bims-imseme 2026-08-30 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2026–08–30
twenty papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Post-translational modifications in CD8+ T cell exhaustion: mechanisms, networks, and epigenetic locking.
Host metadherin coordinates hepatic lipid metabolism and CD8+ T cell immunity to promote tumor progression.
Multiscale modeling of T cell exhaustion: A mathematical framework integrating continuous dynamics with spatial heterogeneity.
C-terminus CD28 phosphorylation, Y218, modulates IL-2 secretion and therapeutic effect of CAR-T cells.
Genome-scale perturb-seq in primary human CD4+ T cells maps context-specific regulators of T cell programs and human immune traits.
The ageing immune system and its battle with viruses.
CD8+ T cell heterogeneity and function in lupus nephritis: a focused review.
Reprogramming immunometabolism: linking nutrient sensing, cell death, and therapeutic innovation.
EPO Receptor Blockade in Dendritic Cells Enhances Antitumor CD8+ T Cell Immunity.
Metabolic switch: lymphocytes and the onset of T-cell-mediated autoimmunity.
The Glucose Transporter GLUT3 Controls Regulatory T Cell Function.
Publisher Correction: Decade-long persistence of CD19 CAR T cells in B cell lymphomas.
Ferroptotic stress promotes hematopoietic stem cell aging through S1P-dependent epigenetic and lipid remodeling.
A Mechanism-Based Framework for Anti-Aging Strategies: From Metabolic Regulation to Senotherapy and Stem Cell-Based Interventions.
Mitochondrial regulation of cellular senescence heterogeneity.
Mitochondrial Reprogramming of Tumor-Infiltrating T Cells as a Next-Generation Strategy to Overcome Immunotherapy Resistance.
Lactobacillus salivarius potentiates gastrointestinal cancer immunotherapy through its metabolite chenodeoxycholic acid.
Cytotoxic CD4+ T cells induce age-associated myelopoiesis through CCL5-CCR5 signaling.
A single-cell transcriptomic atlas reveals the immune panorama of neonatal sepsis.
Amino acid homeostasis by CORVET/HOPS: A metabolic and stress resilience checkpoint for T cells.

Front Immunol. 2026 ;17 1913598

Post-translational modifications in CD8+ T cell exhaustion: mechanisms, networks, and epigenetic locking.

Ting Yu, Mengjuan Xia, Yuxia Wu, Qiongshi Wu, Jing Xie, Haocheng Gao, Shengfeng Hu.

  CD8+ T cells are core effector cells of adaptive immunity. However, in chronic infection and tumor microenvironments, they often lose their effector functions. Under persistent antigenic and metabolic stress, CD8+ T cells may progressively acquire a stable dysfunctional state termed T cell exhaustion. Post-translational modifications (PTMs) constitute a rapid and dynamic regulatory system that targets four core functional modules: membrane receptor signaling, transcription factors, metabolic enzymes, and epigenetic regulators. These modules are interconnected through a multi-layered PTM network. Within this network, PTMs orchestrate a stepwise cascade that proceeds from signal initiation through metabolic reprogramming to transcriptional and epigenetic remodeling. Ultimately, this cascade consolidates the exhaustion program via stable epigenetic memory. Accordingly, we propose a "PTM-driven signal-metabolism-epigenetic locking model" as the central framework of this review. Focusing on five key PTMs, namely phosphorylation, ubiquitination, glycosylation, acetylation, and lactylation, we elucidate how these modifications cooperatively regulate CD8+ T cell exhaustion. Critically, the PTM network drives progressive locking of the exhausted state through three epigenetic layers: DNA methylation, chromatin remodeling, and histone modifications. These layers collectively contribute to the progressive stabilization of the exhausted state over time. This framework integrates transient environmental signals, metabolic fluctuations, and transcriptional changes into permanent cell fate decisions. Building upon this mechanistic understanding, the review further explores novel strategies targeting the PTM network to reverse exhaustion and enhance immunotherapeutic efficacy. This review provides a clear and comprehensive framework for understanding how PTMs govern CD8+ T cell exhaustion and lays a solid foundation for the development of next-generation immunotherapies.

Keywords:  CD8+ T cells; cancer immunotherapy; epigenetic locking; post-translational modifications; t cell exhaustion

DOI:  https://doi.org/10.3389/fimmu.2026.1913598
Cell Metab. 2026 Aug 28. pii: S1550-4131(26)00328-1. [Epub ahead of print]

Host metadherin coordinates hepatic lipid metabolism and CD8+ T cell immunity to promote tumor progression.

Yong Tang, Ziqing Chen, Hirak Sarkar, Yong Wei, Sereno L Lopez-Darwin, Asael Roichman, Ji Woo Park, Qinglan Li, Cao Fang, Zihong Chen, James Gow, Minhong Shen, Jennifer Shi, Lifei Jiang, Richard Klar, Xiang Hang, Janette R Lugo, Christina J DeCoste, Jennifer M Miller, Wei Wang, Peter Romanienko, Alana L Welm, Ileana M Cristea, Liling Wan, Joshua D Rabinowitz, Yibin Kang.

  Cancer progression is systemically influenced by distant organ dysfunction induced by primary tumors, yet how long-distance tumor-organ crosstalk regulates antitumor immunity remains unclear. Here, we identify host metadherin (MTDH) as a critical regulator of tumor-induced immunosuppression and metabolic reprogramming via tumor-liver interactions. Using Mtdh knockout mouse models, we show that concurrent MTDH loss in hepatocytes and CD8+ T cells enhances effector T cell function and suppresses tumor growth and metastasis. Mechanistically, tumor-derived extracellular vesicles and particles (EVPs) activate Kupffer cells to secrete tumor necrosis factor α (TNF-α) and TGF-β, which suppress hepatic PPARα-mediated lipid oxidation via nuclear factor κB (NF-κB) signaling. MTDH loss restores hepatic lipid catabolism, reduces systemic lipid levels, and promotes mitochondrial metabolic reprogramming in CD8+ T cells under lipid-reduced conditions, thereby boosting antitumor immunity. Genetic or pharmacological targeting of MTDH synergizes with anti-PD-1 therapy. These findings establish host MTDH as a key mediator of tumor-liver crosstalk through metabolic and immune interactions, driving systemic cancer progression.

Keywords:  CD8(+) T cells; EVP; MTDH; PPARα; extracellular vesicles and particles; immunotherapy; lipid metabolism; tumor-liver interaction

DOI:  https://doi.org/10.1016/j.cmet.2026.08.003
PLoS Comput Biol. 2026 Aug 26. 22(8): e1014690

Multiscale modeling of T cell exhaustion: A mathematical framework integrating continuous dynamics with spatial heterogeneity.

Chenghang Li, Yuhong Zhang, Xue Liu, Yipu Qu, Xiulan Lai, Jinzhi Lei.

Continuous antigen exposure drives T cells into a progressive state of dysfunction known as exhaustion, enabling tumors to evade immune surveillance and promoting disease progression. Despite its importance, predictive modeling of T cell exhaustion remains a major challenge due to the complexity of its regulatory dynamics. To address this challenge, we developed a mathematical framework that characterizes the dynamic regulation of T cell exhaustion and its impact on tumor-immune interactions. Here, we integrate multi-source data, population dynamics modeling, and agent-based modeling to track the progressive stages of CD8+ T cell exhaustion. Our model demonstrates that immune checkpoint blockade significantly delays exhaustion and promotes the expansion of tumor-reactive T cells compared to untreated conditions. From a pseudo-potential energy perspective, we show that the core mechanism of immunotherapy lies in expanding the tumor-reactive T cell pool, which consequently reduces the overall state of exhaustion within the system. We find that T cell activation and exhaustion signals jointly govern tumor-immune dynamics. Enhancing activation alone without restricting exhaustion can inadvertently accelerate the loss of T cell function. In contrast, combining enhanced activation (via anti-CTLA-4) with suppressed exhaustion (via anti-PD-1) is essential for achieving a sustained antitumor response. Furthermore, spatial simulations confirm that a high-activation and low-exhaustion state effectively restricts tumor spread, maintaining substantially lower tumor densities compared to low-activation, high-exhaustion scenarios. Our framework provides quantitative insights into T cell exhaustion and a theoretical foundation for optimizing combination immunotherapies.

DOI: https://doi.org/10.1371/journal.pcbi.1014690
Mol Ther. 2026 Aug 25. pii: S1525-0016(26)00716-1. [Epub ahead of print]

C-terminus CD28 phosphorylation, Y218, modulates IL-2 secretion and therapeutic effect of CAR-T cells.

Elena Martinez-Planes, Maria Cecilia Ramello, Miguel G Fontela, Mohammad-Reza Shokri, Timothy Tran, Lancia Darville, John Koomen, Youngchul Kim, Daniel Abate-Daga.

CD28 is a co-stimulatory component of several second-generation chimeric antigen receptor (CAR)-T cells, providing signals essential for T cell proliferation, survival, and cytokine secretion. However, the specific contribution of individual CD28 intracellular motifs to CAR-T cell function remains incompletely understood. Here, we identify tyrosine 218 (Y218) in the CD28 cytoplasmic domain as a critical regulatory site, and demonstrate that its phosphorylation is essential for optimal CAR-T cell activity. Using a 218F mutant, we show that loss of Y218 phosphorylation leads to impaired IL-2 production and abrogates antitumor efficacy. Transcriptomic profiling of 218F CAR-T cells revealed increased expression of IL-17A, IL-17F, and related cytokines, suggesting a shift toward a pro-inflammatory Th17-like phenotype that may contribute to dysfunction. Mechanistically, we demonstrate that the interleukin-2-inducible T-cell kinase, ITK, mediates Y218 phosphorylation. To translate this mechanistic insight into improving CAR design, we engineered a novel CAR incorporating a synthetic ITK-binding motif (PYRP). This novel design enhances ITK recruitment, increases Y218 phosphorylation, boosts IL-2 secretion, and improves anti-tumor efficacy in vivo. Our findings underscore the functional relevance of Y218 phosphorylation in modulating CAR-T cell fate and reveal a strategy to fine-tune CAR signaling through targeted kinase recruitment to enhance therapeutic efficacy.

DOI: https://doi.org/10.1016/j.ymthe.2026.08.035
Cell. 2026 Aug 28. pii: S0092-8674(26)00929-3. [Epub ahead of print]

Genome-scale perturb-seq in primary human CD4+ T cells maps context-specific regulators of T cell programs and human immune traits.

Ronghui Zhu, Emma Dann, Jun Yan, Justine Reyes Retana, Ryunosuke Goto, Reese C Guitche, Lillian Brixi, Mineto Ota, Austin Hartman, Theodore L Roth, Ansuman T Satpathy, Jonathan K Pritchard, Alexander Marson.

  Gene regulatory networks encode the fundamental logic of cellular functions, but systematic network mapping remains challenging, especially in cell states relevant to human biology and disease. Here, we perturbed all expressed genes across 22 million primary human CD4+ T cells from four donors and developed a probe-based perturb-seq platform to measure the transcriptome effects in cells at rest and after stimulation. These data allowed us to map genes regulating immune pathways, including previously uncharacterized regulators of cytokine production. Importantly, active regulators and the gene programs they control changed dramatically across stimulation conditions. Perturbation signatures enabled us to model T cell states observed in population-scale transcriptomic atlases, nominating regulators of T cell polarization and of age-related phenotypes. Finally, we leveraged perturb-seq to implicate context-specific gene regulatory pathways in autoimmune disease risk. Our study provides a foundational resource and new approaches to decode T cell function and human immune traits.

Keywords:  CD4(+) T cell polarization; CD4(+) T cells; CRISPR; CRISPR interference; CRISPRi; T cell aging; cell fate decision; functional genomics; gene regulatory networks; human T cells; human genetics; perturb-seq; perturbation signatures; primary human cells; probe-based perturb-seq

DOI:  https://doi.org/10.1016/j.cell.2026.08.002
J Gen Virol. 2026 Aug;107(8):

The ageing immune system and its battle with viruses.

Jessica A Gaevert, Carolien E van de Sandt.

  The global increase in life expectancy has resulted in a growing proportion of older individuals at increased risk of severe disease outcomes following viral infections. CD8+ T cells play a vital role in controlling viral infections and provide protection against severe disease by eliminating virus-infected cells. Furthermore, CD8+ T cells recognize conserved internal viral proteins, enabling cross-reactivity and the formation of long-term immunological memory. However, a lifetime of exposures to acute and persistent latent viruses, vaccinations and the age-associated decline in immune functions (immunosenescence and inflammaging) have a profound impact on virus-specific CD8+ T cell populations. The age-associated progressive decline of naïve CD8+ T cells, reduced T cell receptor (TCR) diversity, the accumulation of highly differentiated memory and/or exhausted CD8+ T cells and low-level chronic inflammation directly affect virus-specific immunity. These age-associated changes impair both primary and recall CD8+ T cell responses to infections and vaccinations in older individuals. Both ageing and exposure history impact the CD8+ T cell correlates of protection, including frequency, phenotype, TCR diversity, polyfunctionality, cytotoxic potential and proliferation capacity. The implications of these changes are discussed in the context of acute (influenza and respiratory syncytial virus), persistent latent (cytomegalovirus, Epstein-Barr virus and varicella-zoster virus) and novel (severe acute respiratory syndrome coronavirus 2) viruses. An in-depth understanding of how lifelong viral exposures intersect with immunosenescence will elucidate how virus-specific CD8+ T cells change with age. These insights will aid vaccine strategies to effectively harness CD8+ T cells and induce long-lasting, broadly reactive virus-specific immunity.

Keywords:  CD8+ T cells; acute and chronic/latent viruses; ageing; correlates of protection; immunosenescence; vaccination

DOI:  https://doi.org/10.1099/jgv.0.002320
Front Immunol. 2026 ;17 1844836

CD8+ T cell heterogeneity and function in lupus nephritis: a focused review.

Zhaomin Mao, Luoyi Wang, Jing Chen, Ming Guan.

  Lupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus marked by immune complex deposition and tissue-specific inflammation. Advances in single-cell transcriptomics and high-dimensional immune profiling have revealed that CD8+ T cells form a highly heterogeneous and compartment-dependent landscape across peripheral blood, kidney, and urine. This review aims to delineate how compartment-specific phenotypes and signaling programs of CD8+ T cells collectively shape the immunopathogenesis of lupus nephritis (LN). We synthesize current evidence into a unified blood-kidney-urine circuit model, in which systemic priming of circulating CD8+ T pools is followed by renal recruitment, tissue retention and functional reprogramming of kidney-infiltrating populations, cytotoxic and inflammatory tissue injury, and subsequent release of intrarenal immune signatures into urine. Circulating CD8+ T cells include IFN-I-primed naïve-like, effector-memory, and cytotoxic subsets that contribute to systemic immune activation. Within the kidney, infiltrating CD8+ T cells display pronounced clonal expansion, tissue-resident and exhaustion-associated phenotypes, and metabolic reprogramming, all of which correlate with local inflammation and histopathologic severity. Urine-derived CD8+ T cells, increasingly recognized as a non-invasive proxy for intrarenal immunity, recapitulate key transcriptional programs of kidney-infiltrating populations and provide a dynamic readout of ongoing renal injury. Across these anatomical niches, CD8+ T-cell effector and regulatory functions are shaped by pivotal pathways, including type I IFN conditioning, JAK-STAT signaling, NLRP3 inflammasome activation, mitochondrial stress responses, and modulation by immune checkpoints. Collectively, these insights highlight CD8+ T cells as an important effector and regulatory component within the broader multicellular immune network of LN and suggest that resolving their compartmental heterogeneity and signaling circuits may accelerate the development of mechanistically grounded biomarkers and targeted immunomodulatory strategies.

Keywords:  CD8+ T; biomarker; lupus nephritis; pathogenesis; subset

DOI:  https://doi.org/10.3389/fimmu.2026.1844836
Immunol Res. 2026 Aug 25. pii: 94. [Epub ahead of print]74(1):

Reprogramming immunometabolism: linking nutrient sensing, cell death, and therapeutic innovation.

Priya Sharma.

  Development of Immunometabolism as a central paradigm in the modern immunology has revolutionized the understanding of metabolism from being a passive supplier of energy to an important determinant of immune cell fate and function. Immune cells are activated, differentiated, survive and undergo programmed cell death through the activity of distinct metabolic programs, including those involving glycolysis, oxidative phosphorylation (OXPHOS), nutrient sensing through Mechanistic Target of Rapamycin (mTOR), AMP-Activated Protein Kinase (AMPK), and HIF‑1α. Rapid proliferation and production of cytokines by effector T cells and pro-inflammatory macrophages is mediated by glycolysis, while persistence and tolerance by memory T cells and reparative macrophages is mediated by oxidative metabolism. Metabolic input and output are also coupled with immune specialization and cell death mechanisms, such as apoptosis, Pyroptosis and ferroptosis, via mitochondrial bioenergetics and production of Reactive Oxygen Species (ROS). Altered immunometabolism is linked to a variety of pathologies: competition for nutrients in tumor physiology leads to T cell exhaustion; an unchecked glycolytic pathway maintains a state of autoimmune inflammation; pathogens exploit host metabolism to escape immunological control; and metabolic diseases, such as obesity and diabetes, foster chronic low‑grade inflammation. Therapies such as rapamycin, metformin, glycolysis and glutamine inhibitors, and metabolic adjuvants in vaccines underscore the translational potential of targeting metabolic checkpoints. But there are still debates on the specificity of the metabolic intervention, the balance between the effector and regulation responses, and the restrictions of the existing experimental models. New strategies, such as single-cell metabolomics and precision medicine, are expected to bring in more sophisticated ways for fine-tuning immune metabolism. Immunometabolism is thus a paradigm shift, with metabolism now being at the heart of immune regulation, and providing new opportunities for critical evaluation and translational innovation in cancer, autoimmunity, infections and metabolic disease.

Keywords:  Cancer immunotherapy; Glycolysis; Immune cell death; Immunometabolism; Metabolic reprogramming; Nutrient sensing

DOI:  https://doi.org/10.1007/s12026-026-09831-w
Cancer Commun (Lond). 2026 ;46 0027

EPO Receptor Blockade in Dendritic Cells Enhances Antitumor CD8+ T Cell Immunity.

Yunfei Zhu, Xuetao Cao.

DOI: https://doi.org/10.34133/cancomm.0027
Cell Mol Immunol. 2026 Aug 24.

Metabolic switch: lymphocytes and the onset of T-cell-mediated autoimmunity.

Andisheh Mosaffa Jahromi, Fatemeh Mirzaei, Sara Mirzazadeh, Seppo Meri, Dieter Kabelitz, Kurosh Kalantar.

  T cell-mediated autoimmune diseases, including multiple sclerosis (MS), rheumatoid arthritis (RA), and type 1 diabetes (T1D), are being increasingly recognized as disorders driven not only by immune dysregulation but also by profound metabolic reprogramming in lymphocytes. Emerging evidence from the field of immunometabolism reveals that altering the balance between oxidative phosphorylation (OXPHOS) and aerobic glycolysis, along with enhancing fatty acid synthesis and dysregulated glutamine metabolism, critically shapes lymphocyte activation, differentiation, and pathogenicity. Here, we review the metabolic pathways that regulate T cells and B cells. We discuss how changes in glucose, lipid, and mitochondrial metabolism influence immune responses that lead to chronic inflammation and autoimmunity in MS, RA, and T1D. Interestingly, similar immunometabolic changes, such as increased glycolysis, mitochondrial dysfunction, and mTOR signaling, have been identified in another autoimmune disorder, systemic lupus erythematosus (SLE). Connecting metabolic dysregulation to immune tolerance failure, this review highlights immunometabolism as a key mechanism in autoimmunity. Immunometabolic pathways represent a new avenue for precision immunotherapy, although challenges persist in targeting cells specifically without systemic toxicity. Understanding these metabolic adaptations and epigenetic-metabolic crosstalk will be essential for translating these insights into next-generation therapies.

Keywords:  Autoimmunity; B cells; Immunometabolism; T cells

DOI:  https://doi.org/10.1038/s41423-026-01460-5
Eur J Immunol. 2026 Aug;56(8): e70272

The Glucose Transporter GLUT3 Controls Regulatory T Cell Function.

Katrin Sinning, Miriam Eckstein, Xiufeng Zhao, Alexandra Freitag, Mathias Rosenfeldt, Sophia M Hochrein, Martin Vaeth.

  Regulatory T (Treg) cells are central mediators of immune tolerance and are generally considered to rely predominantly on mitochondrial metabolism rather than glucose-driven glycolysis. To define the role of glucose metabolism in Treg cells, we investigated the contribution of the hexose transporters GLUT1 and GLUT3. Genetic ablation of GLUT1 in T cells or selectively in Treg cells had minimal impact on Treg cell numbers, phenotype, or immune homeostasis, indicating that GLUT1 is largely dispensable in this lineage. By contrast, deletion of GLUT3 in T cells resulted in a marked reduction in Treg cell numbers. However, it remained unclear whether this reduction reflected diminished IL-2 production by GLUT3-deficient conventional T cells or a cell-intrinsic requirement for GLUT3 in Treg cells. To investigate this, we generated mice with Treg cell-specific deletion of GLUT3. These animals developed severe systemic inflammation accompanied by lethal cellular and humoral autoimmunity. Mechanistically, GLUT3-deficient Treg cells exhibited reduced glycolytic activity and mitochondrial respiration, leading to impaired suppressive function and defective effector and follicular Treg cell differentiation. Collectively, our findings demonstrate a nonredundant requirement for GLUT3 in Treg cell metabolic fitness and immune regulation, refining the prevailing view that Treg cells operate largely independently of glucose metabolism. Our data further suggest that therapeutic strategies targeting glucose uptake and glycolysis in autoimmune and inflammatory diseases should account for potential adverse effects on Treg cell-mediated immune tolerance.

Keywords:  biology; cell biology; cellular differentiation; glucose transporter; glucose uptake; glycolysis; immune tolerance; immunology; regulatory T cell

DOI:  https://doi.org/10.1002/eji.70272
Nat Med. 2026 Aug 26.

Publisher Correction: Decade-long persistence of CD19 CAR T cells in B cell lymphomas.

Luca Paruzzo, Emeline R Chong, Elise A Chong, Zhixuan Zheng, Puneeth Guruprasad, Daniel J Landsburg, Sunita D Nasta, Federico Stella, Ranjani Ramasubramanian, Vitor B de Souza, Mohannad H Alkhatib, Matthew Ho, Antonio Imparato, Gregory M Chen, Don L Siegel, Gabriela Plesa, Anlan Dai, Shane Mackey, Priyamvada Das, Peter Michener, Julie Jadlowsky, Frederic D Bushman, Vrutti Patel, Alberto Carturan, Ellen B Napier, Vanessa E Gonzalez, Danuta Jarocha, Rong Xu, Bruce L Levine, Patrizia Porazzi, Noelle Frey, David L Porter, Jakub Svoboda, Joseph A Fraietta, Carl H June, Stephen J Schuster, Marco Ruella.

DOI: https://doi.org/10.1038/s41591-026-04668-0
Blood. 2026 Aug 24. pii: blood.2026034204. [Epub ahead of print]

Ferroptotic stress promotes hematopoietic stem cell aging through S1P-dependent epigenetic and lipid remodeling.

Yijun Zhao, Yishan Li, Xiaobin Tian, Jingjing Guan, Yixin Ma, Xiaoqi Wang, Hongjian Zhang, Kaitao Wang, Kaizheng Jiang, Yalan Yang, Yuan Pan, Weiwei Liu, Xianzhe Hu, Jiafan Cao, Weiming Liu, Mengyun Xie, Kexin Sun, Jiayin Zheng, Ying Wang, Yucan Zheng, Yanjun Ling, Keyue Yang, Xuying Pei, Xiang-Yu Zhao, Xi Zhang, Pengxu Qian, Changzheng Li, Tian Lan, Linjia Jiang, Meng Zhao.

Aging of hematopoietic stem cells (HSCs) impairs hematopoietic regeneration and differentiation, contributing to immune aging, systemic inflammation, and reduced lifespan. Strategies to rejuvenate aged HSCs and restore immune homeostasis remain limited. Here, we identify ferroptotic stress as a key contributor to HSC aging. Mechanistically, increased sphingosine metabolism elevates sphingosine-1-phosphate (S1P), which suppresses HDAC activity and enhances H3K9 acetylation to upregulate lysophosphatidylcholine acyltransferase 2 (Lpcat2), thereby promoting the accumulation of pro-ferroptotic phospholipids in aged HSCs. Genetic or pharmacological inhibition of sphingosine kinase 2 (Sphk2) reduces S1P levels, suppresses Lpcat2 expression, and attenuates ferroptotic stress in aged mouse and human HSCs. Notably, Sphk2 inhibition improves HSC function, restores immune homeostasis, and modestly extends lifespan in aged mice. Together, these findings identify an S1P-HDAC-Lpcat2 pathway linking epigenetic and lipid remodeling to ferroptotic stress and highlight sphingosine metabolism as a therapeutic target for HSC aging.

DOI: https://doi.org/10.1182/blood.2026034204
Aging Cell. 2026 Sep;25(9): e70658

A Mechanism-Based Framework for Anti-Aging Strategies: From Metabolic Regulation to Senotherapy and Stem Cell-Based Interventions.

Feifei Li, Yankai Wang, Gelin Wang, Jiguo Chen, Song Huang.

  The global prevalence of aging and age-related diseases has increased markedly in recent decades due to extended life expectancy and a growing aging population, posing substantial medical and social burdens. Multiple strategies, including metabolic modulation (e.g., physical exercise, calorie restriction, and calorie restriction mimetics), targeting inflammaging, senotherapy, parabiosis, stem cell-based therapies, and epigenetic rejuvenation, have shown promise in slowing aging and extending lifespan in preclinical models, with some demonstrating efficacy in clinical trials. This review summarizes the current status of leading anti-aging interventions, their clinical progress, and the underlying mechanisms, which include enhancing autophagy, clearing senescent cells and supporting mitochondrial function to reduce chronic inflammation. We propose that metabolic modulation, inflammaging control, and senotherapy constitute three interconnected pillars of contemporary anti-aging strategies.

Keywords:  age‐related diseases; aging; anti‐inflammaging; metabolic modulation; senotherapy

DOI:  https://doi.org/10.1111/acel.70658
Front Cell Dev Biol. 2026 ;14 1866640

Mitochondrial regulation of cellular senescence heterogeneity.

Minseo Ahn, Sung-Jin Yoon, Jae Ho Seo.

  Cellular senescence is a stable cell-cycle arrest program accompanied by extensive metabolic remodeling and acquisition of a senescence-associated secretory phenotype (SASP). Emerging evidence indicates that senescence is not a uniform endpoint but a heterogeneous spectrum of cell states shaped by the nature of the initiating stimulus. Mitochondria have recently emerged as central regulators of this heterogeneity by integrating metabolic, redox, and inflammatory signaling. Senescent cells share common mitochondrial features-including increased mitochondrial mass, elevated reactive oxygen species (ROS), impaired mitophagy, and altered metabolic programs-yet distinct senescence subtypes exhibit unique mitochondrial adaptations. Replicative senescence is governed by a telomere-mitochondria feedback loop, whereas stress- and oncogene-induced senescence involve rapid mitochondrial stress responses and stimulus-specific metabolic rewiring. Therapy-induced senescence further introduces context-dependent mitochondrial dependencies that influence therapeutic resistance and senolytic vulnerability. In this review, we synthesize current understanding of mitochondrial regulation across senescence subtypes and highlight how mitochondrial dysfunction actively drives senescence heterogeneity. We further discuss emerging therapeutic strategies that exploit mitochondrial vulnerabilities to selectively modulate or eliminate senescent cells. Understanding mitochondrial control of senescence heterogeneity provides a conceptual framework for developing precision interventions in aging and cancer.

Keywords:  cellular senescence; metabolic reprogramming; mitochondrial dysfunction; mitophagy; reactive oxygen species (ROS); senescence heterogeneity; senescence-associated secretory phenotype (SASP); senolytics

DOI:  https://doi.org/10.3389/fcell.2026.1866640
Iran J Immunol. 2026 Aug 24. 23(3): 8

Mitochondrial Reprogramming of Tumor-Infiltrating T Cells as a Next-Generation Strategy to Overcome Immunotherapy Resistance.

Piruz Shadbash, Marzieh Bahari Babadi.

DOI: https://doi.org/10.22034/iji.2026.111291.3198
Cell Rep Med. 2026 Aug 28. pii: S2666-3791(26)00426-X. [Epub ahead of print] 103009

Lactobacillus salivarius potentiates gastrointestinal cancer immunotherapy through its metabolite chenodeoxycholic acid.

Bohan Zhang, Yifan Zhang, Yi Cai, Siyuan Cheng, Zihan Han, Xiaochen Yin, Tong Xie, Yan Tan, Yang Feng, Yuxin Wang, Xiaohuan Guo, Lin Shen, Zhi Peng.

  Immune checkpoint inhibitor therapy has improved gastrointestinal (GI) cancer management; however, many patients exhibit resistance. Although gut microbiota influences immunotherapeutic responses, the underlying mechanisms remain unclear. Metagenomic analysis of 278 GI cancer patients reveals that Lactobacillus salivarius (L. salivarius) is enriched in responders and enhances anti-PD-1 efficacy in syngeneic tumor models by increasing the infiltration of antitumor M1-like macrophages and CD8+ T cells and enhancing CD8+ T cell effector function. L. salivarius-associated chenodeoxycholic acid (CDCA) is identified as a functional metabolite. CDCA recapitulates the antitumor effects of L. salivarius and significantly improves anti-PD-1 efficacy in vivo, an effect attenuated by depleting macrophages or CD8+ T cells. Mechanistically, CDCA-induced reactive oxygen species triggers immunogenic cell death in tumor cells and polarizes macrophages toward antitumor M1 phenotype, activating CD8+ T cell antitumor immunity. These findings identify L. salivarius and its associated metabolite CDCA as a promising adjuvant for potentiating immunotherapy in GI cancers.

Keywords:  Lactobacillus salivarius; chenodeoxycholic acid; gastrointestinal cancers; immunotherapy; macrophages; tumor microenvironment

DOI:  https://doi.org/10.1016/j.xcrm.2026.103009
Nat Aging. 2026 Aug 26.

Cytotoxic CD4+ T cells induce age-associated myelopoiesis through CCL5-CCR5 signaling.

Enrique Gabandé-Rodríguez, Gonzalo Soto-Heredero, Elisa Carrasco, Carlos Anerillas, José Ignacio Escrig-Larena, Jorge Martínez-Cano, Sandra Delgado-Pulido, Isaac Francos-Quijorna, Gabriela Desdín-Micó, Tatiana Smirnova, Manuel M Gómez de Las Heras, Álvaro Fernández-Almeida, Alice Leandri, Andrea Cugurra, Eva María Blanco, Elia Winand-Osete, Pablo Ramírez-Ruiz de Erenchun, Virginia Zorita, Camilla Bean, Valentin Basset, Françoise Solly, Amanda Garrido, Rafael de Cabo, Santos Mañes, Manolis Pasparakis, Matteo Iannacone, César Cobaleda, Olaia Naveiras, Myriam Gorospe, María Mittelbrunn.

Age-associated hematopoietic skewing results in an increase in the neutrophil-to-lymphocyte ratio, which serves as a strong predictor of all-cause mortality in older adults, although its causes are incompletely understood. Here we show that cytotoxic CD4+ T lymphocytes accumulate in the bone marrow of mice during aging and induce myelopoiesis, increasing the neutrophil-to-lymphocyte ratio. T cell receptor-dependent induction of mitochondrial stress and activation of STING upregulates the chemokine CCL5 in CD4+ T lymphocytes. During aging, hematopoietic stem cells and downstream myeloid progenitors upregulate CCR5, the primary receptor for CCL5. Genetic ablation of Ccr5 in hematopoietic progenitors mitigates T cell-induced myeloid skewing and neutrophil expansion. Pharmacological blockade of CCR5 using the Food and Drug Administration-approved drug maraviroc normalizes myelopoiesis, reduces circulating and tissue-infiltrating neutrophils, and improves multiple aging-related biomarkers and functional outcomes in aged mice. Together, these findings demonstrate a T cell-bone marrow axis that exacerbates age-associated decline and highlight CCR5 inhibition as a potential geroprotective strategy.

DOI: https://doi.org/10.1038/s43587-026-01209-9
Cell Rep. 2026 Aug 24. pii: S2211-1247(26)00956-3. [Epub ahead of print]45(9): 117878

A single-cell transcriptomic atlas reveals the immune panorama of neonatal sepsis.

Jie Wang, Ying Chen, Peicen Zou, Yue Du, Ying Li, Li Zhang, Juan Zhou, Linglong Wan, Yifei Xu, Yi Wang, Yajuan Wang, Lihui Meng.

  Neonatal sepsis remains a leading cause of infant mortality, yet mechanisms driving concurrent hyperinflammation and immunosuppression remain unclear. Here, we perform single-cell RNA sequencing on 26 blood samples from 18 neonates, spanning acute sepsis, convalescence, and healthy controls. We identify 57 cell subtypes, revealing acute lymphoid depletion and myeloid expansion. S100A8+ myeloid-derived suppressor cell-like (MDSC-like) cells represent a putative cytokine-storm source, potentially amplified by a feedforward S100-TLR4-MYD88 circuit. Innate-like lymphocytes fail to expand, succumbing to apoptosis and exhaustion despite heightened cytotoxicity. CD4+ T cells display mitochondrial dysfunction, while regulatory T cells acquire a hyper-suppressive phenotype via the LGALS9-HAVCR2 axis. CD8+ T cells undergo interferon-driven, innate-like reprogramming before lapsing into exhaustion, and B cells shift toward stress-adaptive, tolerogenic states. Together, our atlas defines a dual pathology in which MDSC-like cell-driven cytokine storm coexists with multi-lineage immunoparalysis, nominating the S100-TLR4 axis and mitochondrial dysregulation as potential therapeutic targets.

Keywords:  CP: immunology; T cell exhaustion; cytokine storm; neonatal sepsis; peripheral immune response; scRNA-seq

DOI:  https://doi.org/10.1016/j.celrep.2026.117878
Proc Natl Acad Sci U S A. 2026 Sep;123(35): e2601318123

Amino acid homeostasis by CORVET/HOPS: A metabolic and stress resilience checkpoint for T cells.

Jing Wang, Zegui Ni, Xinxin Zhang, Linling He, Xinyue Zhang, Xu Cheng, Haimo Wang, Guoying Sun, Zhenwei Lu, Chengxu Liu, Hongjie Qian, Youli Lu, Gangyi Liu, Jingying Jia, Jian Ye, Linzhang Huang, Haobin Ye, Rong Li, Wufan Tao, Peng Li, Tong-Jin Zhao, Xingrong Du.

  Amino acid sufficiency is critical for T cell metabolic reprogramming, yet how T cells maintain amino acid homeostasis remains poorly defined. Here, we identify the CORVET and HOPS (CORVET/HOPS) tethering complexes as essential upstream regulators. In activated T cells, they sustain intracellular amino acid levels by promoting macropinocytosis to acquire extracellular nutrients. This function enables dual signaling outcomes: suppression of the integrated stress response (ISR) and activation of mTORC1, which together license metabolic plasticity and effector function. Genetic ablation of core subunits (VPS18 or VPS11) of CORVET/HOPS induces severe amino acid scarcity, triggers pathological ISR activation, and impairs mTORC1 signaling, leading to reduced peripheral T cell numbers and abrogating both inflammatory and protective immunity in vivo. These defects are mechanistically linked: BIM deletion or enforced mTORC1 activity rescues the survival and proliferative failures, respectively, of CORVET/HOPS-deficient T cells. Our work establishes CORVET/HOPS as fundamental couplers linking nutrient acquisition to immune signaling, revealing a targetable node for immuno-metabolic therapy.

Keywords:  CORVET/HOPS; T cells; amino acid; integrated stress response; metabolism

DOI:  https://doi.org/10.1073/pnas.2601318123