bims-imseme 2026-05-10 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2026–05–10
forty papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Lifelong Exercise as a Modulator of CD4+ T Cell Immunometabolism.
Fasting opens a metabolic window that favors anti-tumor immunity.
Metabolic modulation of immune cell function: mechanisms and therapeutic implications in cancer immunotherapy.
A new twist in metabolic T cell exhaustion.
Overcoming T cell exhaustion and senescence in CAR T cell therapy for solid tumors.
Proteasome-Heme Axis Links Mitochondrial Stress to T-Cell Exhaustion.
CRISPR screen reveals regulators of age-associated CD8+ T cell dysfunction in cancer.
Ikaros degradation by mezigdomide reduces T-cell dysfunction and improves the efficacy of antimyeloma T-cell therapies.
Transcription factor collaboration enables precise T cell state engineering.
Targeting Age-Associated Immune Senescence via Nanoparticle-Based Metabolic Reprogramming.
CKS1B is a tumor-intrinsic factor driving CD8+ T cell exhaustion via maintaining persistent tumor-antigen stimulation.
Lactylation landscape of mitochondrial proteins in myocardial infarction.
Pathogenic CD8+ T cells target K71+ Henle's layer by forming cytolytic immune synapses in Alopecia Areata.
Blocking mitochondrial leucine transamination enhances T-cell activation and improves T-cell immunity against OVA-producing EL4 lymphoma.
Glucocorticoid receptor and RUNX transcription factors cooperatively drive CD8 T cell dysfunction in human cancer.
Author Correction: Early methionine availability attenuates T cell exhaustion.
Transcriptomic evidence of CD8⁺ T-cell exhaustion-like phenotype and mitochondrial impairment underlying immune dysregulation in feline chronic gingivostomatitis.
Peroxisome-derived ether lipids regulate lysosomal exocytosis.
Remodeling memory T cells with chemotherapy and immune checkpoint inhibitors as host pre-conditioning to empower in vivo CAR-T therapy.
Iron as an immunometabolic signal in infection and inflammation.
Metabolic reprogramming in endometriosis: mechanisms and therapeutic prospects.
Computational identification of migrating T cells in spatial transcriptomics data.
Bifidobacterium animalis suppresses melanoma progression and activates anti-tumor immunity by inhibiting YAP1 expression in CD8+ T cells.
Hypoxic tumor microenvironment and immune cell dynamics: From metabolic reprogramming to therapeutic innovation.
Calibrating T cell responsiveness through interactions with self.
ATG5-mediated inducible autophagy sustains CAR-T cell durability under solid tumor stress.
ERα blockade in dendritic cells enhances antigen cross-presentation and induces antitumor CD8+ T cell immunity.
IL-12 augments adoptive cell therapy by reshaping CD8+ T dynamics and broadening antitumor immunity.
Gut microbiota and immunometabolism in obesity.
Whole-genome doubling drives immune evasion by silencing antigen presentation.
Ex vivo cytokine responses and metabolic reprogramming are associated with γδ T cell differentiation in Plasmodium falciparum placental malaria.
CD8 T Cell Sensing of Type I Interferon Impacts Anergy.
Novel recombinant protein PK5-Gal-3C enhances the anti-tumor activity of T cells via binding with TRPV2.
Multimodal analysis of molecular remodeling in aging spleen identified global and cell type specific changes.
Sleep regulates hepatic neutrophil trafficking by modulating uric acid metabolism via sympathetic nervous system activity.
MCT1 governs a metabolic checkpoint at pachytene during spermatogenesis.
Cytotoxic CD4+ T cells and their implication in oral diseases and systemic diseases with oral manifestations.
Preexisting chronic infection skews the epigenetic landscape of subsequent memory CD8 T cell responses.
MCT1 governs a metabolic checkpoint at pachytene during spermatogenesis.
Unlocking healthy aging through gut microbial tryptophan metabolism.

Eur J Clin Invest. 2026 May;56(5): e70204

Lifelong Exercise as a Modulator of CD4+ T Cell Immunometabolism.

Bruna Spolador de Alencar Silva, Amanda Veiga Sardeli, Ricardo R Agostinete, Helena Batatinha, Alessandra Peres, José César Rosa-Neto, José Teixeira, Manuel J Coelho-E-Silva, Paulo J Oliveira, Fábio Santos Lira.

   BACKGROUND: It is commonly assumed that aging and chronic low-grade inflammation compromise adaptive immunity, particularly the function and metabolism of CD4+ T cells. The preceding are key regulators of immune responses. These immunological alterations contribute to increased susceptibility to infections, diminished vaccine efficacy and the progression of age-related diseases. In contrast, adolescence and young adulthood tend to be characterized by more robust immune responses, though these are heavily influenced by modifiable lifestyle factors such as habitual physical activity, level of cardiorespiratory fitness, diet and body adiposity. Emerging evidence suggests that sustained physical activity throughout life may preserve CD4+ T cell competence by favourably modulating their metabolic programming.
METHODS: The current narrative review explores how lifelong physical exercise impacts CD4+ T cell metabolism, with particular emphasis on the developmental window of adolescence and the long-term benefits of early and sustained physical training across the lifespan. Molecular mechanisms linking exercise to metabolic reprogramming of T cells were summarised in parallel with attenuation of immunosenescence and inflammation over the lifespan.
RESULTS: This review suggests that lifelong exercise may reprogram CD4+ T cell metabolism, enhancing oxidative phosphorylation at rest and glycolytic control upon activation, thereby improving Th17/Treg balance, reducing chronic inflammation and enabling effective effector T cell responses. In this context, exercise initiated early in life may act as a critical modulator by promoting optimal immune function from childhood and establishing a functional peak that helps preserve immune competence during aging.
CONCLUSIONS: Lifelong and early-life exercise may reprogram CD4+ T cell metabolism, strengthening immune balance and preserving immune function during aging.

Keywords:  Aging; Energy metabolism; Exercise; Immune function; Immunosenescence

DOI:  https://doi.org/10.1111/eci.70204
Cell Metab. 2026 May 05. pii: S1550-4131(26)00109-9. [Epub ahead of print]38(5): 833-834

Fasting opens a metabolic window that favors anti-tumor immunity.

Ling Cai, Tao Dai.

Short-term fasting reshapes the metabolic landscape of the tumor microenvironment, creating a transient window of altered nutrient availability that cytotoxic CD8⁺ T cells can exploit. Chen and colleagues report that intratumoral isoleucine accumulation during fasting supports T cell effector programs, enhancing responses to immune checkpoint blockade in mice and humans.

DOI: https://doi.org/10.1016/j.cmet.2026.03.015
Oncogenesis. 2026 May 07.

Metabolic modulation of immune cell function: mechanisms and therapeutic implications in cancer immunotherapy.

Nina Fenouille, Camille Lobry, Lina Benajiba, Alexandre Puissant.

Immune cell function is remarkably plastic, allowing T cells, NK cells, and macrophages to transition from resting or quiescent states to proliferative, cytotoxic, or inflammatory programs. These functional shifts are tightly coupled to metabolic reprogramming, which not only fuels energy and biosynthesis but also shapes epigenetic and transcriptional landscapes that guide immune responses. In this review, we highlight how intrinsic metabolic pathways which include glycolysis, fatty acid oxidation, amino acid metabolism, and TCA cycle intermediates, regulate T and NK cell proliferation, cytotoxicity, memory formation, and epigenetic programs. We also examine macrophages, whose polarization into pro-inflammatory M1 or tissue-reparative M2 states is orchestrated by distinct metabolic programs such as arginine metabolism, oxidative phosphorylation, and fatty acid oxidation, with consequences for local immune regulation. We then explore how tumors exploit these metabolic dependencies to create hostile microenvironments that restrict nutrients, accumulate immunosuppressive metabolites, and dampen immune cell activity. Finally, we discuss emerging metabolic interventions designed to restore immune fitness, enhance the efficacy of immune checkpoint inhibitors, and improve the persistence and cytotoxicity of adoptive T cell therapies, including CAR-T cells, in nutrient-deprived and hypoxic tumor niches. By linking immune cell plasticity to metabolic control, this review provides a framework for understanding how metabolism shapes immunity and identifies strategies to harness these pathways for next-generation cancer immunotherapies.

DOI: https://doi.org/10.1038/s41389-026-00622-4
Immunometabolism (Cobham). 2026 Apr;8(2): e00080

A new twist in metabolic T cell exhaustion.

Konstantinos Aliazis, Vassiliki A Boussiotis.

  Metabolic reprogramming of T lymphocytes has a decisive role in their activation, differentiation, and functional fate commitment. Metabolic reprogramming guides not only the generation of T effector and T memory cells but also the development of dysfunctional exhausted (TEX) cells. A recent study by Haku et al published in Nature Immunology provides new insights into the role of mitochondria in regulating the metabolic capabilities of TEX cells and their implications for antitumor immunity.

Keywords:  T cell exhaustion; cancer immunotherapy; checkpoints; metabolism; programmed cell death protein 1

DOI:  https://doi.org/10.1097/IN9.0000000000000080
Clin Transl Oncol. 2026 May 07.

Overcoming T cell exhaustion and senescence in CAR T cell therapy for solid tumors.

Ignacio Pérez-Criado, Mariona Figols, Ainhoa Moya-Sevilla, Ana Bautista, Daniela Gómez-Díaz, Albert Font, Juan Martin-Liberal, Vicenç Ruiz de Porras.

  Chimeric antigen receptor (CAR) T cell therapies have demonstrated remarkable efficacy in hematologic malignancies; however, their clinical benefit in solid tumors remains limited. A major barrier is T cell dysfunction, particularly exhaustion and senescence, which impair persistence, effector function, and durable tumor control. Targeting these dysfunctional states is therefore essential in order to improve CAR T cell efficacy in solid tumors.This review summarizes recent preclinical strategies aimed at preventing or reversing CAR T cell exhaustion and senescence in solid malignancies. While both exhaustion and senescence are relevant dysfunctional states, the preclinical evidence summarized in this review is currently more extensive for modulation of exhaustion-associated programs than for direct reversal of canonical T cell senescence. Approaches are organized according to their primary mechanistic focus, including gene editing, metabolic modulation, receptor redesign, and remodeling of the tumor microenvironment.Across these mechanistic categories, reported benefits include enhanced CAR T cell persistence, reduced expression of inhibitory receptors, such as PD-1, LAG-3, and TIM-3, preservation or restoration of memory-like phenotypes, and improved antitumor cytotoxicity. Notably, combinatorial strategies targeting multiple dysfunction pathways consistently demonstrate superior efficacy in preclinical models. Despite these advances, important translational challenges remain, including the limited predictive value of current preclinical systems, potential safety concerns, and the manufacturing complexity associated with increasingly engineered cell products.Collectively, preclinical evidence supports the rational integration of complementary approaches to generate next-generation CAR T cells capable of resisting dysfunction and maintaining activity within immunosuppressive solid tumor microenvironments. Further validation in clinically relevant models will be critical to facilitate translation into safe and durable cancer immunotherapies.

Keywords:  CAR T cell therapy; Senescence; Solid tumors; T cell exhaustion

DOI:  https://doi.org/10.1007/s12094-026-04383-9
Cancer Discov. 2026 May 05. OF1

Proteasome-Heme Axis Links Mitochondrial Stress to T-Cell Exhaustion.

DOI: https://doi.org/10.1158/2159-8290.CD-RW2026-043
Nat Rev Immunol. 2026 May 05.

CRISPR screen reveals regulators of age-associated CD8+ T cell dysfunction in cancer.

Matthew Bianca, Tracy McGaha.

DOI: https://doi.org/10.1038/s41577-026-01308-z
Blood. 2026 May 08. pii: blood.2025030891. [Epub ahead of print]

Ikaros degradation by mezigdomide reduces T-cell dysfunction and improves the efficacy of antimyeloma T-cell therapies.

Lucia Y Chen, Adolfo Aleman, Marta Larrayoz, Hsiling Chiu, Junfei Zhao, Oliver Van Oekelen, Geoffrey Kelly, Seunghee Kim-Schulze, Alessandro Lagana, Sundar Jagannath, Tracy T Chow, Teresa Lozano, Juan J Lasarte, Joseph C Hamley, Warren Baker, Benjamin L Ebert, Udo Oppermann, Michael D Amatangelo, Anita Krithivas Gandhi, Patrick Ryan Hagner, Jose A Martínez-Climent, Sarah Gooding, Thomas A Milne, Samir Parekh.

T cell dysfunction is an important contributor to both multiple myeloma (MM) disease progression and failure of anti-myeloma chimeric antigen receptor (CAR) T cell and bispecific T cell engager (TCE) therapies. Overcoming T cell dysfunction is therefore key to improving MM patient outcomes. Immunomodulatory drugs (IMiDs) and cereblon E3 ligase modulatory drugs (CELMoDs) have been observed to activate T cells, and more recently reduce T cell dysfunction, however the underlying mechanisms behind this are incompletely understood. Here, using bone marrow samples from MM patients, we demonstrate a significant reduction in dysfunctional T cell populations expressing exhaustion markers such as TIGIT, upon treatment with Mezigdomide. We further demonstrate the ability of Mezigdomide to improve T cell function and cytotoxicity in primary T cell models of T cell dysfunction and bispecific TCE therapy in vitro. Using concurrent ATAC-seq, ChIP-seq, HiC and RNA-seq in primary T cells treated with Mezigdomide, we demonstrate the novel role of transcription factor Ikaros in regulating an important T cell exhaustion gene TIGIT. Finally, we demonstrate the ability of Mezigdomide to enhance survival outcomes from anti-BCMA CAR-T therapy in vivo. Overall, our data show that Mezigdomide treatment improves anti-myeloma T cell therapy efficacy and reduces T cell dysfunction by abrogating Ikaros-mediated upregulation of exhaustion genes.

DOI: https://doi.org/10.1182/blood.2025030891
bioRxiv. 2026 Apr 22. pii: 2026.04.20.718569. [Epub ahead of print]

Transcription factor collaboration enables precise T cell state engineering.

Rachel E Savage, Christian D McRoberts Amador, Conrad T Hock, Ruochi Zhang, Hung-Che Kuo, Aretha R Gao, Max A Horlbeck, Charles A Gersbach, Jason D Buenrostro.

Transcription factors (TFs) collaborate to regulate gene expression programs that define cell fate. In CD8 + T cells, this coordinated regulation underlies exhaustion, a dysfunctional state that constrains immunity in chronic infection and cancer. Here, we screen for cell state-specific TFs by performing pooled overexpression screens of 3,548 TF and TF isoforms in primary T cells across multiple CD8 + T cell states. We identify 82 regulators that collaborate with exhaustion-specific programs and profile their effects using perturb-SHARE-seq, connecting perturbations to changes in chromatin accessibility and gene expression across 702,314 single cells. We identify 38 reproducible regulatory programs and construct a map of 12,616 TF-program connections that shape CD8 + T cell states, nominating KLF2 as predictive of positive response to CAR-T therapy. Using seq2PRINT, a deep learning framework that predicts functional TF interactions, we identify RUNX as a "master collaborator", a TF that broadly collaborates with other factors, and uncover a RUNX2:KLF2 interaction that specifies exhaustion-associated programs. Mutation of the RUNX2:KLF2 protein interface attenuates KLF2-mediated repression of exhaustion, while synthetic tethering of RUNX2 to KLF2 leads to an amplification of the phenotype. More broadly, we identify the collaborative action of RUNX as a driver in CD8 + T cell states, and show that tethering TFs enables the rational engineering of cell state identity for cell and gene therapies.

DOI: https://doi.org/10.64898/2026.04.20.718569
ACS Nano. 2026 May 08.

Targeting Age-Associated Immune Senescence via Nanoparticle-Based Metabolic Reprogramming.

Preethi Gopalakrishnan Nair, Unnikrishnan Babukuttan Sheela, Vishnu Vijay Vijayan, Susan E Howlett, Pieter Cullis, Shashi Gujar.

  Being able to "age" up to 80-100 years is a triumphant hallmark of human evolution. Unfortunately, human aging in the modern era has become synonymous with poor health. Thus, strategies to promote healthy aging are urgently needed to ensure a sustainable future for humanity. Modern-day evidence clearly shows that the immune system is one of the key mechanisms that govern aging. Unfortunately, immunological competence becomes senescent with age. This age-associated immune senescence represents a major therapeutic target to address age-related health issues. Recent advances in the field of "immunometabolomics" reveal that metabolic pathways play a central role in age-associated immune senescence. Thus, metabolism reprogramming innovations targeting immune senescence are key to reinstating desired immune competence in aged hosts. The rapid expansion of nanoparticle science promises to accelerate therapeutic metabolic reprogramming strategies and represents a new frontier for targeting immune senescence. In this perspective, we discuss opportunities for nanoparticle-based systems designed to rejuvenate immunity and promote healthy aging.

Keywords:  aging; immune rejuvenation; metabolism; nanoparticles; senescence

DOI:  https://doi.org/10.1021/acsnano.5c18638
Sci Adv. 2026 May 08. 12(19): eaec9179

CKS1B is a tumor-intrinsic factor driving CD8+ T cell exhaustion via maintaining persistent tumor-antigen stimulation.

Siqi Yu, Pujie Wu, Xiaoting Xie, Liang Zhu, Liping Chen, Yibo Yu, Wen Tan, Shaosen Zhang, Chen Wu, Dongxin Lin.

T cell exhaustion is a major barrier to effective antitumor immunity, yet the tumor-intrinsic mechanisms remain poorly defined. Through single-cell and spatial proteomics analyses of esophageal squamous cell carcinoma (ESCC), we uncover two infection-like CD8+ T cell trajectories, acute-like and chronic-like responses, whose fates are dictated by the tumor cell subtypes they encounter. This concept links tumor heterogeneity to the shaping of local immune niches. Mechanistically, we identify CDC28 protein kinase regulatory subunit 1B (CKS1B) as a tumor-intrinsic inducer of chronic-like exhaustion. CKS1B forms a complex with S-phase kinase-associated protein to promote interferon regulatory factor 3 (IRF3) ubiquitination and degradation, thereby suppressing type I interferon signaling and antigen presentation. This impairs tumor cell elimination and drives progressive CD8+ T cell stimulation and exhaustion. Pharmacological blockade of the CKS1B-IRF3 interaction with 14i restores CD8+ T cell function and synergizes with immune checkpoint blockade. The tumor-intrinsic oncogenic-immune axis, which connects cancer cell signaling to immune dysfunction, is conserved across multiple malignancies, establishing a conceptual and therapeutic framework for overcoming tumor-driven T cell exhaustion.

DOI: https://doi.org/10.1126/sciadv.aec9179
bioRxiv. 2026 Apr 28. pii: 2026.04.27.718938. [Epub ahead of print]

Lactylation landscape of mitochondrial proteins in myocardial infarction.

Ashlesha Kadam, Shiridhar Kashyap, Kunal Samantaray, Natasha Jaiswal, Shanikumar Goyani, Philip A Kramer, Pourhadi Hadi, Jingyun Lee, Cristina M Furdui, Pooja Jadiya, Dhanendra Tomar.

Metabolic reprogramming is a hallmark of myocardial infarction (MI), in which cardiomyocytes shift from fatty acid oxidation to anaerobic glycolysis, leading to elevated lactate production and mitochondrial dysfunction. Lactylation, a recently described lysine post-translational modification, has emerged as a metabolic signaling mechanism; however, its role within mitochondria during MI remains poorly understood. Here, we define the mitochondrial lactylome following MI and examine how modulation of lactate transport influences mitochondrial metabolism and redox homeostasis. Using quantitative proteomics, we identify extensive remodeling of mitochondrial protein lactylation after MI, affecting enzymes involved in bioenergetics, redox regulation, and metabolic control. Pharmacological inhibition of monocarboxylate transporter-1 (MCT1) using AZD3965 further reshapes the mitochondrial lactylome, increasing lactylation of specific metabolic and redox-associated proteins without uniformly exacerbating mitochondrial dysfunction. Despite sustained impairment of global cardiac function, MCT1 inhibition attenuates post-MI fibrosis and inflammation and partially restores mitochondrial respiratory capacity. Consistent with in vivo findings, genetic or pharmacological inhibition of MCT1 in hypoxic cardiomyocytes-derived cells reduces mitochondrial reactive oxygen species, decreases inhibitory pyruvate dehydrogenase phosphorylation, and improves mitochondrial bioenergetics. Together, these findings reveal that mitochondrial lactylation is a context-dependent regulator of mitochondrial metabolism and redox balance following MI. Rather than acting solely as a pathological modification, lactylation integrates lactate availability with mitochondrial function to influence inflammatory and fibrotic remodeling, highlighting mitochondrial metabolic plasticity as a potential therapeutic target in ischemic heart disease.
Highlights: Myocardial infarction (MI) increases mitochondrial protein lactylation, with 361 identified lactylated proteins.AZD3965-mediated MCT1 inhibition further elevates mitochondrial lactylation.Distinct alterations in mitochondrial proteins and pathways (TCA cycle, amino acid metabolism, gene expression) were observed.AZD3965 reduces cardiac fibrosis and inflammation and partly improves mitochondrial respiration post-MI, but cardiac function remains impaired.

DOI: https://doi.org/10.64898/2026.04.27.718938
Res Sq. 2026 Apr 30. pii: rs.3.rs-9487026. [Epub ahead of print]

Pathogenic CD8+ T cells target K71+ Henle's layer by forming cytolytic immune synapses in Alopecia Areata.

Rupali Gund, Jin Yong Kim, Valia Leifer, Eunice Lee, Eddy Wang, Emily Mace, Angela Christiano.

CD8+ NKG2D+ T cells mediate hair follicle (HF) damage in Alopecia Areata (AA); however, the mechanisms and targets of T cell attack are not yet known. Here, we showed that CD8+ T cells penetrate the dermal sheath and epithelial layers of HF in AA and stop abruptly upon reaching Henle's layer of the inner root sheath. CD8+ T cells assembled a cytolytic immune synapse (IS) with polarization of Lck kinase and convergence of granzyme B. The formation of IS and localization of caspase-8-dependent apoptosis in KRT71+ Henle's layer of IRS pinpointed these cells as T cell targets in AA. Using direct visualization of in situ activity of pathogenic CD8+ T cells within AA-affected mice skin, we elucidated the molecular mechanism and target of CD8+ T cell cytotoxicity within HF in AA.

DOI: https://doi.org/10.21203/rs.3.rs-9487026/v1
Br J Cancer. 2026 May 05.

Blocking mitochondrial leucine transamination enhances T-cell activation and improves T-cell immunity against OVA-producing EL4 lymphoma.

Christie M Adam, Tanner J Wetzel, Sheila C Erfan, Leighton M Wheeler, Emily E Baer, Lindsey P Croll, Alexander M Martin, Taha Z Khan, Max L Swain, Michael P Boyer, Elitsa A Ananieva.

BACKGROUND: T-cell metabolism is targeted by cancer cells in an attempt to escape immune surveillance. The mitochondrial branched-chain aminotransferase, BCATm, is overexpressed in cancer, yet its role in T-cell immunity is suggested but understudied.
METHODS: C57BL/6 mice with T-cell specific-single BCATm deficiency were used to determine the impact of BCATm on T-cell function in vitro and in vivo using the murine EL4-OVA lymphoma. The studies were complemented by a transcriptomic correlation analysis of BCATm in human T cells and by using siRNA to knock-down BCATm in Jurkat T cells.
RESULTS: The loss of BCATm from CD4+ T cells increased mitochondrial respiration but reduced the coupling between oxygen consumption and ATP synthesis, redirecting the cells to glycolysis. This compensation sustained T-cell functionality as seen by increased release of IFN-γ from CD4+ T cells or granzyme B and perforin from CD8+ T cells. Human studies further suggested that BCATm negatively affected T-cell mitochondria. While EL4-OVA tumours from T-BCATmKO mice were enriched in memory precursor CD4+ and CD8+ T cells, reduced EL4-OVA lymphoma growth was achieved in mice with T cells carrying a combined deletion of BCATm and BCATc.
CONCLUSIONS: BCATm is an immunosuppressive enzyme that may weaken T-cell performance in the lymphoma microenvironment.

DOI: https://doi.org/10.1038/s41416-026-03455-5
Cell Rep. 2026 May 05. pii: S2211-1247(26)00445-6. [Epub ahead of print]45(5): 117367

Glucocorticoid receptor and RUNX transcription factors cooperatively drive CD8 T cell dysfunction in human cancer.

Christopher J Ward, Soura Chakraborty, Sanu K Shaji, Clara Veiga-Villauriz, Aws Al-Deka, Qiuchen Zhao, Jhuma Pramanik, Xi Chen, Bidesh Mahata.

  Glucocorticoids are potent immune regulators, yet how cortisol controls human CD8 T cell function remains poorly defined. Here, we show that cortisol reshapes the transcriptional landscape of human CD8 T cells through cooperation between the glucocorticoid receptor (GR) and RUNX transcription factors. Integrative RNA sequencing (RNA-seq) and chromatin immunoprecipitation followed by sequencing (ChIP-seq) analyses identified genome-wide cortisol-responsive immunoregulatory genes, and NR3C1 deletion confirmed GR dependency. GR chromatin occupancy was enriched at RUNX motifs rather than canonical glucocorticoid response elements, and co-immunoprecipitation confirmed a ligand-dependent interaction between GR and RUNX3, requiring the N-terminal activation function-1 (AF1) domain of GR and the C-terminal region of RUNX3. Single-cell transcriptomic analyses across multiple solid tumors revealed consistent enrichment of GR-RUNX co-regulated genes in tumor-infiltrating CD8 T cells, predominantly within the predysfunctional state. These findings identify RUNX3 as a critical non-canonical GR partner and uncover a therapeutically actionable mechanism by which endogenous glucocorticoids drive CD8 T cell dysfunction in human cancer.

Keywords:  CD8 T cell; CD8 transcriptome; CP: Cancer; CP: Immunology; GR ChIP sequencing; RUNX transcription factor; cancer immunosuppression; glucocorticoid; glucocorticoid receptor NR3C1; glucocorticoid signaling in cancer; human cancer; steroids in the tumor

DOI:  https://doi.org/10.1016/j.celrep.2026.117367
Nat Immunol. 2026 May 07.

Author Correction: Early methionine availability attenuates T cell exhaustion.

Piyush Sharma, Ao Guo, Suresh Poudel, Emilio Boada-Romero, Katherine C Verbist, Gustavo Palacios, Kalyan Immadisetty, Mark J Chen, Dalia Haydar, Ashutosh Mishra, Junmin Peng, M Madan Babu, Giedre Krenciute, Evan S Glazer, Douglas R Green.

DOI: https://doi.org/10.1038/s41590-026-02534-2
Sci Rep. 2026 May 06.

Transcriptomic evidence of CD8⁺ T-cell exhaustion-like phenotype and mitochondrial impairment underlying immune dysregulation in feline chronic gingivostomatitis.

Maria Soltero-Rivera, Patrawin Wanakumjorn, Yihong Chen, Samantha Barnum, Luis Diego Castillo Charpentier, Boaz Arzi, Natalia Vapniarsky Arzi, Amir Kol.

  Feline chronic gingivostomatitis (FCGS) is a debilitating oral disease characterized by immune dysregulation and chronic inflammation. We hypothesized that CD8 + T cells from FCGS cats exhibit exhaustion features with suppressed mitochondrial pathways, and that mesenchymal stromal cell (MSC) therapy post-extractions might restore these programs. RNA sequencing was performed on peripheral CD8 + T cells from cats with active FCGS before (disease group, D) and after (treated group, M) clinical remission following full-mouth extractions and MSC therapy, with specific-pathogen-free cats as controls (control group, C). CD8 + T cells from active disease displayed terminal effector differentiation and exhaustion-like signatures, including upregulation of cytotoxic markers (GZMB, GZMK, GZMA), differentiation markers (KLRG1, IL18R1/IL18RAP), and exhaustion-associated genes (EOMES, CD244, TNFSF10, CCR5, PRDM1, RGS16). Gene set enrichment analysis confirmed exhaustion-like CD8 + T-cell phenotype enrichment in active disease, which resolved after treatment. Pathway analysis revealed marked downregulation of mitochondrial respiratory chain components, ATP synthesis, and protein import pathways in active FCGS, with partial post-treatment resolution. Immunofluorescence of draining lymph nodes showed significantly increased CTLA-4 + CD3+ T cells in both FCGS groups versus controls, suggesting persistent immunoregulatory signaling despite clinical improvement. These findings identify overlapping T-cell exhaustion and mitochondrial dysfunction-associated transcriptomic signatures in FCGS, supporting therapeutic strategies targeting immune-metabolic pathways.

Keywords:  CD8 + lymphocytes; Exhaustion; Feline; Mesenchymal stromal cells; Oral medicine; Stomatitis; Transcriptomics

DOI:  https://doi.org/10.1038/s41598-026-50658-0
EMBO J. 2026 May 02.

Peroxisome-derived ether lipids regulate lysosomal exocytosis.

Liang Chen, Danielle Henn, Zhongzheng Dong, Jiaxuan Liang, Aleksander Wielenga, Goncalo Vale, Bala Burugula, Junyi Zou, Yamuna Krishnan, Jeffrey G McDonald, Jacob Kitzman, Ming Li.

Lysosomes and peroxisomes are essential for cellular homeostasis, yet how their activities are coordinated remains poorly understood. Here, we identify peroxisome-derived ether lipids as key regulators of lysosomal function. A genome-wide CRISPR/Cas9 screen in LYSET-deficient mucolipidosis V cells revealed that disruption of ether lipid synthesis genes or peroxins markedly reduces lysosome accumulation and restores degradative capacity. Genetic or pharmacological inhibition of ether lipid synthesis enhanced lysosomal exocytosis and promoted the clearance of undigested material independently of mannose-6-phosphate trafficking. Conversely, supplementation with the ether lipid precursor hexadecylglycerol increased lysosome abundance, while reducing their degradative capacity. These findings uncover a peroxisome-lysosome metabolic axis, in which ether lipids act as bidirectional regulators of lysosomal number and function independently of the lysosomal master regulator TFEB. Our findings reveal how peroxisome-localized lipid metabolism modulates lysosomal homeostasis, and suggest potential new strategies to combat lysosomal and peroxisomal disorders.

DOI: https://doi.org/10.1038/s44318-026-00791-3
Synth Syst Biotechnol. 2026 Dec;14 155-170

Remodeling memory T cells with chemotherapy and immune checkpoint inhibitors as host pre-conditioning to empower in vivo CAR-T therapy.

Ding-Ya Sun, Jia-Lu Wang, Xin Li, Shan Wang.

  Chemotherapy and immune checkpoint inhibitors (ICIs) are widely utilized in cancer treatment, exerting not only direct cytotoxic effects on tumor cells but also significantly reshaping the systemic immune status of patients, particularly the composition and function of the T cell repertoire. This review begins with the analysis of the widespread depletion and dysfunction of early T cell subsets in cancer patients, particularly naïve T cells (Tn) and stem-like memory T cells (Tscm). Afterward, it details how chemotherapy and ICIs differentially regulate T cell homeostasis, including their ability to induce T cell exhaustion and differentiation skewing, as well as their ability to stimulate immunity and remodel the tumor microenvironment. On this basis, it is shown that the quality of T cell memory phenotypes is central in determining the in vivo expansion and persistence of chimeric antigen receptor T (CAR-T) cells. To overcome the challenges of classical autologous CAR-T therapy, which stems from raw material quality and in vitro manufacturing bottlenecks, we focus on transforming chemotherapy and ICIs from traditional treatment modalities into beneficial "host preconditioning" regimens aimed at optimizing the baseline state of the endogenous T cell repertoire. All in all, this transformation of traditional therapies into host preconditioning strategies, along with recent advances in in vivo CAR-T approaches, provides theoretical grounds and translatable clues to develop next-generation cellular immunotherapy.

Keywords:  Cancer; Chemotherapy; Immune checkpoint inhibitor; In vivo CAR-T; Memory T cell

DOI:  https://doi.org/10.1016/j.synbio.2026.04.012
Front Immunol. 2026 ;17 1810718

Iron as an immunometabolic signal in infection and inflammation.

Alexander Hoffmann, Laura Homs Pérez, Günter Weiss.

  Iron availability is dynamically remodeled during infection and inflammation and has traditionally been interpreted within the framework of nutritional immunity, where iron sequestration restricts microbial growth. Increasing evidence, however, indicates that inflammatory iron redistribution has broader immunological consequences. Systemic and cell-intrinsic iron levels actively shape immune cell production, differentiation, metabolic configuration, and effector function across innate and adaptive immune compartments. Rather than uniformly suppressing immunity, inflammation-driven hypoferremia selectively biases hematopoiesis and immune output, while locally regulated cellular and subcellular iron handling determines microbe-specific immune effector functions. In addition, the availability of metabolically active iron further defines immunometabolic state by regulating mitochondrial respiration, tricarboxylic acid cycle activity, and redox balance, thereby shaping both immune cell function and the host-pathogen interface. Together, these observations support a view of iron as an instructive immunometabolic signal that integrates systemic regulation with cellular and organelle-specific programs during infection and inflammation. This review synthesizes recent evidence across these organizational scales, highlights emerging trade-offs between host defense and iron homeostasis, and discusses how mechanistic insight into iron-sensitive immune pathways may inform strategies to modulate inflammation and antimicrobial immune effector function.

Keywords:  host-pathogen interaction; immuno-metabolism; inflammation; innate and adaptive immunity; iron homeostasis; iron signaling; lysosomal iron; mitochondrial respiration

DOI:  https://doi.org/10.3389/fimmu.2026.1810718
J Adv Res. 2026 May 03. pii: S2090-1232(26)00372-3. [Epub ahead of print]

Metabolic reprogramming in endometriosis: mechanisms and therapeutic prospects.

Cuishan Guo, Xinni Na, Zechen Guo, Jiao Jiao, Mengyi Yang, Junzhi Liang, Wanlin Dai, Zhijing Na, Zhongxiu Jiang, Yan Li, Da Li.

   BACKGROUND: Endometriosis (EMS) is an estrogen-dependent chronic inflammatory disorder for which metabolic reprogramming has emerged as a central pathological feature. Driven by genetic, epigenetic, and microenvironmental stressors, ectopic endometrial cells undergo extensive metabolic remodeling integrating energy production, redox homeostasis, and biosynthetic demands. These adaptations not only sustain cell survival under hypoxia and inflammation, but reshape epigenetic marks and the immune microenvironment, promoting lesion progression and impairing reproductive function.
AIM OF REVIEW: This review systematically outlines the molecular mechanisms of metabolic reprogramming in EMS, examines its impact on lesion development and fertility, and evaluates the potential of targeting metabolic pathways for precision therapy.
KEY SCIENTIFIC CONCEPTS: Ectopic endometrial cells display a phenotype with enhanced aerobic glycolysis, dysregulated fatty acid oxidation and phospholipid synthesis, and abnormal amino acid metabolism. These alterations support lesion survival and proliferation through epigenetic and immune modulation. Granulosa cell metabolic reprogramming-characterized by excessive glycolysis, mitochondrial dysfunction, lipid accumulation, and iron overload-disrupts oocyte energy and redox balance, reducing oocyte quality, and contributing to EMS-associated infertility. Preclinical studies suggest that targeting glucose, lipid, and amino acid pathways could mitigate disease phenotypes; however, metabolic plasticity, overlap with physiological metabolism, and safety concerns limit clinical translation. These challenges highlight the need for combinatorial interventions, precise delivery, and optimized therapeutic strategies to improve patient outcomes.

Keywords:  Endometriosis; Endometriosis-associated infertility; Glycolysis; Lactate; Metabolic reprogramming; Therapy

DOI:  https://doi.org/10.1016/j.jare.2026.04.069
JCI Insight. 2026 May 08. pii: e192718. [Epub ahead of print]11(9):

Computational identification of migrating T cells in spatial transcriptomics data.

Lin Zhong, Bo Li, Zhikai Chi, Siyuan Zhang, Qiwei Li, Guanghua Xiao.

  T cells are the central players in antitumor immunity, and effective tumor killing depends on their ability to infiltrate into the tumor microenvironment (TME) while maintaining normal cytotoxicity. However, late-stage tumors develop immunosuppressive mechanisms that impede T cell movement and induce exhaustion. Investigating T cell migration in human tumors in vivo could provide insights into tumor immune escape, although it remains a challenging task. In this study, we developed ReMiTT, a computational method that leverages spatial transcriptomics data to track T cell migration patterns within tumor tissue. Applying ReMiTT to multiple tumor samples, we identified potential migration trails. On these trails, chemokines that promote T cell trafficking displayed an increasing trend. Additionally, we identified key genes and pathways enriched on these migration trails, including those involved in cytoskeleton rearrangement, leukocyte chemotaxis, cell adhesion, leukocyte migration, and extracellular matrix remodeling. Furthermore, we characterized the phenotypes of T cells along these trails, showing that the migrating T cells are highly proliferative. Our findings introduce an approach for studying T cell migration and interactions within the TME, offering valuable insights into tumor-immune dynamics.

Keywords:  Cancer; Cell migration/adhesion; Immunology; Oncology; T cells

DOI:  https://doi.org/10.1172/jci.insight.192718
Cancer Biol Med. 2026 May 06. pii: j.issn.2095-3941.2025.0652. [Epub ahead of print]

Bifidobacterium animalis suppresses melanoma progression and activates anti-tumor immunity by inhibiting YAP1 expression in CD8+ T cells.

Chengyi Li, Xuehua Zhang, Yichen Yang, Haotian Zeng, Yanqiang Shi, Jinjin Zhang, Lingjun Liu, Chenwei Zhu, Zhiwen Zhang, Chao Li, Xudong Wang, Xiaowu Bai, Haijun Deng, Qing Li.

   OBJECTIVE: The probiotic, Bifidobacterium animalis, (B. animalis) is known to provide health benefits in humans. This study investigated the role of B. animalis in suppressing malignant melanoma progression and modulating tumor immunity.
METHODS: Bifidobacterium spp. were isolated from human faeces and verified by whole-genome sequencing. The anti-tumor effects were assessed in B16-F10 melanoma cells. B. animalis efficacy was further evaluated in a syngeneic murine model. Immune profiling was performed with flow cytometry and CD8+ T cell dependency was tested with antibody depletion. Functional metabolites were analyzed by liquid chromatography-mass spectrometry (LC-MS). Transcriptome sequencing elucidated the YAP1 mechanism in CD8+ T cells. Gut microbiota composition was assessed via shotgun metagenomic sequencing.
RESULTS: Among the selected Bifidobacterium spp., B. animalis and its conditioned medium effectively inhibited melanoma cell proliferation. Oral administration of B. animalis significantly reduced the growth of B16-F10 allografts, accompanied by an increase in tumor-infiltrating effector T cells. The bioactive component of B. animalis was identified as a < 3-kDa non-protein fraction containing mannose, which phenocopied the anti-tumor and immunostimulatory effects of B. animalis. Microbiota profiling revealed probiotic enrichment in mannose-treated mice. CD8+ T cell depletion abrogated mannose efficacy. Combination therapy with B. animalis and anti-PD-1 synergistically enhanced tumor control and T cell activation. Mechanistically, the bioactive fraction and mannose downregulated YAP1 expression in CD8+ T cells.
CONCLUSIONS: B. animalis suppresses melanoma tumorigenesis in mice by restoring gut microbiota and secreting functional mannose. Mannose enhances anti-PD-1 efficacy by inhibiting YAP1 expression in CD8+ T cells, thereby improving effector function. B. animalis may serve as a preventive measure for melanoma management.

Keywords:   Bifidobacterium animalis ; CD8+ T cells; anti-PD-1; mannose; melanoma

DOI:  https://doi.org/10.20892/j.issn.2095-3941.2025.0652
Iran J Basic Med Sci. 2026 ;29(3): 334-352

Hypoxic tumor microenvironment and immune cell dynamics: From metabolic reprogramming to therapeutic innovation.

Azadehsadat Razavi, Hanieh Mojtahedi, Fatemeh Aghakhani, Hedieh Haji Khodaverdi Khani, Ramazan Rezaei, Davar Amani.

  The tumor microenvironment (TME) comprises the cellular and non-cellular components present within and around a tumor and plays a critical role in tumor progression and development. Metabolic changes in immune cells within the TME have been reported, including alterations of glycolysis, oxidative phosphorylation, and fatty acid oxidation pathways that contribute to tumorigenesis. In the present review, we highlight the significant role of hypoxia within the TME as a primary characteristic of most solid tumors. A comprehensive search of the EMBASE, MEDLINE, and Web of Science databases was conducted, encompassing all literature published up to and including June 2025. This study emphasizes the critical role of hypoxia in the TME and its impact on immune cell function. By understanding how hypoxia affects immune cell metabolism, researchers can develop therapeutic approaches targeting immune cell metabolism in the TME. In this regard, we discussed the role of targeting hypoxia via HIF-1 for immunotherapeutic implications; targeting HIF-1 for immunotherapeutic purposes is an area of active research and holds promise for developing new and more effective cancer treatments.

Keywords:  Hypoxia; Immune cells; Immunometabolism; Molecular targeted therapy; Tumor microenvironment

DOI:  https://doi.org/10.22038/ijbms.2025.90209.19446
Nat Rev Immunol. 2026 May 08.

Calibrating T cell responsiveness through interactions with self.

Judith N Mandl, Heather J Melichar, Byron B Au-Yeung, Johannes Textor, Ludger Klein.

During an immune response, T cells face one of the most consequential decisions of their lifespan upon recognition of a ligand they have not previously encountered: whether to exit the naive basal state, undergo clonal expansion and acquire effector functions. This process is often portrayed as a binary switch, in which naive cells from a highly diverse repertoire transition from an 'off' state to an 'on' state. However, this digital view overlooks the crucial prior information that T cells integrate through T cell receptor (TCR) interactions with self-peptide-MHC (self-pMHC). During thymic selection, immature T cells encounter a unique self-pMHC ligandome that shapes their development. After maturation, naive T cells continue to engage self-ligands as they patrol secondary lymphoid organs. Here we review evidence that these encounters with self-peptides are not only essential for T cell survival but also have lasting consequences that dynamically tune T cell function when called into action. The naive off state, therefore, is neither fixed nor functionally neutral. We argue that a deeper understanding of an individual's self-peptide repertoire is crucial for deciphering TCR self and non-self discrimination and for effectively harnessing T cell responses to foreign antigens.

DOI: https://doi.org/10.1038/s41577-026-01305-2
Front Immunol. 2026 ;17 1720544

ATG5-mediated inducible autophagy sustains CAR-T cell durability under solid tumor stress.

Sang-Eun Jung, Minji Lim, Hyungwoo Jeong, Youngchae Moon, Hyungseok Seo.

  Autophagy functions as a context-dependent stress adaptation pathway in T cells; however, its role in sustaining chimeric antigen receptor (CAR)-T cell function within solid tumor environments remains insufficiently defined. In this study, we investigated whether ATG5-mediated autophagy regulation contributes to CAR-T cell functional durability under tumor-associated stress conditions. ATG5 overexpression (OE) CAR-T cells did not increase basal autophagy activity but instead selectively enhanced autophagy flux in response to inducible stimuli. Under tumor-mimicking immunosuppressive conditions, ATG5 OE CAR-T cells maintained cytotoxic activity during prolonged antigen exposure and exhibited preserved effector cytokine production together with reduced oxidative stress. Consistent with these in vitro findings, ATG5 OE CAR-T cells exhibited enhanced antitumor efficacy in vivo under IR-preconditioned settings, characterized by improved tumor control and survival, which was associated with sustained effector function of tumor-infiltrating CAR-T cells. Collectively, these findings demonstrate that reinforcing inducible autophagy capacity through ATG5 promotes the maintenance of CAR-T cell function under tumor-associated challenges, highlighting a targeted strategy to enhance CAR-T cell persistence in solid tumor immunotherapy.

Keywords:  ATG5 overexpression; CAR-T cell therapy; CAR-T persistence; autophagy; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2026.1720544
Nat Commun. 2026 May 05.

ERα blockade in dendritic cells enhances antigen cross-presentation and induces antitumor CD8+ T cell immunity.

Yaxin Liu, Zhongfei Ma, Xuelian Li, Yuanyuan Ding, Zhiqing Li, Bin Zhang, Yumei Zhou, Jun Zhou, Shuo Liu, Shuxun Liu, Lianjun Zhang, Chunmei Wang, Xuetao Cao.

Dendritic cells (DC) dysfunction impedes antitumor immunity, so understanding intrinsic regulators of DC antigen presentation and the resulting activation of antitumor CD8+ T cells could benefit therapy. Here, we use a genome-wide CRISPR screen for antigen presentation-regulating genes in DCs, and identify estrogen receptor α (ERα) as an intrinsic checkpoint inhibiting antigen cross-presentation. ERα genomic deficiency or pharmacological degradation enhances antigen presentation and CD8+ T cell priming in mouse and human DCs. Mechanistically, independently of canonical estrogen signaling, ERα sustains Galectin-3-mediated recruitment of CHMP4b to damaged phagosomes, thereby facilitating ESCRT-III-mediated membrane repair and restricting cytosolic antigen translocation. In vivo, ERα-deficient or ERα-degraded DC vaccines expand tumor-specific CD8+ T cells to suppress tumor growth in mice bearing subcutaneous cancers. In vitro, FDA-approved ERα antagonists enhance human DC-mediated activation of antigen-specific human CD8+ T cells. Our work thus uncovers a non-canonical role of ERα in phagosome integrity as a checkpoint for antigen cross-presentation in DCs, and implicates ERα-targeted DC vaccines as a potential immunotherapeutic strategy.

DOI: https://doi.org/10.1038/s41467-026-72647-7
Cancer Lett. 2026 May 05. pii: S0304-3835(26)00326-5. [Epub ahead of print]652 218563

IL-12 augments adoptive cell therapy by reshaping CD8+ T dynamics and broadening antitumor immunity.

Yue Huang, Xiangming Liu, Yiwei Chen, Huihui Zhang, Junshi Zhang, Yang-Xin Fu, Xuanming Yang, Zaopeng Yang.

Adoptive cell therapy (ACT) against solid tumors is constrained by tumor heterogeneity, immunosuppressive microenvironments, and insufficient T cell potency and persistence. Although IL-12 has long been recognized as a potent enhancer of T-cell immunity, its clinical application has been hindered by systemic toxicity and the lack of a strategy to harness its benefits without chronic exposure. Here, we show that ex vivo IL-12 preconditioning programs tumor-specific T cells with increased antigen sensitivity, yielding superior antitumor activity compared with IL-7/IL-15. Systemic delivery of Pro-IL-12 further rejuvenates exhausted CD8+ tumor-infiltrating lymphocytes (TILs) by restoring IL-2 hypersensitivity, sustaining persistence, and strengthening effector machinery. When combined with ACT, a single dose of Pro-IL-12 reinstated IFN-γ production in exhausted TILs and doubled intratumoral T-cell accumulation via upregulation of IL-2Rα and increased IL-2 sensitivity. Pro-IL-12 markedly improved therapeutic outcomes, inducing durable complete tumor regression, promoting antigen spreading, and establishing long-term immune memory that prevented relapse from antigen-loss tumor. Across multiple xenograft models, including pancreatic cancer, lymphoma and triple negative breast cancer, distinct human CAR-T products paired with Pro-IL-12 enhanced tumor eradication without cytokine release syndrome. Together, these findings establish precision delivery of IL-12 as a translatable strategy that harnesses known IL-12 biology to achieve robust antitumor efficacy without systemic toxicity.

DOI: https://doi.org/10.1016/j.canlet.2026.218563
Gut Microbes. 2026 Dec 31. 18(1): 2667610

Gut microbiota and immunometabolism in obesity.

Alba Torres-Mayo, Rebeca Liébana-García, Marta Olivares, Aize Pellón, Juan Anguita, Yolanda Sanz.

  The gut microbiota plays a central role in modulating both immunity and metabolism. Obesity-associated microbiota configuration is a critical driver of persistent inflammatory activation and immune dysfunction, ultimately leading to chronic metabolic disorders. Immunometabolism examines how metabolic demands shape immune cell function and how immune responses influence cellular metabolism. Emerging research on how the gut microbiota contribute to immune cell metabolic processes and the resulting health outcomes is deepening our understanding of the mechanisms underlying obesity and metabolic diseases. In this review, we summarize how intracellular metabolic pathways and master regulators, such as mTOR and AMPK, orchestrate immune cell function and how their dysregulation contributes to obesity-associated immune and metabolic dysfunction. We also discuss how gut microbiota influences the immunometabolism of different myeloid and lymphoid cell subsets and intestinal epithelial cells. Finally, we review the role of microbially produced metabolites, including short-chain fatty acids, lactate, succinate, bile acids, and amino acids, in reprogramming immune cell metabolism. We also discuss whether modulating gut microbiota function to regulate immunometabolic pathways could help restore immune homeostasis and reduce obesity-related complications.

Keywords:  Gut microbiota; diet; immunometabolism; obesity

DOI:  https://doi.org/10.1080/19490976.2026.2667610
Cancer Cell. 2026 May 07. pii: S1535-6108(26)00218-7. [Epub ahead of print]

Whole-genome doubling drives immune evasion by silencing antigen presentation.

Pierre Foidart, Zheqi Li, Xinran Cai, Marco Seehawer, Daniel D Brown, Amatullah Tawawalla, Pilar Baldominos, Salma Parvin, Jun Nishida, Ernesto Rojas-Jimenez, Triet M Bui, Benedetto Diciaccio, Rahul Kumar, Brent T Schlegel, Marie-Anne Goyette, TashJae Scales, Pengze Yan, Xintao Qiu, Rong Li, Yijia Jiang, Yingtian Xie, Mahmoud Aarabi, Xiao-Yun Huang, Laura E Stevens, Paloma Cejas, Lise Mangiante, Cristina Irene Sotomayor Vivas, Kathleen E Houlahan, Christina Curtis, Steffi Oesterreich, Isaac S Harris, Anthony G Letai, Adrian V Lee, Henry W Long, Judith Agudo, Kornelia Polyak.

  Whole-genome doubling (WGD) is a common yet poorly understood event associated with poor clinical outcomes. Here, we characterize mechanisms by which WGD drives tumor evolution, utilizing mouse mammary tumor models of WGD established through cell fusion. We find that WGD increases transcriptomic and epigenetic heterogeneity and identify the YM155 BIRC5 inhibitor as a compound specifically suppressing WGD+ tumors. WGD triggers immune evasion by escaping CD8+ T cell responses, rendering WGD+ tumors more sensitive to anti-PD-L1. Through single-cell profiling, we discover that WGD+ cancer cells exhibit reduced antigen presentation and response to IFNγ, attributed to the epigenetic silencing of MHCI transcriptional regulators via elevated histone H3 lysine 27 trimethylation. Further investigations reveal decreased KDM6 activity and increased succinate levels in WGD+ tumors. PRC2 inhibition preferentially suppresses WGD+ tumor growth, enhances antigen presentation, and CD8+ T cell infiltration. Our results underscore metabolic and epigenetic alterations as critical drivers of WGD-associated immune escape.

Keywords:  antigen presentation; breast cancer; epigenetic silencing; immune escape; whole genome doubling

DOI:  https://doi.org/10.1016/j.ccell.2026.04.007
Front Immunol. 2026 ;17 1803384

Ex vivo cytokine responses and metabolic reprogramming are associated with γδ T cell differentiation in Plasmodium falciparum placental malaria.

Chris Marco Nana Mbianda, Bodin Darcisse Kwanou Tchakounte, Bernard Marie Bitye Zambo, Joséphine Ntankheuh Tchinkou, Derrick Atchombat Nyasse, Balotin Fogang, Rafael José Argüello, Lawrence Ayong, Rosette Megnekou.

   Background: γδ T cells play a key role in modulating immune responses to pregnancy-associated malaria and can enhance vaccine efficacy through their activation and cytotoxic functions. However, the mechanisms guiding γδT cell differentiation in placental malaria (PM) remain poorly understood. We examined ex vivo associations between cytokines, metabolic profiles and γδ T-cell differentiation in women with PM.
Methods: A case-control study including 50 women at delivery (21 PM+, 29 PM-) was carried out. Peripheral, placental intervillous space, and cord blood mononuclear cells were isolated, and multiparametric flow cytometry was performed to characterize γδT-cells and memory phenotypes, its subsets (Vδ1+, Vδ2+, Vδ3+), and the expression of exhaustion (TIM-3, PD1) and activation (HLA-DR) markers. Ex vivo plasma levels of IL-8, IL-33, and IL-35 were quantified by Luminex assay or ELISA. Immunometabolic profiles were assessed in a subset of 15 samples from uninfected women following cell stimulation with phytohemagglutinin (PHA) by SCENITH assay.
Results: In general, the frequency of γδ T cells and their subsets varied depending on the different blood compartments, with naïve and central memory (CM) phenotypes observed mainly in CBMC, while effector memory (EM) and terminally differentiated effector memory (TEMRA) phenotypes were found mainly in PBMC and IVBMC. Ex vivo analyses showed that γδ T cell-modulating cytokine IL-8 were associated, in a compartment-dependent manner, with down-regulation of immunoregulatory markers TIM-3 and PD-1. Interestingly, IL-8 and IL-33 were associated with increased frequency of the TEMRA cell phenotype in peripheral blood, consistent with enhanced differentiation of naïve γδT cells during PM. Metabolic profiling of the different cell types further established an enhanced mitochondrial metabolic activity in predominantly terminally differentiated γδ T cells in PBMC, compared to the mainly glycolytic activities of non-terminally differentiated cells in CBMC and IVBMC.
Conclusion: Placental malaria is associated with a compartment-specific memory γδ T cell differentiation, with cytokines and metabolic reprogramming regulating exhaustion. These findings reveal key regulatory processes that determine the function of γδ T cells during placental malaria, which constitute potential targets for new therapeutic intervention against PM.

Keywords:  Plasmodium falciparum; cytokines; metabolic reprogramming; placental malaria; γδT cells memory

DOI:  https://doi.org/10.3389/fimmu.2026.1803384
Eur J Immunol. 2026 May;56(5): e70192

CD8 T Cell Sensing of Type I Interferon Impacts Anergy.

Anne S Haefke, Hanna Gröber, Ioana Sandu, Vanessa Skipness, Nikos Pantouloufos, Fabienne Gräbnitz, Marie-Elen Tuchel, Nathan Zangger, Dominique Stark, Marvin Kříž, Carmine Cristinzio, Hanspeter Pircher, Roman Spörri, Isaak Quast, Annette Oxenius.

  Peripheral tolerance is indispensable for the maintenance of immune homeostasis, allowing protective immunity while limiting responses to self-antigens. CD8 T cells activated in the absence of co-stimulation and pro-inflammatory cytokines are either deleted, rendered anergic, or actively suppressed. These mechanisms are well established, but the cues determining the mode and depth of peripheral tolerance remain incompletely understood. Here, we identify type I interferon (IFN-I) signalling in T cells as a key modulator of peripheral tolerance in the absence of infection. In the complete absence of IFN-I signalling, autoreactive CD8 T cells are rendered anergic, and their expansion, phenotype and function are tightly controlled. Basal levels of IFN-I are sufficient for self-reactive CD8 T cells to expand and retain partial effector functions in the absence of viral infections. This is dependent on T cell-intrinsic IFN-I sensing and is associated with the generation of a partially anergic, TCF1+ CD8 T cell subset that can contribute to a pathogen-specific immune response. Collectively, our results suggest that elevated basal IFN-I levels limit anergy induction, providing a potential mechanistic explanation for the association of baseline inflammation with the development of autoimmunity.

Keywords:  CD8 T cells; anergy; autoimmunity; peripheral tolerance; type I interferon

DOI:  https://doi.org/10.1002/eji.70192
Cancer Immunol Immunother. 2026 May 08.

Novel recombinant protein PK5-Gal-3C enhances the anti-tumor activity of T cells via binding with TRPV2.

Guopeng Zhang, Wei Zhang, Xiaohuan Wei, Zhenyu Wang, Feitong Wang, Shishuo Sun, Haiheng Xu, Xiangye Liu, Qing Zhang, Xiaoge Gao.

  Investigating strategies to enhance T cell effector function can improve the adoptive immune responses to tumors and complement existing tumor immunotherapies. Here, we present a novel artificially designed recombinant protein, PK5-Gal-3C, which is composed of the fifth kringle domain of plasminogen (PK5) and the C-terminal carbohydrate-recognition domain of galectin-3 (Gal-3C). This protein exhibited potent anti-tumor activity by significantly enhancing T cell effector function. Specifically, PK5-Gal-3C directly activated T cells by binding to glycosylated TRPV2 via Gal-3C, a thermosensitive calcium-permeable cation channel, thereby promoting the influx of calcium ions to enhance T cells cytotoxicity via the activation of c-Jun. Correspondingly, inhibition of TRPV2 or c-Jun impaired the cytotoxicity of T cell mediated by PK5-Gal-3C. Additionally, PK5-Gal-3C demonstrated significant anti-tumor activity by enhancing T cell tumor infiltration and cytotoxicity in a mouse model, as well as improving the anti-tumor efficacy of CAR-T cells in solid tumors. In summary, PK5-Gal-3C is a safe and potent anti-tumor agent with promising potential for T cell-mediated cancer immunotherapy.

Keywords:  Immunotherapy; Novel recombinant protein PK5-Gal-3C; Solid tumor; T cell; Transient receptor potential cation channel, subfamily V member 2

DOI:  https://doi.org/10.1007/s00262-026-04401-3
bioRxiv. 2026 Apr 21. pii: 2026.04.17.719305. [Epub ahead of print]

Multimodal analysis of molecular remodeling in aging spleen identified global and cell type specific changes.

Katarina Vlajic, Alison Luciano, Gennifer E Merrihew, Carla R Sanchez, Michael Riffle, Kristine A Tsantilas, Sahar Attar, Brian J Beliveau, Mariya T Sweetwyne, Michael J MacCoss, Gary Churchill, Devin K Schweppe.

Aging reshapes the cellular and molecular landscape of mammalian tissues. These changes can be progressive, preceding linearly with age, or occur as abrupt transitions of the course of lifespan. To investigate the age-dependent cellular and molecular shifts we profiled matched proteomes and transcriptomes from male and female murine spleens across eight time points, from stable adults through late life. The spleen was chosen to integrate understanding of age-dependent changes associated with immune surveillance, inflammaging, and immune-related proteostasis. Male and female mice follow distinct aging trajectories particularly in protein-RNA correlation in late life, reflecting both compositional shifts and failure of post-transcriptional buffering. To investigate whether these changes could be attributed to specific cell-types within the spleen, we developed Celestial, a machine-learning framework to identify cell-type-specific changes in bulk tissue samples. We found that age-related bulk molecular changes could be attributed in part to compositional remodeling of cell-types-expansion of GZMK+ CD8+ T cells and C1Q+ macrophages alongside naive T cell and global B cell loss. These results demonstrate that cell-type-aware interpretation can inform bulk multi-omic data for accurate mechanistic inference in heterogeneous tissues undergoing complex molecular remodeling.

DOI: https://doi.org/10.64898/2026.04.17.719305
bioRxiv. 2026 Apr 30. pii: 2026.04.28.721287. [Epub ahead of print]

Sleep regulates hepatic neutrophil trafficking by modulating uric acid metabolism via sympathetic nervous system activity.

Pawan K Jha, Utham K Valekunja, Jing Chen-Roetling, Akhilesh B Reddy.

Sleep is essential for survival and serves as a key regulator of metabolic and immune function. Sleep loss is strongly associated with metabolic stress and liver inflammation. The mechanisms linking sleep disruption to hepatic metabolic inflammation (metaflammation) remain poorly defined. Here, we show that sleep loss triggers metaflammation through a sympathetic-metabolic-immune axis. Acute sleep deprivation (SD) activates hepatic sympathetic signaling, leading to increased uric acid (UA) synthesis driven by enhanced expression and activity of xanthine dehydrogenase/xanthine oxidase (XDH/XO) in the liver. Elevated UA, acting as an immune-stimulatory metabolic signal, promotes hepatic neutrophil recruitment and pro-inflammatory cytokine production, a response that is rapidly reversed upon sleep recovery. Our findings identify sleep-dependent sympathetic control of hepatic UA metabolism as a driver of acute liver inflammation and reveal how acute sleep loss reprograms liver immune-metabolic homeostasis.

DOI: https://doi.org/10.64898/2026.04.28.721287
Res Sq. 2026 Apr 30. pii: rs.3.rs-9544748. [Epub ahead of print]

MCT1 governs a metabolic checkpoint at pachytene during spermatogenesis.

Ning Wang, Xiaoyu Zhang, Yan Liu.

The transition from mitosis to meiosis represents a fundamental cell-fate decision that requires coordinated remodeling of transcriptional and metabolic programs. While key transcriptional regulators of meiotic entry have been defined, how metabolic flux directly governs this process remains unclear. Here, we identify a monocarboxylate transporter1 (MCT1)-dependent metabolic checkpoint that controls meiotic progression in mammalian spermatogenesis. Through integrative single-cell transcriptomics, metabolic profiling, and computational perturbation modeling, we show that Stra8-driven meiotic initiation is coupled to a metabolic switch favoring monocarboxylic acid metabolism, prominently involving MCT1 (encoded by Slc16a1). Germ cell-specific deletion of Slc16a1 results in a complete arrest at the pachytene stage, characterized by defective homologous recombination, persistent DNA damage, and failure to activate the meiotic transcriptional program. Multi-omic analyses reveal that loss of MCT1 induces a metabolic stress-like state, suppresses expression of key meiotic regulators, and disrupts progression through the pachytene checkpoint. Mechanistically, we demonstrate that MCT1-mediated lactate influx drives histone H4 lysine 12 lactylation (H4K12la) at promoters of meiotic genes, thereby epigenetically licensing their expression. In the absence of MCT1, H4K12la deposition is lost at meiotic loci and redistributed toward stress-response pathways. Together, our findings suggest MCT1-mediated metabolism as an instructive signal that integrates metabolic state with epigenetic regulation to govern meiotic cell-fate progression, defining a previously unrecognized metabolic checkpoint at pachytene.

DOI: https://doi.org/10.21203/rs.3.rs-9544748/v1
Int Immunopharmacol. 2026 May 06. pii: S1567-5769(26)00636-3. [Epub ahead of print]182 116790

Cytotoxic CD4+ T cells and their implication in oral diseases and systemic diseases with oral manifestations.

Xin-Xin Huang, Si-Ting Hu, Gang Zhou, Jing Zhang.

  T cells are derived from multipotent stem cells in the bone marrow and migrate to the thymus, where they differentiate into two main subpopulations: CD4+ T cells and CD8+ T cells. It is usually believed that CD4+ T cells mainly play a supplementary function in immune processes such as antibody production, antigen-specific CD8+ T cell activation, and immune regulation; whereas CD8+ T cells are able to kill the target cells through cell killing mechanism, and play an important role in the immune defense against intracellular pathogens and tumor immunity. A unique cytotoxic subpopulation of CD4+ T cells, designated CD4+ cytotoxic T lymphocytes (CD4+ CTLs), has emerged as a significant focus of research in recent years. This review focuses on biological properties and mechanisms of CD4+ CTLs, as well as the research progress of CD4+ CTLs in oral diseases and systemic diseases with oral manifestations, including Sjögren's syndrome, IgG4-related disease, HIV infection, and inflammatory bowel disease, with the aim of elucidating the contributions of CD4+ CTLs to disease pathogenesis and uncovering novel therapeutic targets for these conditions.

Keywords:  CD4(+) CTLs; Head and neck squamous cell carcinoma; Oral disease; Systemic diseases with oral manifestations

DOI:  https://doi.org/10.1016/j.intimp.2026.116790
bioRxiv. 2026 Apr 29. pii: 2026.04.28.721334. [Epub ahead of print]

Preexisting chronic infection skews the epigenetic landscape of subsequent memory CD8 T cell responses.

Abdelhameed S Dawood, Elizabeth E Wolfson, Silmi Jiwani, Ahmet Ozdilek, Youssef M Zohdy, Tylisha Gourdine, Sheikh Abdul Rahman, Jefferey A Tomalka, Mohamed S Abdel-Hakeem.

Previous studies suggest that preexisting chronic disease impairs immune responses to subsequent infection and vaccination. However, the underlying epigenetic mechanisms are understudied. Here, we show that preexisting chronic infection with LCMV clone 13 (CL13) compromised the formation of central memory CD8 T cells (T CM ) to subsequent Listeria monocytogenes infection, despite not profoundly impacting effector responses. This correlated with a skewed cytokine milieu. Our chromatin-accessibility profiling of Listeria-specific CD8 T cells showed significant epigenetic skewing of both T CM and effector memory (T EM ) in mice with preexisting LCMV-CL13, a skewing that started in memory-precursor effector cells (MPECs) during the effector phase. Transcription-factor binding sites (TFBS) analyses highlighted the interferon regulatory factor (IRF) family as major TFs implicated in this skewing. Thus, our results suggest that preexisting persistent inflammation skews the phenotypic and epigenetic landscape of subsequent memory responses, arguing for interventions to optimize vaccine-induced memory in hosts with preexisting chronic disease.

DOI: https://doi.org/10.64898/2026.04.28.721334
bioRxiv. 2026 Apr 22. pii: 2026.04.21.720010. [Epub ahead of print]

MCT1 governs a metabolic checkpoint at pachytene during spermatogenesis.

Xiaoyu Zhang, Yan Liu, Ning Wang.

The transition from mitosis to meiosis represents a fundamental cell-fate decision that requires coordinated remodeling of transcriptional and metabolic programs. While key transcriptional regulators of meiotic entry have been defined, how metabolic flux directly governs this process remains unclear. Here, we identify a monocarboxylate transporter1 (MCT1)-dependent metabolic checkpoint that controls meiotic progression in mammalian spermatogenesis. Through integrative single-cell transcriptomics, metabolic profiling, and computational perturbation modeling, we show that Stra8 -driven meiotic initiation is coupled to a metabolic switch favoring monocarboxylic acid metabolism, prominently involving MCT1 (encoded by Slc16a1 ). Germ cell-specific deletion of Slc16a1 results in a complete arrest at the pachytene stage, characterized by defective homologous recombination, persistent DNA damage, and failure to activate the meiotic transcriptional program. Multi-omic analyses reveal that loss of MCT1 induces a metabolic stress-like state, suppresses expression of key meiotic regulators, and disrupts progression through the pachytene checkpoint. Mechanistically, we demonstrate that MCT1-mediated lactate influx drives histone H4 lysine 12 lactylation (H4K12la) at promoters of meiotic genes, thereby epigenetically licensing their expression. In the absence of MCT1, H4K12la deposition is lost at meiotic loci and redistributed toward stress-response pathways. Together, our findings suggest MCT1-mediated metabolism as an instructive signal that integrates metabolic state with epigenetic regulation to govern meiotic cell-fate progression, defining a previously unrecognized metabolic checkpoint at pachytene.

DOI: https://doi.org/10.64898/2026.04.21.720010
Pharmacol Res. 2026 May 05. pii: S1043-6618(26)00144-1. [Epub ahead of print] 108229

Unlocking healthy aging through gut microbial tryptophan metabolism.

Lianbin Xu, Teresa G Valencak, Luzhen Wang, Xiaowen Wang, Xiuli Li, Hui-Zeng Sun.

  Healthy aging has become an attractive focus of biomedical research worldwide. Tryptophan (Trp) metabolism pathways that yield kynurenine, indole derivatives, and 5-hydroxytryptophan during microbiota-host crosstalk regulate molecular processes critical to healthy aging. Here, we synthesize the most recent advances concerning the mechanisms by which microbial Trp metabolism maintains homeostasis from the perspectives of improving intestinal function, modulating immune signaling, restoring redox balance, and optimizing energy production. We further evaluate the latest evidence regarding how microbiota-derived Trp metabolites influence age-related disorders. Finally, we summarize the clinical applications of Trp metabolites and key metabolic enzymes to promote healthy aging. Our review provides comprehensive insights into the relationship between microbial Trp metabolism and human aging, and it opens up novel opportunities for prevention, diagnosis, and therapy of disease.

Keywords:  AhR pathway; gut microbiota; healthy aging; indole; tryptophan

DOI:  https://doi.org/10.1016/j.phrs.2026.108229