bims-imseme 2026-05-24 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2026–05–24
thirty-six papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Lymphatic egress recycles tumor-experienced effector CD8 T cells to sustain immune surveillance.
T Cell Dysfunction in the Acidic Tumor Microenvironment.
The USP7-VIM axis mediates lipid metabolic remodelling and compromises CD8+ T-cell mitochondrial fitness in glioblastoma.
Drug Delivery Engineering Strategies Targeting CD4+/CD8+ T Cell Exhaustion to Improve the Tumor Immunosuppressive Microenvironment.
β-hydroxybutyrate potentiates anti-tumor immunity by modulating cytotoxic CD8+ T cell responses.
Peroxisomes orchestrate metabolic flexibility and longevity via an interorganelle cascade.
PARK7-induced delactylation of ATAD3A impairs mitochondrial fitness to promote exhaustion of tumor-infiltrating CD8+ T cells.
Licochalcone A targets ADRB2 to enhance CD8+ T cell anti-leukemia activity via regulation involving the AKT2/FOXO1/GLUT2 axis.
Iron overload in the tumor microenvironment induces CD8+ T cell ferroptosis and dysfunction.
Bidirectional roles of senescence in tumor-infiltrating immune cells: mechanisms, impact on immunotherapy, and therapeutic strategies.
12-HETE: a novel lipid mediator of CD8+ T cell dysfunction in MASH/HCC.
Functional immune profiling reveals CD4+ T cell dysregulation in coeliac disease.
Glucose metabolic reprogramming as a driver of immunosuppression in the tumour microenvironment.
GSK-3 regulates CD4-CD8 cooperation for super-armed CD8+ cytolytic T cells in immunotherapy against tumors.
Immunometabolic control of cytokine production by micronutrients in health, aging, and inflammation.
Interplay between microRNAs and TGF-β signaling in T cells: implications for Th9 differentiation and immune pathogenesis.
Treatment implications of T cell DNA damage in anti-tumor immunity.
Multiregional profiling reveals THBS1-SPP1 monocyte-macrophage axis drives immunosuppression and outcome in colorectal liver metastases.
Single-cell RNA sequencing unveils CD8+ T cell heterogeneity in the diffuse large B-cell lymphoma microenvironment: A systematic review.
Coincident epithelial signals restrain commensal-specific CD8αβ + T cells in the intestine.
Protein homeostasis as a determinant of CD8⁺ T cell fate.
Mechanism of Qiling Fuzheng Qingjie granules in alleviating doxorubicin-induced T cell immune dysfunction via mitochondrial energy metabolism.
Funk CR, Wang S, Chen KZ, et al. PI3Kδ/γ inhibition promotes human CART cell epigenetic and metabolic reprogramming to enhance antitumor cytotoxicity. Blood. 2022;139(4):523-537.
Metabolic Plasticity in Embryogenesis Throughout the Lens of NAD.
TNFAIP3 Reprograms T Cell Exhaustion and Restores Anti-Leukemia Immunity in Acute Myeloid Leukemia.
Inhibition of salt-inducible kinases reprograms T cells and antitumor immunity in ovarian cancer.
Expansion of NKG2A+CD8+ T cells with regulatory signatures distinguish individuals living with HIV-2 from those with HIV-1.
Glycolysis-driven cancer-associated fibroblasts shape T-Cell exclusion via the CXCL16-CXCR6 Axis: a metabolic-chemokine mechanism in tumor immunity.
Cell-autonomous control of CAR signaling and receptor shedding via ADAM17-mediated proteolysis.
HLA-E-restricted T cells primed by a modified HLA-B*57:01 restricted HIV-1 peptide suppress HIV-1 replication.
Publisher Correction: Microbiota-induced T cell plasticity enables immune-mediated tumour control.
PD-1: CD28 chimeric receptors enhance phenotypic and functional features of T cell subsets.
Immunosenescence and Vaccine Efficacy in Aging: Dynamic Interplay of Gut Microbiota and mTOR Signaling Pathways.
Protective coinfection: influenza reprograms myeloid cells to limit CD8 T cell-mediated malaria pathology.
Skin as a sentinel and modulator of systemic aging: a translational framework for evidence-based gerotherapeutics.
Ion-coupled transfersome complexes for enhanced transdermal NAD+ repletion and mitigation of cellular senescence signatures.

bioRxiv. 2026 May 05. pii: 2026.04.30.721705. [Epub ahead of print]

Lymphatic egress recycles tumor-experienced effector CD8 T cells to sustain immune surveillance.

Ines Delclaux, Katherine S Ventre, Naomi R Besson, Tara Muijlwijk, Milad Ibrahim, Guanning Wang, Taylor A Heim, Maria M Steele, Alexander C Huang, Markus Schober, Iman Osman, Amanda W Lund.

Successful anti-tumor immune surveillance depends on stem-like CD8 + T cells that are enriched in tumor-draining lymph nodes (LN), but how they are maintained over time remains poorly understood. Here, we identify a continuous lymphatic circuit that sustains stem-like CD8 + T cells. Using photoconversion to fate-map intratumoral T cells we demonstrate that effector cells exit the tumor microenvironment and migrate back to the draining LN. These tumor-specific, migratory effector T cells avoid chronic antigen stimulation, re-express the transcription factor associated with self-renewal, TCF1, and enter a stem-like state in the LN. Antigen presentation in LNs by dendritic cells drives their proliferation thereby inflating the LN stem-like population. Consequently, maintenance of stem-like T cells and ICB response depends on constitutive lymphatic transport, while LN metastasis compromises the stem-like niche, diminishing ICB response. We, therefore, define a continuous, peripheral lymphatic circuit that recycles tumor-experienced effector T cells to fuel durable, systemic immune surveillance.

DOI: https://doi.org/10.64898/2026.04.30.721705
Acta Physiol (Oxf). 2026 Jun;242(6): e70260

T Cell Dysfunction in the Acidic Tumor Microenvironment.

F B Christiansen, E S Novella, A V Lindemann, J F H Cordes, S F Pedersen.

  Solid tumors are characterized by profound metabolic and vascular abnormalities that generate a hostile tumor microenvironment (TME) marked by extracellular acidosis, hypoxia, and nutrient deprivation. While the consequences of these conditions for cancer cell behavior have been extensively studied, their impact on anti-tumor immune responses-particularly T cell function-has only recently gained attention. In this review, we summarize and critically discuss current knowledge on how acidic TME conditions affect the cytotoxic CD8+ T cells which are essential for anti-tumor immunity, and the protumorigenic, regulatory T cells (Tregs). An emerging body of literature shows that TME acidosis restricts cytotoxic CD8+ T cell motility and tumor penetration, suppresses cytokine production and secretion despite preserved transcription, impairs proliferation, and reduces cytotoxic killing capacity. These effects are closely linked to acid-induced metabolic reprogramming, including inhibition of glycolysis, altered mTOR and MYC signaling, and a shift toward fatty acid-dependent oxidative metabolism. In contrast, Tregs, which are metabolically adapted to rely on oxidative phosphorylation and lactate utilization, are comparatively resilient to acidic stress, and acidosis can enhance their suppressive capacity, thereby further skewing the immune balance toward tolerance. We highlight emerging evidence that tumor acidosis modulates immune checkpoint pathways, including pH-sensitive signaling through VISTA and regulation of PD-L1 expression, with important implications for immunotherapy sensitivity. We posit that limiting tumor acidosis may enable restoration of anti-tumor T cell function and improve therapeutic response to immune checkpoint blockade and adoptive T cell therapies.

Keywords:  CD8+; Treg; anticancer immune response; cancer; immune oncology

DOI:  https://doi.org/10.1111/apha.70260
Int J Biol Macromol. 2026 May 19. pii: S0141-8130(26)02550-X. [Epub ahead of print] 152623

The USP7-VIM axis mediates lipid metabolic remodelling and compromises CD8+ T-cell mitochondrial fitness in glioblastoma.

Liyan Tang, Hao Wang, Jinming Chen, Yang Zhang, Yulun Huang, Xuetao Li.

  Glioblastoma (GBM) remains a highly lethal malignancy for which current treatments offer only a limited therapeutic benefit. Although vimentin (VIM) is classically regarded as a cytoskeletal protein, its role in tumour immune regulation is poorly understood. Here, we showed that extracellular tumour-derived VIM was associated with impaired CD8+ T-cell antitumour immunity and altered metabolic fitness. Single-cell RNA sequencing revealed that CD8+ T cells within VIM-high tumour microenvironments exhibited dysfunctional transcription in GBM. Functional assays revealed that VIM knockdown (VIM-KD) increased the antitumour activity of CD8+ T cells. Notably, under in vitro monoculture conditions, the modulation of VIM expression did not induce significant changes in GBM cell proliferation or apoptosis, indicating that VIM did not exert direct cytotoxic or growth-promoting effects on tumour cells. In contrast, in vivo tumour growth was strongly correlated with VIM expression levels, which was subsequently demonstrated to be mediated by CD8+ T-cell-dependent immune suppression. Metabolic analyses indicated that exposure to VIM-overexpressing (VIM-OE) tumour cells correlated with reduced triglyceride levels and decreased mitochondrial oxidative phosphorylation in CD8+ T cells. In vivo, VIM-KD mice exhibited decreased intracranial tumour growth and prolonged survival. Mechanistically, VIM stability is subject to posttranslational regulation, and we identified the deubiquitinase USP7 as a key regulator associated with maintaining VIM protein levels by limiting its proteasomal degradation. Collectively, these findings reveal a previously unrecognized USP7-VIM axis that mediates metabolic dysfunction and immune suppression in GBM, providing a mechanistic foundation for future therapeutic investigations.

Keywords:  CD8(+) T cells; Glioblastoma; Lipid metabolism; Mitochondrial fitness; Tumour microenvironment; USP7; Vimentin

DOI:  https://doi.org/10.1016/j.ijbiomac.2026.152623
Int J Nanomedicine. 2026 ;21 595199

Drug Delivery Engineering Strategies Targeting CD4+/CD8+ T Cell Exhaustion to Improve the Tumor Immunosuppressive Microenvironment.

Jingsi Yue, Min Chen, Zuanyu Xiong, Jing Qiu, Yi Liu, Long Chen.

  CD4⁺/CD8⁺ T cell exhaustion, characterized by impaired effector function, sustained expression of inhibitory receptors, and diminished proliferative capacity, is a core driver in the formation of the tumor immunosuppressive microenvironment (TME) and a major obstacle to antitumor immunotherapy. Nanomaterial-based drug delivery systems (NDDSs) have emerged as potential tools for targeting exhausted T cells (Tex), leveraging their unique advantages in precise targeting, controlled release, enhanced bioavailability, and reduced off-target toxicity. This article reviews the latest advances in NDDS-mediated delivery strategies targeting CD4⁺/CD8⁺ Tex cells, encompassing the delivery of immune checkpoint inhibitors, cytokines, small molecule modulators, and nucleic acid drugs. These strategies aim to reverse Tex cell dysfunction by modulating key molecular pathways involved in T cell exhaustion (like, PD-1/PD-L1, CTLA-4, NF-κB, and STAT signaling pathways), thereby enhancing T cell-mediated antitumor immune responses and remodeling the tumor immunosuppressive microenvironment. Finally, the challenges and prospects of utilizing NDDSs to target T cell exhaustion for tumor immunotherapy are briefly discussed, providing a reference for the development of novel antitumor therapeutic strategies.

Keywords:  T cell exhaustion; T cells; nanomaterials; tumor immunotherapy; tumor microenvironment

DOI:  https://doi.org/10.2147/IJN.S595199
Cancer Immunol Immunother. 2026 May 20.

β-hydroxybutyrate potentiates anti-tumor immunity by modulating cytotoxic CD8+ T cell responses.

Yupan Bai, Han Xue, Yujie Bao, Yue Pan, Jiayin Tang, Mengna Wang, Ying Wang, Jie Xu, Jing Huang.

  Ketogenic diets (KDs) have been reported to influence tumor progression through metabolic and immunological modulation of the tumor microenvironment. β-hydroxybutyrate (βOHB), the predominant ketone body elevated by KD, functions not only as an energy substrate but also as a potent signaling metabolite. Despite its role in modulating the tumor microenvironment, the direct impact of βOHB on the function of CD8+ T cell, a key mediator of anti-tumor immunity, remains incompletely understood. Here, we demonstrate that βOHB suppresses tumor growth in multiple mouse tumor models by enhancing the accumulation, survival, and effector function of tumor-infiltrating CD8+ T cells. In contrast, acetoacetate does not exert comparable immunomodulatory effects. Mechanistically, βOHB upregulates the Tcf7-Lck signaling pathway by engaging with the cell surface receptor Hcar2, an effect potentially working in parallel with its role as an HDAC inhibitor. Knockdown of either Tcf7 or Hcar2 in CD8+ T cells abolishes the promoting effect of βOHB on CD8+ T function. Our findings elucidate a metabolite-immune axis that directly regulates the functional state of tumor-infiltrating CD8⁺ T cells and provide experimental evidence linking ketone metabolism to anti-tumor immune regulation.

Keywords:  Anti-tumor therapy; CD8+ T cell; Lck; Tcf7; β-hydroxybutyrate

DOI:  https://doi.org/10.1007/s00262-026-04420-0
Nat Aging. 2026 May;6(5): 987-1006

Peroxisomes orchestrate metabolic flexibility and longevity via an interorganelle cascade.

Arpit Sharma, Aditi Prabhakar, Miriam Valera-Alberni, Jamie D Kraft, Abigail E Ellis, Ryan D Sheldon, Meeta Mistry, Pallas Yao, Yanshan Liang, Sheng Hui, William B Mair.

Aging impairs coordinated organelle dynamics essential for lipid metabolism, causing a decline in intracellular metabolic flexibility. However, the drivers of organelle collapse and their temporal order remain unclear. Here we identify peroxisomal function as a critical regulator of metabolic flexibility during youth and low-energy states. Using Caenorhabditis elegans, we show that fasting robustly induces peroxisomal function in youth, whereas this response is blunted during aging. Loss of peroxisomal import via PRX-5 declines over age, causing pathological lipid droplet expansion, dysfunctional mitochondrial bioenergetics and metabolic inflexibility. Although targeted PRX-5 degradation recapitulates metabolic aging, its overexpression preserves lipid dynamics and mitochondrial integrity. Notably, dietary restriction maintains peroxisomal pathways and organelle coordination into late life and peroxisomal function causally underpins dietary restriction-mediated longevity. Our findings highlight peroxisomes as central upstream regulators of a dynamic interorganelle cascade driving metabolic plasticity and highlight peroxisomal maintenance as a key determinant of metabolic flexibility during aging.

DOI: https://doi.org/10.1038/s43587-026-01122-1
Cell Mol Immunol. 2026 May 20.

PARK7-induced delactylation of ATAD3A impairs mitochondrial fitness to promote exhaustion of tumor-infiltrating CD8+ T cells.

Jing Liu, Mengjun Xu, Yi Zhou, Jiahao Li, Xi Zhou, Zhibo Ma, Qingwen Li, Yuhang Wang, Sichuan Yi, Naonao Yuan, Zhishui Chen, Hua Xiong, Peixiang Lan.

  Mitochondrial dysfunction is a critical factor driving the exhaustion of tumor-infiltrating CD8+ T cells and impeding the efficacy of tumor immunotherapy. However, the key regulatory proteins and molecular mechanisms governing mitochondrial function in CD8+ T cells remain enigmatic. Here, we report that PARK7 is significantly enriched in the mitochondria of tumor-infiltrating CD8+ T cells. T-cell-specific PARK7 deficiency enhanced mitochondrial function in CD8+ T cells, alleviated T-cell exhaustion, and suppressed tumor growth. Mechanistically, we found that PARK7 directly interacted with the mitochondrial membrane protein ATAD3A and downregulated its lactylation level, thereby suppressing the expression of mitochondrial-related genes and ultimately promoting CD8+ T-cell exhaustion. Overall, our study not only identifies the critical role of PARK7 in regulating mitochondrial function in CD8+ T cells but also elucidates the molecular mechanism through which the PARK7-ATAD3A axis modulates mitochondrial gene expression, providing a potential therapeutic strategy for targeting PARK7 in tumor immunotherapy.

Keywords:  ATAD3A; CD8+ T-cell exhaustion; Lactylation; Mitochondria; PARK7

DOI:  https://doi.org/10.1038/s41423-026-01425-8
Pathol Res Pract. 2026 May 12. pii: S0344-0338(26)00180-9. [Epub ahead of print]284 156527

Licochalcone A targets ADRB2 to enhance CD8+ T cell anti-leukemia activity via regulation involving the AKT2/FOXO1/GLUT2 axis.

Pingping Han, Huaiyu Wang, Yun Cai, Ye Sun, Dongzhi Zhou.

   OBJECTIVE: To investigate the effect of Licochalcone A (Lico A) on the function of CD8+ T cells in the tumor microenvironment and its underlying mechanism, and to evaluate its role in enhancing the anti-tumor activity of CD8+ T cells.
METHODS: Flow cytometry was used to analyze the effect of Lico A on the proportion of CD8+ T cells, the expression of activation markers and effector molecules; the in vivo anti-tumor effect of Lico A was evaluated through leukemia tumor-bearing mouse models, CD8+ T cell depletion experiments and adoptive transfer models; meanwhile, glycolysis and related metabolic changes were detected; molecular biology techniques were applied to verify the regulatory relationship of the ADRB2/AKT2/FOXO1/GLUT2 pathway.
RESULTS: Lico A significantly increased the proportion and activation status of CD8+ T cells in the tumor microenvironment, enhanced the expression of effector molecules and reduced early apoptosis. In vivo experiments showed that the tumor volume and weight in the Lico A treatment group were significantly lower than those in the control group, and this effect was dependent on CD8+ T cells. Lico A promoted glycolytic metabolism in CD8+ T cells, up-regulated the expression of GLUT2, and increased the levels of pyruvate, lactic acid and ATP. Molecular docking showed that Lico A stably bound to ADRB2 and inhibited its expression, thereby activating the AKT2/FOXO1 signaling pathway and relieving the transcriptional inhibition of GLUT2 by FOXO1.
CONCLUSION: Lico A appears to act on ADRB2, and the AKT2/FOXO1/GLUT2 axis may be involved in promoting GLUT2-mediated glycolysis, thereby enhancing the survival, activation, and cytotoxic effector function of CD8⁺ T cells in the tumor microenvironment. These findings provide preclinical mechanistic insights into the immunomodulatory activity of Lico A, with the AKT2/FOXO1/GLUT2 pathway emerging as a potentially primary contributing signaling route.

Keywords:  ADRB2/AKT2/FOXO1/GLUT2 pathway; CD8(+) T cells; Glycolysis; Leukemia; Licochalcone A

DOI:  https://doi.org/10.1016/j.prp.2026.156527
Nat Commun. 2026 May 22.

Iron overload in the tumor microenvironment induces CD8+ T cell ferroptosis and dysfunction.

Zhenyu Lin, Huanpeng Chen, Yujing Ke, Hanyue Xiao, Chao Li, Zilong Wu, Huixin Gao, Nanqi Huang, Lijuan Lu, Peng Sun, Yingjie Bian.

While iron homeostasis in cancer cells is well-established, its role in mediating crosstalk between tumors and CD8+ T cells within the tumor microenvironment (TME) remains largely elusive. In this study, we compare iron levels across primary tissues populated by CD8+ T cells. Contrary to the systemic iron deficiency commonly found in cancer patients, the TME exhibits marked iron enrichment compared to lymphatic fluid and peripheral blood, a phenomenon primarily attributed to tumor necrosis. However, this iron-overloaded TME is detrimental to CD8+ T cells, triggering their ferroptosis and dysfunction. Mechanistically, tumoral T cell receptor (TCR) hyperactivation and tumor-derived hepcidin cooperatively downregulate the iron exporter SLC40A1 in CD8+ T cells, leading to intracellular iron accumulation and ferroptosis. Both genetic restoration of SLC40A1 and iron chelation inhibit CD8+ T cell ferroptosis and restore their cytotoxic activity, thereby suppressing tumor growth. Finally, to enhance chimeric antigen receptor T (CAR-T) cell adaptability to the iron-overloaded TME, we engineer SLC40A1-overexpressing CAR-T cells. These engineered cells resist ferroptosis induced by the TME and elicit potent anti-tumor immunity.

DOI: https://doi.org/10.1038/s41467-026-73379-4
Crit Rev Oncol Hematol. 2026 May 21. pii: S1040-8428(26)00272-6. [Epub ahead of print] 105385

Bidirectional roles of senescence in tumor-infiltrating immune cells: mechanisms, impact on immunotherapy, and therapeutic strategies.

Ruohan Zhao, Yangbo Li, Runhe Zhu, Ruiyu Zong, Maowei Sun, Miaomiao Liu, Hong Guo.

  Immunosenescence refers to the progressive functional decline of the immune system with age. Traditionally, it has been regarded as detrimental because it weakens immune surveillance and increases the risk of tumor development. With the growing understanding of the tumor microenvironment (TME), accumulating evidence indicates that the senescence of tumor-infiltrating immune cells is context-dependent and exerts bidirectional regulatory effects. On the one hand, the senescence-associated secretory phenotype (SASP) and immunosuppressive phenotypes can drive chronic inflammation, immune escape, and stromal remodeling, thereby promoting tumor initiation and progression. In contrast, subsets of senescent immune cells can retain or even acquire enhanced effector functions under specific stimuli, contributing to antitumor immune responses. This review focuses on tumor-infiltrating immune cells, particularly T cells, NK cells, and macrophages, and summarizes their senescence-associated phenotypes and dual roles in cancer development. We outline the central mechanisms by which DNA damage, epigenetic remodeling, metabolic reprogramming, and key signaling pathways drive the process of immunosenescence. We systematically examined how immunosenescence shapes the efficacy of major immunotherapies. Finally, we discuss emerging strategies, such as gene editing and metabolic interventions, to improve cancer immunotherapy in older patients.

Keywords:  aging; immunosenescence; immunotherapy; tumor microenvironment

DOI:  https://doi.org/10.1016/j.critrevonc.2026.105385
Gut. 2026 May 17. pii: gutjnl-2025-337730. [Epub ahead of print]

12-HETE: a novel lipid mediator of CD8+ T cell dysfunction in MASH/HCC.

Mathias F Heikenwälder, Bertram Bengsch.



Keywords:  HEPATOCELLULAR CARCINOMA; IMMUNE RESPONSE

DOI:  https://doi.org/10.1136/gutjnl-2025-337730
Immunol Cell Biol. 2026 May 17.

Functional immune profiling reveals CD4+ T cell dysregulation in coeliac disease.

Anthony J Farchione, HoChan Cheon, David Vremec, Julika Neumann, Gwenny M Verstappen, Melinda Y Hardy, Mai B Margetts, Lauren J Howson, Lee M Henneken, Maureen Forde, Jason A Tye-Din, Susanne Heinzel, Philip D Hodgkin, Vanessa L Bryant.

  T cells integrate signals from antigen and costimulatory receptors to calibrate response magnitude and quality, with genetically encoded programs shaping activation thresholds for immune tolerance and feedback regulation. Coeliac disease (CeD) is an autoimmune disorder with well-defined genetic risk and immune dysregulation triggered by dietary gluten. However, how genetic risk translates into cell-intrinsic functional variation, particularly within the naïve T-cell compartment, remains poorly defined. Here, we developed the T cell momentum assay, a quantitative functional profiling platform combining standardized T-cell activation with defined stimulus withdrawal to measure proliferation, survival and activation dynamics over time. Integrated with the Cyton2 mathematical model, this approach infers cellular fate programs from population-level dynamics, enabling high-resolution analysis of intrinsic T-cell behavior. Applying this assay to naïve T cells from individuals with CeD and healthy donors (HDs), we identified disease-associated abnormalities predominantly in CD4+ T cells, including hypoproliferation, reduced IL-2 secretion, impaired survival and delayed downregulation of CD69, indicating prolonged activation and impaired feedback regulation. Distinct early alterations in CD8+ T cells were also observed. These abnormalities were present in both newly diagnosed individuals and those on a gluten-free diet, supporting a cell-intrinsic phenotype not solely attributable to active inflammation and is consistent with altered baseline immune function. Together, our findings reveal previously unrecognized alterations in naïve T-cell programming in CeD, linking inherited immune variation to functional dysregulation beyond antigen-specific responses. More broadly, the momentum assay offers a scalable, model-informed framework to detect subtle early T cell dysregulation and functionally stratify immune variation across autoimmune diseases.

Keywords:  CD4+ T cells; Coeliac disease; IL‐2; Immune dysregulation; Mathematical modelling; T cell activation

DOI:  https://doi.org/10.1111/imcb.70132
Clin Transl Med. 2026 May;16(5): e70665

Glucose metabolic reprogramming as a driver of immunosuppression in the tumour microenvironment.

Yang Wang, Yijun Lu, Jian Zhou, Xinrong Yang.

  Immunotherapy has emerged as a transformative approach to cancer treatment, yet its clinical efficacy in most solid tumours remains limited, largely because of the immunosuppressive tumour microenvironment (TME). In this context, glucose metabolic reprogramming has emerged as a central determinant of tumour progression and immune dysfunction because it not only sustains the proliferative and biosynthetic demands of malignant cells but also profoundly reshapes immune responses within the TME. Effective antitumour immunity depends on the metabolic adaptability of effector immune cells, particularly the coordinated use of glycolysis and oxidative phosphorylation to support activation, expansion and cytotoxic function. Under the nutrient-deprived, hypoxic and acidic conditions that characterize the TME, however, these cells undergo metabolic restriction that progressively drives dysfunction and exhaustion. By contrast, regulatory T cells, tumour-associated macrophages and myeloid-derived suppressor cells exhibit greater metabolic plasticity, enabling their persistence and reinforcing their immunosuppressive activity. In this review, we discuss how glucose metabolic reprogramming drives immune dysfunction through several interconnected processes, including glucose competition, lactate accumulation, reciprocal regulation between glucose metabolism and cytokine signalling, glycosylation remodelling and dynamic crosstalk with immune checkpoint signalling. Collectively, these mechanisms position glucose metabolism as a pivotal immunometabolic axis linking tumour bioenergetics to immune evasion and therapeutic resistance. A deeper understanding of this regulatory network may inform the rational development of combination strategies that integrate metabolic intervention with immunotherapy, ultimately improving therapeutic precision and the durability of clinical benefit. HIGHLIGHT: Glucose metabolic reprogramming is a central driver of immunosuppression in the tumour microenvironment. Glucose competition establishes a selective bioenergetic hierarchy that constrains antitumour immunity. Lactate accumulation and reciprocal regulation with cytokine signalling amplify immunosuppressive signalling and reinforce immune exclusion. Glycosylation remodelling translates altered metabolic flux into sustained changes in receptor stability, ligand recognition and checkpoint responsiveness. Dynamic crosstalk with immune checkpoint signalling entrenches chronic immune dysfunction and therapeutic resistance.

Keywords:  Warburg effect; glucose metabolic reprogramming; immunometabolism; immunosuppression; immunotherapy; tumour microenvironment

DOI:  https://doi.org/10.1002/ctm2.70665
Signal Transduct Target Ther. 2026 May 20. pii: 188. [Epub ahead of print]11(1):

GSK-3 regulates CD4-CD8 cooperation for super-armed CD8+ cytolytic T cells in immunotherapy against tumors.

Bastien Moës, Janna Krueger, Chen Liu, Nikhil Ponnoor Anto, Atena Nemati, Mikhael Attias, Alexandra Kazanova, Yunfeng Gao, Linda Castoun-Puckett, Andres Carlos Oroya, Lan Huong Nguyen, Auryane Laure Cabald, Thai Hien Tu, Christopher E Rudd.

Although the efficacy of immune checkpoint blockade (ICB) depends on coordinated activity across progenitor and terminal effector CD4⁺ and CD8⁺ T-cell compartments, the cell-intrinsic pathways that enable this cooperation remain incompletely defined. Here, we identify glycogen synthase kinase-3 (GSK-3) as a central regulator of TCF-1⁺ progenitor and memory CD8⁺ T-cell differentiation, where reduced GSK-3 expression enhances antiviral and anti-tumor immunity. In GSK-3 knockdown (GSK-3 KD) mice, diminished GSK-3 reshaped basal T-cell homeostasis, skewing differentiation toward memory-phenotype subsets even in the absence of antigenic stimulation. During chronic LCMV Cl13 infection, GSK-3 KD promoted the expansion and proliferation of GP33-specific memory-precursor effector cells (MPECs). Metabolic profiling by Seahorse and SCENITH revealed increased glycolysis and oxidative phosphorylation in GSK-3 KD TCF-1⁺ stem-like CD8⁺ T cells, with greater GLUT1 expression and mitochondrial mass, indicative of enhanced metabolic adaptability. GSK-3 was also required for regulatory T-cell (Treg) suppressive function, while GSK-3 inhibition and reduced expression synergized with PD-1 blockade to "super-arm" cytolytic CD8⁺ T cells, characterized by upregulation of perforin and seven distinct granzymes. Notably, whereas B16-F10 tumor rejection in wild-type mice relied on CD4+ CTLA-4+ Tregs, tumor control in GSK-3 KD mice required CD4⁺ T-cell help for optimal granzyme induction and tumor rejection. Together, these findings define a GSK-3-PD-1 signaling axis that links metabolic and differentiation programs to govern T-cell fate and cytotoxicity, providing a mechanistic framework for overcoming ICB resistance.

DOI: https://doi.org/10.1038/s41392-026-02663-y
Front Immunol. 2026 ;17 1781797

Immunometabolic control of cytokine production by micronutrients in health, aging, and inflammation.

Joyeta Ghosh, Debprasad Chattopadhyay.

  Micronutrients serve as critical metabolic sensors and epigenetic regulators that orchestrate cytokine production through multiple overlapping signalling cascades, transcriptional networks, and cellular metabolic states. This comprehensive review synthesizes recent research demonstrating that micronutrient status regulates cytokine biology at five hierarchical levels: (i) nutrient sensing via mTORC1/GCN2 and amino acid sensor networks; (ii) transcriptional control through VDR/RARα-mediated epigenetic remodelling and histone deacetylase inhibition; (iii) redox signalling via SELENOK/selenoprotein-stabilized calcium homeostasis and Nrf2/ARE pathway activation; (iv) Pyroptosis/ferroptosis execution via metallothionein-zinc-caspase axes and NLRP3/GSDMD regulation; and (v) metabolic bioenergetics through NAD+/CD38/SIRT-mediated immune cell differentiation and aging. Recent discoveries establish that vitamin D directly suppresses IL-22 through repressive VDREs independent aryl-hydrocarbon receptor (AhR) signalling, zinc-metallothionein-3 that suppresses non-canonical inflammasome activation via TRIF-IRF3-STAT1 modulation, selenium-dependent SELENOK which stabilizes IP3 receptor-mediated store-operated calcium entry in immune cells, and folate-dependent one-carbon metabolism generating S-adenosyl methionine (SAM) that tunes epigenetic landscapes of cytokine genes. This review compiles the integrated mechanistic frameworks linking micronutrient availability to immunometabolic checkpoints, with implications for nutritional immunotherapy in chronic inflammatory diseases and immune-senescence.

Keywords:  calcium signalling; cytokines; epigenetics; ferroptosis; immunometabolism; inflammaging; metabolic sensing; micronutrients

DOI:  https://doi.org/10.3389/fimmu.2026.1781797
Front Immunol. 2026 ;17 1828634

Interplay between microRNAs and TGF-β signaling in T cells: implications for Th9 differentiation and immune pathogenesis.

Tae Sung Kim, Yun-Ji Lim, WanJun Chen.

  Since the discovery of microRNAs (miRNAs) in 1993, they have been established as key post-transcriptional regulators of immune cell function. In particular, miRNAs have emerged as key modulators of CD4+ T cell activation and differentiation. Accumulating evidence indicates that miRNAs influence CD4+ T cell fate through modulating transforming growth factor β (TGF-β) signaling, which negatively regulates T helper (Th) 1 and Th2 cell differentiation, while promoting the generation of regulatory T (Treg) cells, Th17 as well as Th9 cells. Despite these advances, our understanding of specific roles of miRNAs and their target molecules in CD4+ T cells remains limited, particularly in Th9 cells. In this review, we discuss the regulatory networks of miRNAs targeting the TGF-β signaling pathway in CD4+ T cells, with a special focus on their roles in Th9 cell differentiation and function.

Keywords:  CD4+ T cell; TGF-b signalling; Th9; autoimmune disease (AD); cancer; microRNA

DOI:  https://doi.org/10.3389/fimmu.2026.1828634
Cancer Biol Med. 2026 May 20. pii: j.issn.2095-3941.2026.0020. [Epub ahead of print]

Treatment implications of T cell DNA damage in anti-tumor immunity.

Xiaofei Jiao, Yiyang Shen, Yixuan Tang, Jiahao Liu, Qinglei Gao.

  T cell activity is fundamental to effective immunotherapies and sustained tumor control. Recent studies have demonstrated that the therapeutic potential of T cells is notably affected by DNA damage dynamics. Notably, DNA damage within T cells is both a predictive biomarker for therapeutic responses and a druggable vulnerability whose modulation enhances the anti-tumor efficacy of immunotherapies and targeted treatments. This review is aimed at assessing current understanding of the origins of DNA damage in T cells, its consequences, and therapeutic implications within the tumor microenvironment and during anticancer treatment. By elucidating the mechanisms through which DNA damage dictates T cell fate and function, we highlight its dual role as a biomarker and a therapeutic target. Our goal is to accelerate the optimization of immunotherapeutic regimens and the development of combinatorial approaches leveraging a dynamically regulated immune microenvironment by integrating T cell-intrinsic DNA damage response into patient stratification and trial design, together with rational optimization of genotoxic therapies and immunotherapy, to enable a durable response while minimizing immune toxicity.

Keywords:  DNA damage; T cell; anti-tumor immunity; treatment

DOI:  https://doi.org/10.20892/j.issn.2095-3941.2026.0020
Sci Adv. 2026 May 22. 12(21): eaed1296

Multiregional profiling reveals THBS1-SPP1 monocyte-macrophage axis drives immunosuppression and outcome in colorectal liver metastases.

Gaia Bellomo, Jayden Gittens, Christopher Brunning, Maidinaimu Abudula, Robert P Jones, Michael C Schmid, Ainhoa Mielgo.

Colorectal cancer (CRC) commonly metastasizes to the liver (CRLM), where it is the leading cause of CRC-related deaths. While immune checkpoint therapies show promise, their effectiveness is limited in CRLM due to the immunosuppressive liver tumor microenvironment (TME). Using multiregional tissue sampling from CRLM patient samples, we identified distinct immune zones within CRLM. Active Granzyme+CD8+ T cells were found in normal liver tissue, while CD8+ T cells in the tumor core were dysfunctional. At the tumor margin, we observed a pre-exhausted immune zone enriched in THBS1+ monocytes and CD47+CD8+ T cells. Trajectory analysis showed that THBS1+ monocytes differentiate into SPP1+ macrophages, which accumulate in the tumor core and promote immune suppression via TIM-3 and CTLA-4 on exhausted CD8+ T cells. The presence of SPP1+ macrophages correlates with increased T cell exhaustion and poor survival, suggesting them as potential targets to restore antitumor immunity in CRLM.

DOI: https://doi.org/10.1126/sciadv.aed1296
Crit Rev Oncol Hematol. 2026 May 16. pii: S1040-8428(26)00268-4. [Epub ahead of print]224 105381

Single-cell RNA sequencing unveils CD8+ T cell heterogeneity in the diffuse large B-cell lymphoma microenvironment: A systematic review.

Alimire Maimaiti, Xiaolong Qi, Zhenghao Zhang, Yan Li.

   BACKGROUND: The heterogeneous response to immunotherapy in diffuse large B-cell lymphoma (DLBCL) is largely attributable to the diverse functional states of CD8⁺ T cells within the tumor microenvironment. Although single-cell RNA sequencing (scRNA-seq) has revolutionized cellular resolution, a systematic synthesis of this evidence to map CD8⁺ T cell heterogeneity and its clinical implications in DLBCL is currently lacking.
METHODS: Following the PRISMA guidelines and a PROSPERO-registered protocol (CRD420261282336), we conducted a qualitative systematic review (without meta-analysis) of 18 eligible scRNA-seq studies published up to September 2025. Dual reviewers independently performed study selection, data extraction, and quality assessment using a self-designed scRNA-seq checklist combined with the AMSTAR-2 tool.
RESULTS: We constructed a dynamic exhaustion trajectory atlas of CD8⁺ T cells in DLBCL, revealing a hierarchical continuum comprising multiple functionally distinct subclusters. Key findings include: ① the progenitor exhausted T cell (Tpex) subset is associated with favorable prognosis and holds therapeutic targetability, whereas the terminally exhausted (Tex-term) subset correlates with poor prognosis; ② the CXCR5⁺TCF7⁺ S1 subset predicts sensitivity to RB-CHOP chemotherapy, and CD58 pathway impairment is linked to CAR-T resistance; and ③ the recently identified CD8‑fit cells show promise as a synergistic immunotherapy target.
CONCLUSION: This review provides a comprehensive single-cell atlas of CD8⁺ T cells in DLBCL, advocating a shift toward cell‑state‑guided precision immunotherapy. The identified biomarkers facilitate pre‑treatment patient stratification and reveal novel combinatorial targets. Future multicenter studies should focus on validating these targets (e.g., CD58, CD8‑fit) and standardizing scRNA‑seq analytical frameworks to translate these findings into clinical practice.

Keywords:  CD8-positive T-lymphocytes; Diffuse large B-cell lymphoma; Single-cell RNA sequencing; Systematic review; T-cell exhaustion; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.critrevonc.2026.105381
bioRxiv. 2026 May 04. pii: 2026.04.29.720676. [Epub ahead of print]

Coincident epithelial signals restrain commensal-specific CD8αβ + T cells in the intestine.

Tayla M Olsen, Matthew J Dufort, Sheenam Verma, Venkata Krishna Kanth Makani, Benjamin Cameron, Addison R Gralen, Aaron J Johnson, Alok V Joglekar, Allyson L Byrd, Adam Lacy-Hulbert, Oliver J Harrison.

The intestinal epithelium harbors a large population of microbiota-dependent CD8αβ + T cells whose antigen specificity and regulation are ill-defined. By identifying MHCIa-restricted TCRs and generating tetramers against the gut commensal Segmented Filamentous Bacteria, we demonstrate that a single commensal species drives a clonally expanded, antigen-specific CD8αβ + T cell within the intraepithelial lymphocyte compartment. Mechanistically, the intestinal epithelium coordinates coincident signals governing this population: peptide:MHC-dependent TCR engagement drives pIEL accumulation, while αvβ6-mediated TGFβ activation restraints effector cell differentiation. Perturbation of epithelial cell-mediated TGFβ activation diverts commensal-specific CD8 + T cells toward inflammatory differentiation states transcriptionally convergent with those observed in ulcerative colitis. The intestinal epithelium thus functions as a dual-signal organizer of commensal-specific CD8 + T cell responses, coupling differentiation to restraint through spatially coincident molecular cues.

DOI: https://doi.org/10.64898/2026.04.29.720676
Nat Rev Immunol. 2026 May 19.

Protein homeostasis as a determinant of CD8⁺ T cell fate.

Yen-Tzu Chang, Felix Clemens Richter, Wen Jiang.

DOI: https://doi.org/10.1038/s41577-026-01314-1
Chin Med. 2026 May 19. pii: 135. [Epub ahead of print]21(1):

Mechanism of Qiling Fuzheng Qingjie granules in alleviating doxorubicin-induced T cell immune dysfunction via mitochondrial energy metabolism.

Ruiming Yang, Jie Yuan, Ruihan Sun, Shunyong Wang, Zewei Zhuo, Xiaoyuan Zhang, Shuyou Chen, Junying Guo, Lisheng You, Zhiyun Cao, Xuzheng Chen, Haiying Fu.

  This study investigates the mechanism by which Qiling Fuzheng Qingjie Granule (QFQ) regulates immune function following doxorubicin (DOX) chemotherapy. Network pharmacology analysis was employed to explore the relationship between QFQ and the immune system. A mouse model of DOX-induced immune dysfunction was established and treated with QFQ. Techniques including histological staining, peripheral complete blood count analysis, flow cytometry, and seahorse metabolic analysis were used to systematically evaluate the effects of QFQ on immune organs, bone marrow hematopoiesis, T-cell subset distribution and function, mitochondrial metabolism, and antitumor efficacy. The results demonstrated that QFQ significantly alleviated DOX-induced atrophy of the thymus and spleen, preserved bone marrow hematopoietic function, and reduced peripheral blood cell loss. Mechanistically, QFQ improved mitochondrial membrane potential and oxidative phosphorylation, thereby restoring T-cell metabolic capacity, enhancing T-cell activation and proliferation, and restoring cytotoxic T lymphocyte (CTL) function. Consequently, QFQ rebalanced the dynamics among Th1/Th2/Th17/Treg, Effector Memory T/Effector T cells (Tem/Teff), and Central Memory T cells (Tcm) subsets, ameliorated DOX-induced immune dysregulation. In addition, QFQ intervention not only enhanced antitumor efficacy in the A20 lymphoma mouse model but also significantly alleviated the exhaustion phenotype in CD8+T cells. In summary, this investigation establishes that QFQ enhances T-cell functional performance primarily through the regulation of mitochondrial energy metabolism. By restoring metabolic homeostasis in T lymphocytes, QFQ effectively counteracts DOX-induced immune dysfunction, highlighting its potential as a promising adjunctive therapy in chemotherapy-induced immunosuppression.

Keywords:  Doxorubicin; Mitochondrial energy metabolism; Qiling Fuzheng Qingjie granules; T lymphocyte subsets

DOI:  https://doi.org/10.1186/s13020-026-01405-0
Blood. 2026 May 21. 147(21): 2555

Funk CR, Wang S, Chen KZ, et al. PI3Kδ/γ inhibition promotes human CART cell epigenetic and metabolic reprogramming to enhance antitumor cytotoxicity. Blood. 2022;139(4):523-537.

DOI: https://doi.org/10.1182/blood.2026034163
Methods Mol Biol. 2026 ;3010 175-188

Metabolic Plasticity in Embryogenesis Throughout the Lens of NAD.

Quetzalcoatl Escalante-Covarrubias, Paul Delgado-Olguín.

  Changes in cell fate during early mammalian development are supported by the dynamic regulation of energy metabolic pathways. These transitions fulfill energetic demands and influence transcriptional reprogramming and cell differentiation. Variations in NAD+/NADH ratios during early developmental transitions correlate with metabolic remodeling. Indeed, NAD+ bioavailability acts as an early signal for a change in the metabolic landscape by controlling the redox state and activity of multiple NAD+ dependent enzymes. Here, we summarize recent studies on NAD+ bioavailability and its function as the master organizer of energy metabolism during early mouse development. Additionally, we examine the function of NAD+ dependent chromatin remodelers in synchronizing transcriptional programs with pathways that fulfil the metabolic demands of developmental stage transitions.

Keywords:  2-; 4-cell stage; Blastocyst; Energy metabolism; NAD+/NADH radio; Redox state; Zygote

DOI:  https://doi.org/10.1007/978-1-0716-5126-1_17
Cancer Manag Res. 2026 ;18 592664

TNFAIP3 Reprograms T Cell Exhaustion and Restores Anti-Leukemia Immunity in Acute Myeloid Leukemia.

Yanhong Li, Hongxia Wu, Jun Bai, Xiaohuan Peng, Yue Chen, Jinping Zhang, Liansheng Zhang, Lijuan Li.

   Purpose: Acute myeloid leukemia (AML) is an aggressive hematological malignancy that is associated with profound immune dysfunction. T-cell exhaustion is a major mechanism of immune evasion in AML; however, the key molecular regulators driving this process remain unclear. This study aimed to identify immunoregulatory genes associated with T cell exhaustion in AML and define their functional roles.
Patients and Methods: Single-cell RNA sequencing (scRNA-seq) data from patients with AML and healthy donors were integrated to identify genes associated with T-cell exhaustion. TNFAIP3 was identified as a candidate hub gene and subsequently validated in peripheral T cells from 24 AML patients and 12 healthy donors using qRT-PCR and Western blotting. Functional studies were performed using lentivirus-mediated TNFAIP3 overexpression in patient-derived CD4+ and CD8+ T-cells. Apoptosis, immune checkpoint expression, cytokine production, and NF-κB signaling activity were assessed using pathway enrichment analyses.
Results: scRNA-seq analysis revealed widespread immune remodeling in AML, with TNFAIP3 consistently downregulated in AML T cells. Reduced TNFAIP3 expression was confirmed at both the mRNA and protein levels in patients with AML. TNFAIP3 overexpression in CD4+ and CD8+ T cells attenuates apoptosis, reduces the expression of the immune checkpoint molecules PD-L1 and TIM-3, and promotes a pro-inflammatory cytokine profile characterized by increased IFN-γ and TNF-α production. Mechanistically, these effects were associated with the suppression of NF-κB signaling and enrichment of pathways related to immune synapse formation and T-cell receptor signaling.
Conclusion: Our findings demonstrate that TNFAIP3 is a critical regulator of T cell dysfunction and exhaustion in AML. Downregulation of TNFAIP3 contributes to impaired anti-leukemic immunity, whereas its restoration enhances T-cell survival and effector function. TNFAIP3 therefore represents a promising therapeutic target for immune-based interventions aimed at restoring T-cell-mediated immunity in AML.

Keywords:  NF-κB; T cell; TNFAIP3; acute myeloid leukemia; immune checkpoint

DOI:  https://doi.org/10.2147/CMAR.S592664
Nat Immunol. 2026 May 20.

Inhibition of salt-inducible kinases reprograms T cells and antitumor immunity in ovarian cancer.

Han Dong, Arindam Ray, Lara K Rotter, Jinhua Wang, Isabella Grabski, Heemaja Mewada, Lulu Wang, Kun Huang, Ye Tian, Maxime Meylan, Graham Barlow, Chenyang Yu, Mahesh Raundhal, Sung-Hee Yoon, Shreya Nakhawa, Liya Ding, Jean J Zhao, Ursula A Matulonis, Marc Foretz, Kai W Wucherpfennig, Rafael A Irizarry, Marc N Wein, Laurie H Glimcher.

Patients with metastatic high-grade serous ovarian carcinoma are often unresponsive to immunotherapies; here we identify salt-inducible kinases (SIKs) as key drivers of immunosuppression. Human T cells in the presence of patient ascites express high levels of SIK and the upstream kinase LKB1, whereas SIK inhibition reprograms human T cells and strongly activates antitumor responses. In syngeneic mice with resistant high-grade serous ovarian carcinoma, genetic ablation and pharmaceutical inhibition of SIK consistently demonstrated therapeutic efficacy and survival advantages, and combination of PD-1 blockade with SIK inhibition further extended survival. We identified a major role of T cell-intrinsic SIK2 and -3 signaling in driving immunosuppression in part by TXNIP induction and LYST suppression. Multi-omics analyses on SIK inhibitor therapy revealed reduced disease progression, increased T cell infiltration with enhanced cytotoxicity and effector cytokine IFN-γ, and a shift from immunosuppressive to immunostimulatory cellular niche. We propose SIK inhibitors as a new immunotherapy.

DOI: https://doi.org/10.1038/s41590-026-02512-8
Med. 2026 May 15. pii: S2666-6340(26)00146-7. [Epub ahead of print] 101143

Expansion of NKG2A+CD8+ T cells with regulatory signatures distinguish individuals living with HIV-2 from those with HIV-1.

ANRS-MIE CO21 CODEX study group

   BACKGROUND: NKG2A+CD8+ T cells are unconventional T cells described in the context of various diseases. However, their role remains poorly understood. People living with HIV-2 (PLWH2), unlike people living with HIV-1 (PLWH1), exhibit minimal intestinal inflammation despite continuous viral replication in the absence of antiretroviral treatment, but the mechanisms underlying this protection are unknown.
METHODS: We characterized NKG2A+ and NKG2C+ CD8+ T cells from PLWH1 and PLWH2 with distinctive clinical phenotypes using spectral flow cytometry. Their functional response was evaluated using target cells, polyclonal T cell receptor activation, and cytokine stimulations. Cellular and plasma markers of gut mucosal integrity, T cell activation, and systemic inflammation were quantified.
FINDINGS: NKG2A+ and NKG2C+ CD8+ T cells demonstrated stronger responsiveness to stimulation than conventional CD8+ T cells. NKG2A+CD8+ T cells frequently expressed regulatory molecules, homing receptors, and interleukin-22 (IL-22). The frequencies of NKG2A+ and NKG2C+ CD8+ T cells were increased in PLWH2 compared to PLWH1. They more frequently expressed DNAM-1 (CD226), CCR5, and CD49d. NKG2A+CD8+ T cells from PLWH2 correlated with gut integrity (CD4+ T helper 17/regulatory T cell ratio) and reduced chronic immune activation. PLWH2 displayed lower levels of plasma biomarkers of inflammation, gut integrity, and IL-23, but higher levels of IL-15 compared to PLWH1. IL-15 promoted the functional activity of NKG2A+CD8+ T cells and enhanced their expression of CD39 and DNAM-1.
CONCLUSIONS: Our findings suggest that NKG2A+CD8+ T cells contribute to the maintenance of gut homeostasis and low systemic inflammation in PLWH2.
FUNDING: This work was funded by Sidaction, ANRS-MIE, Institut Pasteur, and the MESRI (France).

Keywords:  HIV controllers; HIV-1; HIV-2; IL-15; IL-22; NKG2A(+)CD8(+) T cells; NKG2C(+)CD8(+) T cells; translation to patients; unconventional T cells

DOI:  https://doi.org/10.1016/j.medj.2026.101143
J Transl Med. 2026 May 18.

Glycolysis-driven cancer-associated fibroblasts shape T-Cell exclusion via the CXCL16-CXCR6 Axis: a metabolic-chemokine mechanism in tumor immunity.

Yunya Liu, Chutong Xiong, Guichen Huang, Menghao Xu, JinXiao Li, Minfeng Zhou, Fengxia Liang, Rui Chen.

   BACKGROUND: Immune-excluded tumors are characterized by abundant CD8+ T cells at the invasive margin but scarce infiltration within tumor nests, leading to limited responses to immunotherapy. Emerging evidence identifies cancer-associated fibroblasts (CAFs) as key mediators of immune exclusion.
MAIN BODY: This review highlights a glycolysis-driven CAFs (glyCAFs) pathway that orchestrates immune exclusion. Glycolysis CAFs upregulate Glucose Transporter 1 (GLUT1) to sustain CXCL16 secretion, which in turn engages CXCR6 on CD8+ T cells and effectively traps them at the tumor margin. We summarize the evidence supporting this glyCAF-GLUT1-CXCL16-CXCR6 signaling circuit and its functional impact on T-cell positioning. A distinct advantage of this axis lies in its ability to integrate a targetable metabolic phenotype with a spatially measurable immunologic outcome. We discuss potential spatial biomarkers-such as glyCAFs enrichment at the margin, elevated GLUT1 and CXCL16 expression, and CXCL16-high stromal niches closely associated with CD8+ T cells-and outline therapeutic strategies aimed at modulating this pathway. Pharmacologic inhibition of GLUT1 (e.g. BAY-876) can suppress glycolysis and CXCL16 production, while blockade of CXCL16 or CXCR6 may release T-cell retention and enhance responses to chemotherapy, radiotherapy, and immune-checkpoint blockade. Finally, we highlight open questions, regarding the cellular origins and regulatory networks of glyCAFs, the classification of the glyCAFs state as a transient adaptation or a stable entity and its biomarker potential, the spatial mechanisms of glyCAF-immune interplay through integrated metabolic and proteomic mapping, the preclinical validation of multi-target strategies informed by spatial biomarkers, and the preclinical validation of combinatorial therapeutic strategies using biomarker-guided approaches.
CONCLUSIONS: The glyCAF-GLUT1-CXCL16-CXCR6 axis establishes a clear mechanistic and translational framework linking stromal metabolism to immune spatial architecture, paving the way for precision immunometabolic strategies to overcome T-cell exclusion in solid tumors.

Keywords:  CXCL16; CXCR6; Cancer-associated fibroblasts; Combined immunotherapy for Cancer; GLUT1; GlyCAF; Immune exclusion

DOI:  https://doi.org/10.1186/s12967-026-08160-8
Cell. 2026 May 15. pii: S0092-8674(26)00504-0. [Epub ahead of print]

Cell-autonomous control of CAR signaling and receptor shedding via ADAM17-mediated proteolysis.

Jeremy R Bjelajac, Adrià Cañellas-Socias, Preeti Nehra, Kevin Reynolds, Meena Malipatlolla, Naiara Martinez Velez, Diane C Manjarrez, Katie Ho, Peng Xu, Jennifer L Hamad, Sean A Yamada-Hunter, Louai Labanieh, Elena Sotillo, Crystal L Mackall.

  We sought to endow T cell autonomous regulation of cell surface protein expression by exploiting the conditional proteolytic activity of ADAM17 following T cell activation. Screening of canonical ADAM17 substrates yielded a minimal 15-aa CD62L-derived motif that confers rapid and reversible cleavage of a receptor following T cell activation-termed activation-induced release (AIR). Embedding AIR into tonic-signaling CARs reduced basal CAR expression proportional to the degree of tonic signaling induced, curtailing exhaustion and improving antitumor potency. In non-tonic signaling CARs, AIR decreased activation-induced cell death and enhanced T cell expansion after stimulation. AIR's modularity supports higher-order logic-gating; AIR-regulated peptide masks enable antigen-dependent unmasking of an EGFR-targeting CAR. Finally, CRISPR knockin of AIR into endogenous FAS or TGFBR2 endowed them with activation-induced shedding, which enhanced tumor clearance while preserving signaling in non-activating conditions. AIR is a compact switch that provides fast, autonomous regulation of surface proteins for next-generation cell therapies.

Keywords:  ADAM17; CAR; T cells; bioengineering; cancer; immunotherapy; protease; synthetic biology

DOI:  https://doi.org/10.1016/j.cell.2026.04.037
JCI Insight. 2026 May 19. pii: e203593. [Epub ahead of print]

HLA-E-restricted T cells primed by a modified HLA-B*57:01 restricted HIV-1 peptide suppress HIV-1 replication.

Hong Sun, Hongbing Yang, Max N Quastel, Simon Brackenridge, Wanlin He, Anna E Kliszczak, Margarida Rei, Persephone Borrow, Geraldine M Gillespie, Andrew J McMichael.

  HLA-E-restricted HIV-specific T cells offer exciting possibilities for immunotherapy. However, HLA-E binding peptides are rare. A recent study showed that in HLA-B*57:01 people living with HIV (PLWH), the peptide that dominates the T cell response, KAFSPEVIPMF (KF11), also stimulates HLA-E-restricted T cells, even though direct binding of this peptide to HLA-E could not be demonstrated. We therefore changed position 2 alanine for methionine in the peptide (referred to as KMF11) which greatly enhanced binding to HLA-E. This enabled the generation of stabilised HLA-E-KMF11 tetramers which were used to select and then grow specific T cell clones from T cells of HLA-B*57:01 negative blood donors primed with this peptide in vitro. Approximately 20% of these T cell clones reacted with HLA-E positive cells presenting the native KF11 peptide. Furthermore, these T cells inhibited replication of HIV-1 NL4-3 in CD4 T cells in vitro. Therefore, this native peptide can be presented by HLA-E to CD8 T cells, although priming in vivo may depend on cross reactivities to classical MHC Ia types. Nevertheless, such T cells could be exploitable for immunotherapy given the conservation of this HIV1 peptide epitope and the non-polymorphism in HLA-E.

Keywords:  AIDS/HIV; Adaptive immunity; Immunology; MHC class 1; T cells

DOI:  https://doi.org/10.1172/jci.insight.203593
Nature. 2026 May 18.

Publisher Correction: Microbiota-induced T cell plasticity enables immune-mediated tumour control.

Tariq A Najar, Yuan Hao, Yuhan Hao, Gabriela Romero-Meza, Alexandra Dolynuk, Emma Almo, Dan R Littman.

DOI: https://doi.org/10.1038/s41586-026-10649-7
Res Pharm Sci. 2026 Apr;21(2): 236-250

PD-1: CD28 chimeric receptors enhance phenotypic and functional features of T cell subsets.

Saba Feghhi-Najafabadi, Farhad Riazi-Rad, Mohammad Ali Shokrgozar, Shahriyar Abdoli, Fatemeh Hajari Taheri, Arash Arashkia, Zahra Sharifzadeh.

   Background and purpose: The PD-1/PD-L1 immune checkpoint pathway inhibits T cell function, allowing tumors to escape immune responses. This study aimed to reprogram this inhibitory signaling using a PD- 1:CD28 switch receptor (SR) to convert inhibitory signaling into a co-stimulatory signal and to assess its effects on the function of CD4+ and CD8+ T cells.
Experimental approach: PBMCs isolated from both sources were retrovirally transduced with PD-1:CD28 SR. Intracellular expression of cytokines, including IFN-γ, IL-4, IL-10, as well as the surface CD25 in CD4+ and CD8+ T cells, and the rate of cell apoptosis during engineering and exposure to target cells were assessed.
Findings/Results: Both buffy coat (BC) and whole blood showed comparable transduction efficiency (21.4% versus 18.5%, respectively), but BC yielded nearly double the number of viable PBMCs per 50 mL. Upon stimulation and co-culture with target cells, CD4+ SR T cells produced significantly higher levels of IFN-γ, IL-4, and IL-10 compared to CD8+ SR T cells. These cytokines also significantly increased in co-culture supernatants exposed to PD-L1+ cells. No significant differences were found in CD4/CD8 ratios, CD25 expression, or cytokine profiles between PBMC sources. However, BC-derived T cells showed higher apoptosis rates during co-culture.
Conclusion and implications: BC can be a practical and effective source of PBMCs for T cell engineering. These findings underscore the SR signaling in the activation of CD4+ T cells that may impact the activation of CD8+ T cells, which is essential for effective tumor eradication.

Keywords:  Blood buffy coat; CD4-positive T-lymphocytes and CD8-positive T-lymphocytes; Immunotherapy; PD-1:CD28 switch receptor; PD-L1; Whole blood

DOI:  https://doi.org/10.4103/RPS.RPS_82_25
Aging Cell. 2026 Jun;25(6): e70548

Immunosenescence and Vaccine Efficacy in Aging: Dynamic Interplay of Gut Microbiota and mTOR Signaling Pathways.

Jiaxuan Li, Yuhong Zhang, Daijun Yu, Jianhua Li, Keda Chen, Lisheng Chu.

Aging significantly impairs vaccine efficacy in older adults, driven by immunosenescence, inflammaging, and disruptions in the gut microbiota-mTOR-immune axis. This review synthesizes current evidence on how aging alters vaccine-induced immune responses through the interplay of gut microbiota dysbiosis and dysregulated mTOR signaling. Age-related microbial diversity declines and reduced short-chain fatty acid (SCFA) production exacerbate inflammation, while heightened mTOR activity suppresses autophagy, promotes pro-inflammatory states, and impairs T/B cell function, collectively diminishing antibody production and immune memory formation. We highlight the bidirectional interaction between SCFAs and mTOR, where SCFAs mitigate mTOR overactivation to enhance immune regulation, and mTOR dysregulation further aggravates microbial dysbiosis, forming a vicious cycle. Critically, this review systematically stratifies the evidence, distinguishing preclinical mechanistic insights from correlative human data. Animal and human studies suggest that targeting this axis-via mTOR inhibitors, probiotics, or dietary interventions-holds promise for improving vaccine responses in the elderly. We propose future research directions, including personalized vaccine strategies leveraging microbiota profiling and mTOR modulation, to address the challenges of infection in aging populations and advance precision medicine for healthy aging.

DOI: https://doi.org/10.1111/acel.70548
Res Sq. 2026 May 08. pii: rs.3.rs-9404453. [Epub ahead of print]

Protective coinfection: influenza reprograms myeloid cells to limit CD8 T cell-mediated malaria pathology.

Tracey Lamb, Jenna Reed, Ritika Nayan, Margot Deckers, Douglas Cornwall, Suzanne Ostrand-Rosenberg, Brian Evavold.

Malaria-associated acute lung injury (MA-ALI) is a life-threatening complication of malaria driven by pathogenic CD8 T cell responses with no effective pharmaceutical interventions. Here, we show that co-infection with non-lethal influenza/A/HKx31 (X31) protects mice from malarial pulmonary vascular leak and death. X31 co-infection drove the expansion of Ly6C+ monocyte-derived alveolar macrophages, which inhibited pathogenic CD8 T cells in a contact-dependent manner. Moreover, in vivo blockade of monocytic myeloid cells with gemcitabine eliminated the protective phenotype. Protection occurred independently of parasite burden and did not require type I interferon signaling. Instead, co-infected pulmonary CD8 T cells exhibited broad transcriptional reprogramming and impaired inflammatory cytokine production. Our findings demonstrate that virus-induced myeloid cells suppress pulmonary CD8 T cells to prevent lung immunopathology in severe malaria. This work suggests that therapeutics that expand suppressive myeloid cells should be considered for adjunctive therapy for MA-ALI.

DOI: https://doi.org/10.21203/rs.3.rs-9404453/v1
Geroscience. 2026 May 22.

Skin as a sentinel and modulator of systemic aging: a translational framework for evidence-based gerotherapeutics.

Diala Haykal, Frederic Flament.

  Aging is increasingly recognized as a dynamic and potentially modifiable biological process, yet translation of mechanistic discoveries into clinically validated interventions that extend human healthspan remains limited. Because dermatologists can directly observe, sample, and quantify age-related changes in vivo, the skin provides an accessible platform for gerotherapeutic evaluation. As the largest and most environmentally exposed organ, the skin integrates intrinsic hallmarks of aging, including cellular senescence, mitochondrial dysfunction, extracellular matrix remodeling, epigenetic alterations, and chronic low-grade inflammation, with lifelong environmental stressors. These mechanisms manifest as structural, functional, and molecular phenotypes that can be monitored longitudinally using non-invasive technologies. Beyond serving as a visible indicator of organismal aging, cutaneous dysfunction may also influence systemic aging through inflammatory, immune, vascular, and neuroendocrine signaling. Here we examine how skin-based biomarkers and functional endpoints can support three translational priorities: aligning interventions with heterogeneous aging trajectories, defining functionally meaningful outcome measures, and responsibly integrating emerging diagnostic technologies. Anchoring gerotherapeutic development in dermatologic science may accelerate validation of interventions aimed at preserving resilience, physiological function, and independence across the lifespan.

Keywords:  Gerotherapeutics; Hallmarks of aging; Skin aging; Skin biomarkers; Translational dermatology

DOI:  https://doi.org/10.1007/s11357-026-02331-7
Mater Today Bio. 2026 Jun;38 103218

Ion-coupled transfersome complexes for enhanced transdermal NAD+ repletion and mitigation of cellular senescence signatures.

Seongsu Kang, Shibo Wei, Bon Il Koo, Yunju Jo, Junhyeon Park, Yingqi Xue, Sanghyun Ye, Jiwon Park, Byung Woo Hwang, Jin Hyun Kim, Euitaek Jeong, Juewon Kim, Nea-Gyu Kang, Seung-Hyun Jun, Dongryeol Ryu.

  Nicotinamide adenine dinucleotide (NAD+) is a pivotal coenzyme whose decline drives mitochondrial dysfunction and senescence. However, NAD+ delivery to skin is limited by poor stability and tissue accessibility. Here, we develop an ion-coupled NAD+ transfersome (ICoN) that stabilizes NAD+ and enables efficient, non-invasive transdermal delivery. ICoN restores intracellular NAD+ levels and reverses transcriptomic programs associated with DNA damage, oxidative stress, and senescence in vitro. Functionally, ICoN promotes mitochondrial functional integrity and sustains proliferative and migratory competence under senescent and NAD+-depleted conditions. In ex vivo porcine and human skin explants, ICoN achieves superior intratissue NAD+ penetration while attenuating senescent signatures compared with free NAD+ or precursors. Integrated high-spatial-resolution transcriptomic profiling and bulk transcriptomic analyses of UV-stressed human skin reveal that ICoN mitigates histological disruption and senescence-associated transcriptional programs at the tissue level. Moreover, ICoN extends lifespan and enhances healthspan in C. elegans. These findings characterize ICoN as a transdermal NAD + delivery platform supporting localized NAD + restoration in the context of skin aging.

Keywords:  Human skin explants; Ion-coupled transfersome; NAD+; Nanovesicles; Skin aging; Spatially resolved transcriptomics; Transdermal delivery

DOI:  https://doi.org/10.1016/j.mtbio.2026.103218