.2025.101185
Biochem Biophys Res Commun. 2025 Sep 25. pii: S0006-291X(25)01424-X. [Epub ahead of print]785 152708

Mini review: Gene therapy targets for aging-associated diseases.

Shchukina Elza, Eremin Ilya, Mazunin Ilya, Moskalev Alexey.

  Contemporary gene therapy approaches represent a promising avenue for intervening in aging mechanisms and treating age-associated diseases. This review analyzes findings from preclinical and clinical studies of gene therapeutic strategies targeting age-related pathologies, including neurodegenerative, cardiovascular, metabolic, and ophthalmological disorders. We examine how specific aging mechanisms - DNA damage accumulation, telomere attrition, mitochondrial dysfunction, and chronic inflammation - can be addressed through targeted gene therapies. Key therapeutic targets include telomerase reactivation through TERT overexpression for genomic stability, KLOTHO supplementation for anti-inflammatory effects, metabolic regulation via SIRT family genes and FoxO3, and protein homeostasis modulation through APOE variants. Additional approaches encompass growth differentiation factors such as GDF11 for tissue regeneration, senolytic strategies for eliminating senescent cells, and epigenetic reprogramming techniques for tissue rejuvenation. Rather than characterizing these as universal 'longevity genes,' we emphasize their context-dependent effects, disease-specific applications, and associated benefit-risk profiles. Current methodological limitations and promising directions for developing personalized gene therapy interventions targeting the biological processes underlying aging are discussed.

Keywords:  Age-related diseases; Aging mechanisms; Cellular senescence; Delivery systems; Gene therapy

DOI:  https://doi.org/10.1016/j.bbrc.2025.152708
Research (Wash D C). 2025 ;8 0927

Intercellular Nanotube Mitochondrial Transplantation Strategy Mediating T Cell "Supercharging".

Baikun Liu, Jie Chen, Wenguo Cui.

The functional exhaustion of T cells in the tumor immune microenvironment is closely related to mitochondrial dysfunction. Current mitochondrial-targeted strategies have failed to restore the mitochondrial impaired function effectively. Mitochondrial transplantation technology has brought a revolution to the treatment of organelle-related diseases. Here, we first summarize the therapeutic potential and available platforms for mitochondrial transplantation, and focus on a type of mitochondrial transplantation technology mediated by tunneling nanotubes. This technology transfers functional mitochondria from bone marrow mesenchymal stem cells to CD8+ T cells, obtaining "supercharged T cells", which markedly enhance the metabolic adaptability and antitumor efficacy of T cells. It provides new ideas and technical platforms for the application of organelle medicine in tumor immunotherapy.

DOI: https://doi.org/10.34133/research.0927
Front Immunol. 2025 ;16 1654034

Steroid hormone regulation of immunometabolism and inflammation.

Ley Cody Smith, Mohankumar Ramar, Gregory L Riley, Clinton B Mathias, Ji-Young Lee.

  The metabolism of immune cells adapts to support the energy demands for their activation, differentiation, and effector functions through a process known as metabolic reprogramming. This metabolic plasticity is influenced by both extrinsic and intrinsic factors, including steroid hormones such as glucocorticoids, androgens, progestogens, and estrogens. These critical mediators modulate immune function and inflammatory responses through genomic and non-genomic regulation of intracellular metabolic pathways, including glycolysis, the tricarboxylic acid cycle, and oxidative phosphorylation. Interestingly, these effects appear to be dependent on cell type, hormonal concentration, and microenvironmental context. Herein, we discuss how steroid hormones regulate inflammation and immunometabolism and summarize recent studies highlighting immunometabolic regulation by steroid hormones as the key driver of their immunomodulatory effects. We also address potential mechanisms contributing to their seemingly dichotomous and context-specific regulation. Understanding the link between steroid hormone signaling, immunometabolism, host defense, chronic inflammation, and immunity will expand our understanding about how biological sex and stress influence the immune system and facilitate more precise therapeutic targeting of immune cell activity to mitigate inflammation- and immune-mediated diseases.

Keywords:  glycolysis; immune; immunometabolism; inflammation; oxidative phosphorylation; steroid hormones

DOI:  https://doi.org/10.3389/fimmu.2025.1654034
Immun Ageing. 2025 Sep 30. 22(1): 35

Targeting immunosenesence promotes clearance of senescent cells.

Anteneh Mehari Tizazu, Eyerusalem Amossa Tessema, Olivier Nf Cexus.

  Known as immunosenescence, the major dysregulation of the immune system with age is associated with poor vaccination efficacy, and increased susceptibility to infections, age-related pathologies, and neoplasms, with incidences exacerbated with age. Cellular senescence is a crucial process that puts cells in an irreversible cell-cycle arrest which prevents damaged or stressed cells from uncontrolled propagation and eventually potential malignancy. Paradoxically, senescence also contributes to the occurrence of cancer and increases the risk of metastasis through different secretory mediators. Altogether, the recent use of senotherapy to eliminate senescent cells has been shown to delay tumorigenesis, attenuate age-related deterioration of organs, and promote healthy aging. Interestingly, immune cells have been shown to specifically interact with, and kill senescent cells, thus opening new opportunities for the development of specific therapeutic strategies similar to immunotherapy in cancer. Through its detrimental impact on the immune system, immunosenescence is also leading to the accumulation of senescent cells with age thus further contributing to the occurrence and worsening of multiple age-related pathologies such as cancer. Understanding the molecular and cellular events occurring during the aging process, and triggering immunosenescence as well as the mechanisms by which senescent cells escape immune surveillance would help to improve immune responses to senescent cells and their clearance. In this review, we highlight how senescent cells interact with immune cells, and how immunosenescence-associated phenotypical and functional deregulation hinder the ability of immune cells to clear senescent cells. We further characterize strategies aimed at promoting the clearance of senescent cells by the immune system.

Keywords:  Aging; Cancer; Cellular senescence; Immunosenescence

DOI:  https://doi.org/10.1186/s12979-025-00518-8
Prostate. 2025 Oct 01.

MEIS2 Modulates Oxidative Phosphorylation and ROS Generation to Affect CD8+ T Cell Antitumor Immunity in Prostate Cancer.

Dengjun Han, Changyi Jiang, Hongjian Liu, Dayong Ye, Xiaofu Zeng, Yujie Wang, Xianyong Li, Mingqiang Su, Yang Cheng.

   BACKGROUND: The response of prostate cancer (PCa) to immunotherapy remains suboptimal. Although MEIS homeobox 2 (MEIS2) has been shown to delay the malignant progression of PCa by inhibiting cancer cell proliferation, promoting DNA damage, and affecting CD8+ T cell immune surveillance, its role in immune regulation and the underlying mechanisms remain elusive.
METHODS: MEIS2 expression in PCa and its correlation with CD8+ T cells were characterized using bioinformatics analysis and cell experiments. Using qPCR, flow cytometry, and ELISA, the impact of MEIS2 on CD8+ T cell antitumor immunity was assessed. To delineate the role of MEIS2 in oxidative phosphorylation and ROS generation, OCR, ATP, and ROS measurements were collected. Finally, the oxidative phosphorylation inhibitor MCH32 was introduced and rescue experiments were conducted to elucidate the mechanism by which MEIS2 regulated CD8+ T cell cytotoxicity.
RESULTS: MEIS2 expression in PCa was found to be downregulated, positively correlating with CD8+ T cell infiltration. Functionally, MEIS2 overexpression enhanced the cytotoxicity of CD8+ T cells. Mechanistically, MEIS2 was notably enriched in oxidative phosphorylation and ROS pathways. Knockdown of MEIS2 in cancer cells stimulated oxidative phosphorylation and ROS production, which impaired CD8+ T cell antitumor immunity. Treatment with the oxidative phosphorylation inhibitor MCH32 reversed these effects induced by MEIS2 knockdown.
CONCLUSION: Targeting MEIS2 could represent a clinically relevant approach to enhancing CD8+ T cell antitumor efficacy in PCa, our findings indicate.

Keywords:  CD8+ T cells; MEIS2; PCa; ROS; oxidative phosphorylation

DOI:  https://doi.org/10.1002/pros.70051
J Clin Invest. 2025 Sep 30. pii: e182480. [Epub ahead of print]

Acetyl-CoA carboxylase-1 inhibition increases regulatory T-Cell metabolism and graft-vs-host disease treatment efficacy via mitochondrial fusion.

Cameron McDonald-Hyman, Ethan G Aguilar, Ewoud B Compeer, Michael C Zaiken, Stephanie Y Rhee, Fathima A Mohamed, Jemma H Larson, Michael L Loschi, Christopher Lees, Govindarajan Thangavelu, Margaret L Sleeth, Kyle D Smith, Jennifer S Whangbo, Jerome Ritz, Tim D Sparwasser, Roddy S O'Connor, Peter A Crawford, Jeffrey C Rathmell, Leslie S Kean, Robert Zeiser, Keli L Hippen, Michael L Dustin, Bruce R Blazar.

  Regulatory T-cells (Treg) are critical for maintaining immune homeostasis, and their adoptive transfer can treat murine inflammatory disorders. In patients, Treg therapies have been variably efficacious. Therefore, new strategies to enhance Treg therapeutic efficacy are needed. Treg predominantly depend upon oxidative phosphorylation (OXPHOS) for energy and suppressive function. Fatty acid oxidation (FAO) contributes to Treg OXPHOS and can be important for Treg "effector" differentiation, but FAO activity is inhibited by coordinated activity of isoenzymes acetyl-CoA Carboxylase-1 and -2 (ACC1/2). Here, we show that small molecule inhibition or Treg-specific genetic deletion of ACC1 significantly increases Treg suppressive function in vitro and in mice with established chronic GVHD. ACC1 inhibition skewed Treg towards an "effector" phenotype and enhanced FAO-mediated OXPHOS, mitochondrial function, and mitochondrial fusion. Inhibiting mitochondrial fusion diminished the effect of ACC1 inhibition. Reciprocally, promoting mitochondrial fusion, even in the absence of ACC1 modulation, resulted in a Treg functional and metabolic phenotype similar to ACC1 inhibition, indicating a key role for mitochondrial fusion in Treg suppressive potency. Ex vivo expanded, ACC1 inhibitor treated human Treg similarly augmented suppressor function as observed with murine Treg. Together, these data suggest that ACC1 manipulation may be exploited to modulate Treg function in patients.

Keywords:  Bone marrow transplantation; Immunology; Metabolism; Mitochondria; T cells

DOI:  https://doi.org/10.1172/JCI182480
Nat Aging. 2025 Oct 01.

Aging puts Leydig cells in a tough spot.

Anna Kriebs.

DOI: https://doi.org/10.1038/s43587-025-00995-y
Clin Cancer Res. 2025 Sep 29.

Rewiring antitumor immunity: targeting CLDN18.2 with conditional 4-1BB activation.

Giulia Pretelli, Elena Garralda.

Claudin 18.2 has emerged as a validated target in solid tumors, spurring next-generation therapies. Bispecific antibodies linking Claudin 18.2 to conditional 4-1BB activation offer a novel approach to enhance T cell function. By confining co-stimulation to the tumor microenvironment, they aim to boost efficacy while limiting systemic toxicity.

DOI: https://doi.org/10.1158/1078-0432.CCR-25-2554
bioRxiv. 2025 Apr 14. pii: 2024.04.01.587634. [Epub ahead of print]

IL-7-mediated expansion of autologous lymphocytes increases CD8 + VLA-4 expression and accumulation in glioblastoma models.

Kirit Singh, Kelly M Hotchkiss, Sarah L Cook, Pamy Noldner, Ying Zhou, Eliese M Moelker, Chelsea O Railton, Emily E Blandford, Bhairavy J Puviindran, Shannon E Wallace, Pamela K Norberg, Gary E Archer, Beth H Shaz, Katayoun Ayasoufi, John H Sampson, Mustafa Khasraw, Peter E Fecci.

The efficacy of T cell-activating therapies against glioma is limited by an immunosuppressive tumor microenvironment and tumor-induced T cell sequestration. We investigated whether peripherally infused non-antigen specific autologous lymphocytes (ALT) could accumulate in intracranial tumors. We observed that non-specific autologous CD8 + ALT cells can indeed accumulate in this context, despite endogenous T cell sequestration in bone marrow. Rates of intratumoral accumulation were markedly increased when expanding lymphocytes with IL-7 compared to IL-2. Pre-treatment with IL-7 ALT also enhanced the efficacy of multiple tumor-specific and non-tumor-specific T cell-dependent immunotherapies against orthotopic murine and human xenograft gliomas. Mechanistically, we detected increased VLA-4 on mouse and human CD8 + T cells following IL-7 expansion, with increased transcription of genes associated with migratory integrin expression ( CD9) . We also observed that IL-7 increases S1PR1 transcription in human CD8 + T cells, which we have shown to be protective against tumor-induced T cell sequestration. These observations demonstrate that expansion with IL-7 enhances the capacity of ALT to accumulate within intracranial tumors, and that pre-treatment with IL-7 ALT can boost the efficacy of subsequent T cell-activating therapies against glioma. Our findings will inform the development of future clinical trials where ALT pre-treatment can be combined with T cell-activating therapies.
Brief Summary: T cell immunotherapies are limited by few T cells in glioma. Adoptively transferred lymphocytes expanded with IL-7 exhibit increased VLA-4 expression and accumulate in tumors.

DOI: https://doi.org/10.1101/2024.04.01.587634
Aging Cell. 2025 Sep 29. e70222

Vascular Endothelial NAMPT-Mediated NAD+ Biosynthesis Regulates Angiogenesis and Cardiometabolic Functions in Male Mice.

Shotaro Kosugi, Shintaro Yamaguchi, Ken Nishioka, Taichi Nagahisa, Yasuhiro Watanabe, Daiki Kojima, Kenji Kaneko, Ryunosuke Mitsuno, Ran Nakamichi, Yoshinaga Kawano, Kenichiro Kinouchi, Koichiro Homma, Takeshi Kanda, Junichiro Irie, Kazutoshi Miyashita, Toshiaki Monkawa, Jun Yoshino, Hiroshi Itoh, Kaori Hayashi.

  Aging is associated with metabolic dysfunction and cardiovascular abnormalities. Defective nicotinamide adenine dinucleotide (NAD+) biosynthesis correlates with aging and aging-associated complications. However, the precise molecular mechanisms linking aging-associated NAD+ deficiency to cardiometabolic dysfunction remain unclear. Herein, we examined whether nicotinamide phosphoribosyltransferase (NAMPT), a key enzyme in NAD+ biosynthesis, influences vascular endothelial function and whole-body metabolic and hemodynamic homeostasis during aging. Vascular endothelial cell-specific Nampt knockout (VeNKO) mice fed a regular chow diet exhibited no cardiometabolic abnormalities, whereas male VeNKO mice fed a high-fat diet exhibited reduced angiogenesis, resulting in impaired subcutaneous adipogenesis, impaired glucose metabolism, and hemodynamic disturbances. Mechanistically, NAMPT loss attenuated NAD+-dependent deacetylase sirtuin-1 (SIRT1) and endothelial nitric oxide synthase (eNOS) signaling, impairing angiogenesis. Aged mice exhibited endothelial NAD+ depletion driven by an imbalance between NAMPT-mediated NAD+ biosynthesis and consumption, leading to impaired eNOS signaling and associated angiogenic and cardiometabolic dysfunction, similar to that observed in VeNKO mice. Nicotinamide mononucleotide administration replenished vascular endothelial NAD+ levels, improved angiogenesis, restored subcutaneous adipose tissue volume, and ameliorated aging-associated cardiometabolic dysfunction. Collectively, our findings provide mechanistic and therapeutic insights into vascular endothelial NAMPT-NAD+-SIRT1-eNOS signaling related to aging-associated cardiometabolic disorders.

Keywords:  NAMPT‐mediated NAD+ biosynthesis; aging; angiogenesis; glucose metabolism; hypertension; vascular endothelial cell

DOI:  https://doi.org/10.1111/acel.70222
Mol Ther. 2025 Sep 30. pii: S1525-0016(25)00818-4. [Epub ahead of print]

BiTE-secreting T cells rationally combine with PD-1 blockade and vaccine boosting to reshape antitumor immunity in ovarian cancer.

Jessie L Chiello, Nijamuddin Shaikh, Justine Jacobi, Nicole Gaulin, Gabriel Santos, Christopher Keck, Suzanne M Hess, Brian Lichty, Prashant K Singh, Spencer R Rosario, Scott I Abrams, Emese Zsiros, Mark D Long, A J Robert McGray.

Despite some clinical success, ovarian cancer (OC) patients rarely achieve durable benefit from current immunotherapies, suggesting a need for strategies that improve OC immune recognition. We previously reported that engineered T cells secreting folate receptor alpha (FRα) targeted bispecific T cell engagers (FR-B T cells) elicit robust antitumor responses in OC, in part by engaging endogenous T cells. Here, we use clinical OC specimens and preclinical OC to evaluate FR-B T cells combined with PD-1 blockade. Assessing the tumor microenvironment during acute and prolonged FR-B T cell + anti-PD-1 responses revealed broad immune cell engagement/reorganization. Early CD8+ T cell-driven responses and myeloid cell influx were followed by accumulation of CXCL13-producing macrophages, activated B cells, and effector memory CD4+ T cells with durable response, hallmarks that were diminished with progressive disease. Resistant OC (characterized by FRα loss and metabolic reprogramming) emerged at disease relapse, suggesting a need to target additional vulnerabilities to extend responses. As FR-B T cells promoted epitope spreading beyond FRα, we employed a booster vaccine to enhance antitumor immunity, improving OC control. Our findings point to rationally combining FR-B T cells with PD-1 blockade in OC and an opportunity to apply personalized cancer vaccines to limit OC relapse.

DOI: https://doi.org/10.1016/j.ymthe.2025.09.047
bioRxiv. 2025 Sep 28. pii: 2025.09.25.678523. [Epub ahead of print]

Lactate promotes longevity through redox-driven lipid remodeling in Caenorhabditis elegans.

Arnaud Tauffenberger, Payton J Netherland, Hubert Fiumelli, Joshua D Meisel, Frank C Schroeder, Pierre Magistretti.

Lactate has emerged as a key metabolite involved in multiple physiological processes, including memory formation, immune response regulation, and muscle biogenesis. However, its role in aging and cellular protection remains unclear. Here, we show that lactate promotes longevity in C. elegans through a mechanism that requires early-life intervention, indicating a hormetic priming effect. This pro-longevity action depends on its metabolic conversion via LDH-1 and NADH, which drives redox-dependent metabolic reprogramming. Multi-omics approaches revealed that lactate induces early-stage metabolic adaptations, with a strong modulation of lipid metabolism, followed by late-life transcriptional remodeling. These shifts are characterized by enhanced stress response pathways and suppression of energy- associated metabolic processes. Our genetic screening identified sir-2.1 /SIRT1 and rict- 1/ RICTOR as essential for lactate-mediated lifespan extension. Our findings establish lactate as a pro-longevity metabolite that couples redox signaling with lipid remodeling and nutrient- sensing pathways. This work advances our understanding of lactate's dual role as a metabolic intermediary and geroprotector signaling molecule, offering insights into therapeutic strategies for age-related metabolic disorders.

DOI: https://doi.org/10.1101/2025.09.25.678523
Cancer Immunol Immunother. 2025 Sep 29. 74(10): 319

Single-cell transcriptomic analyses provide insights into SPP1+ TAM-mediated immune suppression and CD8+ T cell dysfunction in lung cancer.

Rahma Taher Almgrami, Tengyue Zhang, Qitai Zhao, Mingming You, Jinyan Liu, Yi Zhang.

   BACKGROUND: Metastatic lung carcinoma poses considerable treatment difficulties. It exhibits cellular characteristics that differ from those of early-stage cancer. Immunotherapy demonstrates enhanced hope for patients with advanced and metastatic lung cancer. Tumor-associated macrophages (TAMs) may be a contributing factor that diminishes the effectiveness of immunotherapy. Secreted phosphoprotein 1 (SPP1)+ TAMs are considered to possess immunosuppressive characteristics, as their interaction with CD8+ T lymphocytes results in the exhaustion of these cells.
METHODS: We analyzed single-cell RNA sequencing datasets of lung cancer metastases in order to examine the development of brain metastatic tumors. Furthermore, the cell-cell interactions between SPP1+ TAM cells and CD8+ T cells within primary and brain metastatic cancers were systematically compared. Additionally, we utilized a flow cytometer and immunofluorescence to demonstrate how SPP1 affects the function of CD8+ T cells. In vitro, we generated SPP1-overexpressing macrophages and performed qPCR, Western blot, and co-culture assays with or without anti-SPP1 or anti-A2AR treatment to evaluate immunosuppressive effects.
RESULTS: The results demonstrated that the proportions of immune cells in metastatic brain tissues are lower, while the infiltration of macrophages is higher. SPP1+ TAMs contribute to immune suppression in lung cancer by limiting the activation of CD8+ T cells and cytokine production. Anti-SPP1 treatment positively impacts CD8+ T cell function, counteracting SPP1-induced dysfunction and facilitating the production of cytokines. SPP1 overexpression in macrophages enhanced their immunosuppressive phenotype by upregulating CD73 and cytokines such as IL-10 and TGF-β, leading to impaired CD8⁺ T cell function via A2AR signaling; notably, neutralization of SPP1 or A2AR successfully restored CD8⁺ T cell activity.
CONCLUSIONS: Our findings characterize the immunological environment of both primary and metastatic lung cancer, highlighting SPP1-mediated immune suppression as a potential therapeutic target to restore T cell responses. Preclinical data demonstrate that Anti-SPP1 antibodies can reverse T cell exhaustion and enhance immune responses in lung cancer.

Keywords:  A2AR; Brain metastasis; CD73; CD8+ T cell dysfunction; SPP1; SPP1+ TAMs

DOI:  https://doi.org/10.1007/s00262-025-04180-3
Cell Rep. 2025 Oct 01. pii: S2211-1247(25)01130-1. [Epub ahead of print]44(10): 116359

Targeting an essential viral oncoprotein with an IL-7-enhanced mRNA vaccine induces durable immunity to Merkel cell carcinoma.

Alexander Frey, Kathryn Clulo, Yuewei Fei, Therese Cordero Dumit, Frankie Scallo, Jerry Allen Williams, Emily Chang, Curtis J Perry, Lena V Wirth, Daniel Jacobs, David A Braun, Marcus W Bosenberg, Thuy T Tran, James Clune, Harriet M Kluger, Kelly Olino, Jeffrey J Ishizuka.

  Although mRNA technologies have reinvigorated cancer vaccine development, the identification of strong antigens with consistent tumor cell expression and generation of durable antigen-specific CD8+ T cell memory remain key challenges. We identified the Merkel cell carcinoma (MCC) large T antigen (LTA) as an optimal vaccine target, essential for tumor cell survival and immunogenic in a cancer with high unmet clinical need. We developed an mRNA vaccine to MCC-LTA in murine studies and patient samples. We showed that antigen loss develops rapidly and causes resistance in mouse models when immunogenic, but non-essential antigens are targeted. To improve T cell response durability, we co-encoded LTA and IL-7, co-localizing proliferative and memory signals spatially and temporally with antigen exposure. IL-7-containing mRNA vaccines improved antigen-specific T cell expansion, memory differentiation, and tumor control. We propose that the principles of antigen essentiality and memory signal co-encoding may be adapted to improve the efficacy of mRNA therapeutics.

Keywords:  CP: Cancer; CP: Immunology; IL-7; Merkel cell carcinoma; Merkel cell polyomavirus; T cell memory; adjuvants; driver antigens; human translation; mRNA; patient samples; vaccines

DOI:  https://doi.org/10.1016/j.celrep.2025.116359
Theranostics. 2025 ;15(18): 9580-9600

Macrophage-TREM2 promotes cardiac repair by restricting the infiltration of CD8+ T cells via CXCL16-CXCR6 axis after myocardial infarction.

Linlin Zhang, Sheng Wang, Yu Ding, Tao Zheng, Jie Sheng, Yanshan Chen, Zhiyue Wang, Ximei Dai, Canbiao Wang, Long Ma, Jing Pan, Yunming Zhang, Longjiang Zhang.

Background: Infiltrated CD8+ T cells following myocardial infarction (MI) are potential myocardial injury factors, triggering autoimmunity by binding to myocardial cell-specific proteins. It has been reported that autoimmunity after MI is restricted during the fibrosis period. Nevertheless, the relevant mechanisms of this process have scarcely been explored. Cell-cell communication analysis suggests that macrophages are the most promising group for restricting T cell activity. Unbiased single-cell sequencing data screening indicates that TREM2 is a leading gene significantly upregulated after MI. However, how TREM2 restricts the activity of CD8+ T cells remains unknown. Methods and Results: The adoptive transfer of circulating CD8+ T cells after MI proved their autoimmune attribute of attacking cardiomyocytes. CD8 antagonistic antibodies and the anti-autoimmune drug Ozanimod effectively inhibited the infiltration of CD8+ T cells and significantly ameliorated the damage to cardiomyocytes after MI. In TREM2 KO mice, the infiltration of CD8+ T cells in the myocardium was significantly increased without influencing the number of Treg cells. The results of cell-cell communication revealed that CXCL16-CXCR6 was the most predominant receptor-ligand pair between macrophages and CD8+ T cells. The results of ELISA and Transwell indicated that TREM2 deficiency led to an increase in CXCL16 secretion, thereby enhancing the chemotaxis of CD8+ T cells. The KEGG analysis and Western Blot results demonstrated that the deficiency of TREM2 augmented the activation of the PI3K-AKT signaling pathway, thereby resulting in an increase in CXCL16 secretion. Moreover, TREM2 deficiency also reduced VEGFC secretion and cardiac lymphangiogenesis, thereby leading to the impairment of immune cell drainage. Additionally, TREM2 deficiency reversed Ozanimod's effect on inhibiting CD8+ T cell infiltration. The overexpression of TREM2 significantly decreased CD8+ T cell infiltration and improved cardiac function. Conclusions: Macrophage TREM2 promotes cardiac repair by limiting the infiltration of CD8+ T cells and facilitating lymphangiogenesis.

DOI: https://doi.org/10.7150/thno.118014
Res Sq. 2025 Sep 23. pii: rs.3.rs-7483419. [Epub ahead of print]

Ferritinophagy Loss Drives Mitochondrial Iron Import and Colorectal Tumorigenesis.

Xiang Xue, Hyeoncheol Kim, Luke Villareal, Naiara Santana-Codina, Christian Cabanlong, Lavanya Goodla, Eric Prossnitz, David Martin, Joseph Mancias.

Iron is an essential cofactor for mitochondrial metabolism, yet the regulatory networks linking cellular iron homeostasis to colorectal cancer (CRC) progression remain incompletely understood. Here, we identify nuclear receptor coactivator 4 (NCOA4), a ferritinophagy receptor, as a context-dependent tumor suppressor that coordinates cytosolic and mitochondrial iron handling in CRC. Analysis of human tumors and colon-specific Ncoa4 knockout mice revealed that NCOA4 loss drives tumorigenesis by inducing transferrin receptor-mediated iron uptake and mitochondrial calcium uniporter (MCU)-dependent mitochondrial iron import. This dual iron overload elevates mitochondrial reactive oxygen species, activates STAT3 signaling, and enhances tumor cell proliferation. NCOA4 overexpression reverses these effects, reducing MCU expression and tumor growth. Pharmacological inhibition of MCU, STAT3, or mitochondrial iron transport mitigated tumorigenesis in NCOA4-deficient models. Our findings define an NCOA4-MCU-STAT3 metabolic signaling axis that couples iron metabolism to oncogenic progression and reveal mitochondrial iron handling as a therapeutic vulnerability in CRC.

DOI: https://doi.org/10.21203/rs.3.rs-7483419/v1
Front Immunol. 2025 ;16 1643941

Current strategies for armoring chimeric antigen receptor T-cells to overcome barriers of the solid tumor microenvironment.

Dorothy D Yang, William Macmorland, James N Arnold.

  Chimeric antigen receptor (CAR) T-cell therapy is a transformative immunotherapeutic approach, yet its application in solid tumors is hindered by the immunosuppressive tumor microenvironment (TME). The TME restricts T-cell trafficking, impairs effector functions, and promotes exhaustion through soluble factors, metabolic stress, and suppressive cell populations. Recent efforts to enhance CAR T-cell efficacy have focused on armoring strategies that 'reprogram' and 'boost' T-cell responses within the TME. These include engineered expression of dominant-negative receptors or cytokine-releasing constructs (such as IL-12 and IL-18) to reshape the local immune milieu and improve T-cell effector function, synthetic Notch receptors for inducible gene expression, and chemokine receptor knock-ins to improve tumor infiltration. Additional approaches aim to modulate intrinsic metabolic pathways to improve CAR T-cell persistence under hypoxic or nutrient-deprived conditions. Armoring strategies that recruit bystander or endogenous immune cells also activate broader anti-tumor immunity that prevents antigen escape and may induce more durable anti-tumor responses. This review highlights the molecular and cellular mechanisms by which current armoring strategies enhance CAR T-cell functions in solid tumors, offering a perspective on improving immune cell engineering for overcoming the hurdles encountered in deploying these therapies against solid cancers.

Keywords:  T-cells; armored; chimeric antigen receptor; immunosuppression; immunotherapy; microenvironment; solid tumors; stroma

DOI:  https://doi.org/10.3389/fimmu.2025.1643941
Front Immunol. 2025 ;16 1672072

Metabolic regulation of Th9 cell differentiation: insights for IL-9-driven diseases.

Swetha Peesari, Jeremy P McAleer.

  Th9 cells are a CD4 T cell subset that produces interleukin-9 (IL-9), a pleiotropic cytokine implicated in allergies, autoimmunity and cancer. Defining the cellular effects of IL-9 and factors regulating its expression are essential for fully understanding its roles in immunity and disease. IL-9 acts on a variety of immune and non-immune cells through a heterodimeric receptor composed of IL-9Rα and the common gamma chain. In CD4 T cells, IL-9 promotes mTOR activation, aerobic glycolysis, proliferation and reinforces its own expression. Additional cellular effects include mast cell activation, B cell antibody production and anti-tumor immunity. These biological activities are complemented by recent studies that expand our understanding of Th9 differentiation beyond canonical cytokine and transcription factor pathways. Notably, glycolytic reprogramming and fatty acid metabolism have emerged as key regulators of IL-9 production, mediated through the activities of mTOR, PPAR-γ and acetyl-CoA carboxylase 1 (ACC1). mTOR-driven aerobic glycolysis is essential for Th9 cell differentiation, supporting survival, proliferation, and IL9 expression through HIF-1α activation. In contrast, ACC1 suppresses IL-9 through fatty acid synthesis, which enhances RARα-mediated transcriptional repression. PPAR-γ appears to have dual functions: it promotes IL-9 production by increasing glucose uptake and activating mTOR, but reduces IL-9 in response to synthetic agonists that may increase fatty acid uptake. Overall, these findings highlight critical roles for metabolic regulators in Th9 responses and suggest that targeting these pathways may offer new therapeutic strategies for IL-9-driven diseases.

Keywords:  ACC1; MTOR activation; PPAR-gamma; Th9 cells; allergies; autoimmunity; cancer; interleukin-9 (IL-9)

DOI:  https://doi.org/10.3389/fimmu.2025.1672072