bims-imseme 2026-08-02 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2026–08–02
nineteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

GRP75 sustains CD8+ T cell homeostasis and memory generation through ensuring mitochondrial fitness.
CRISPR screens identify targets to rescue age-related T cell dysfunction in cancer.
Targeting the fate of exhausted CD8+ T cells.
Dendritic cell circadian clocks shape memory CD8+ T cell differentiation.
Deoxycholic acid impairs mitochondrial fitness and suppresses mitophagy through Parkin ubiquitination driving CD8+ T cell Exhaustion in Colorectal Cancer.
Methionine Regulates Antitumour Function of CD8+ T Cells Through Polyamine Synthesis.
Spatial metabolic heterogeneity shapes CD8+ T cell function in cancer.
Cryoelectron tomography reveals an age-related decline in mitoribosomes that contributes to T cell dysfunction in older individuals.
CD8+ T-cell effector programming is epigenetically regulated by DUSP2 through BAF complex-driven chromatin remodeling.
Dynamic expression of IL-21 in effector CD8 T cells helps control chronic infections.
CEACAM5 drives psoriatic inflammation by regulating CD8+ T cell recruitment and activation.
Haploidentical hematopoietic stem cell transplantation drives time-dependent premature T cell senescence: Recipient microenvironment modulates donor T cell epigenetic aging, telomere homeostasis and SASP remodeling.
Radiation Induces Persistent Dysregulation and Functional Impairment in CD8+ T Cell Immunity.
High-Density Wild-Type IL-2 Nanoparticles Preferentially Enhance CD8⁺ T-Cell Expansion and Reprogram the Tumor Microenvironment.
Metabolic cell competition in the glioblastoma tumour microenvironment: glucose, glutamine, and lactate as determinants of immune exclusion and targets for pharmacological reprogramming.
Persistent cytolytic CD8+ T cells recognize SARS-CoV-2 and herpesvirus epitopes in long COVID.
IL-21 controls CD8 + T cell immunity and antibacterial defense in fish via STAT3 signaling.
ACSL5 programs fatty acid metabolism and mitochondrial fitness to sustain pathogenic T cells and exacerbate Sjögren's syndrome.
A Synthetic Microbial Therapy Rewires Antitumor Immunity Across Multiple Cancer Types.

Cell Death Differ. 2026 Jul 31.

GRP75 sustains CD8+ T cell homeostasis and memory generation through ensuring mitochondrial fitness.

Fan Zhao, Pengfei Wang, Zejin Cui, Zhishan Zhao, Lize Wu, Rui Zhang, Dale Gao, Jiayan Wu, Yuwen Shao, Xuexiao Jin, Yadan Bai, Kaixiang Zhu, Linrong Lu.

The development and functional maintenance of CD8+ T cells are metabolically regulated processes in which mitochondria serve as the central hub. Here, we identify glucose-regulated protein 75 (GRP75) as a critical mitochondrial regulator controlling these processes. Using T cell-specific Hspa9 (encodes GRP75) knockout mice, we demonstrate that GRP75 deficiency disrupts CD8+ T cell fate, leading to defective T cell homeostasis and impaired memory differentiation. Mechanistically, impaired mitochondrial function in GRP75-deficient CD8+ T cells leads to perturbation of IL-7R signaling and aberrant expression of effector-associated molecules. Further studies reveal that GRP75 deficiency leads to upregulation of interferon regulatory factor 4 (IRF4), a critical transcription factor for effector versus memory fate, which in turn suppresses memory CD8+ T cell differentiation. Our findings establish GRP75 as a pivotal mitochondrial checkpoint that coordinates metabolic state and functional fate in CD8+ T cells.

DOI: https://doi.org/10.1038/s41418-026-01830-6
Cell. 2026 Jul 29. pii: S0092-8674(26)00814-7. [Epub ahead of print]

CRISPR screens identify targets to rescue age-related T cell dysfunction in cancer.

Alex C Y Chen, Keely Y Ji, Cansu Yerinde, Nelson H Knudsen, Kevin Bi, Shumeng Hao, Vasyl Zhabotynsky, Daniela Martinez, Thomas J Carmona-LaSalle, Kazuhiro Taguchi, Katherine H Xu, Elizabeth M Seider, Marc A Schwartz, Maria Zschummel, Linda T Nieman, Kathleen B Yates, Francesca S Gazzaniga, Brian C Miller, Thorsten R Mempel, Robert T Manguso, Nir Hacohen, Debattama R Sen.

  Immune aging impairs T cell-mediated tumor control as well as cancer immunotherapy outcomes. The most important drivers of T cell dysfunction in aged tumors remain unknown. We performed single-cell CRISPR screens to identify Dusp5 and Zfp219 as key regulators of CD8+ T cell persistence and effector differentiation within aged tumors. Loss of Dusp5 increased extracellular signal-regulated kinase (ERK) phosphorylation and globally enhanced T cell proliferation. Conversely, Zfp219 deletion induced epigenetic reprogramming and increased expression of cytotoxic molecules, enhancing antitumor immunity specifically in aging. Levels of the human ortholog ZNF219 were higher within intratumoral CD8+ T cells from older cancer patients, which correlates with worse survival following immunotherapy. Zfp219 ablation synergized with immune checkpoint inhibitors to expand effector-like CD8+ T cells, leading to tumor clearance in aged mice. Our findings highlight Dusp5 and Zfp219 as critical drivers of age-related T cell dysfunction that can be targeted to rejuvenate antitumor immunity in older cancer patients.

Keywords:  T cells; antitumor immunity; cancer immunology and immunotherapy; immune aging; in vivo single-cell CRISPR screen

DOI:  https://doi.org/10.1016/j.cell.2026.07.016
Trends Immunol. 2026 Jul 31. pii: S1471-4906(26)00181-X. [Epub ahead of print]

Targeting the fate of exhausted CD8+ T cells.

Daniel T Utzschneider, Stephen J Turner.

CD8+ T cell exhaustion is increasingly recognized as a regulated adaptation to chronic antigenic stimulation rather than a simple immune failure. Indeed, recent studies reveal that exhaustion is imprinted early after T cell activation, integrating transcriptional and epigenetic cues to balance effector function with long-term persistence. Key regulators, including Inhibitor of DNA binding 3 (ID3), Thymocyte selection high mobility box protein (TOX), MYB, Krüppel-like factor 2 (KLF2), and Special AT-rich sequencing binding protein 1 (SATB1), orchestrate this process, preserving stem-like precursor populations that sustain immunity during chronic infection and cancer. This emerging view frames exhaustion as a context-dependent extension of the memory program rather than its collapse. By defining the molecular and functional logic of exhaustion, we highlight how these insights can inform new approaches to manipulate T cell fate for therapeutic benefit.

DOI: https://doi.org/10.1016/j.it.2026.07.002
Sci Adv. 2026 Jul 31. 12(31): eaeh3719

Dendritic cell circadian clocks shape memory CD8+ T cell differentiation.

Ward Vleeshouwers, Suzanne van Duikeren, J Fréderique de Graaf, Dominique M B Veerkamp, Marissa E Linger, Sytze H T Jorritsma, Sebenzile K Myeni, Laura Kervezee, Ramon Arens.

Circadian rhythms regulate diverse immune processes, yet how they influence memory CD8+ T cell differentiation remains unclear. Here, we show that the time of day of antigen encounter shapes CD8+ T cell fate and antiviral immunity. Immunization during the active phase promotes the generation of progenitor-like memory CD8+ T cells and enhances T cell-mediated protection upon viral challenge. Mechanistically, dendritic cell-intrinsic circadian clocks regulate expression of the costimulatory ligand CD70, thereby directing T cell differentiation. These findings uncover a dendritic cell-mediated circadian mechanism that governs memory T cell fate decisions and suggest that aligning immune priming with circadian time may be leveraged to optimize T cell immunity.

DOI: https://doi.org/10.1126/sciadv.aeh3719
Redox Biol. 2026 Jul 25. pii: S2213-2317(26)00321-6. [Epub ahead of print]96 104322

Deoxycholic acid impairs mitochondrial fitness and suppresses mitophagy through Parkin ubiquitination driving CD8+ T cell Exhaustion in Colorectal Cancer.

Yang Gao, Jiaxin Wang, Shihui Lai, Mingwei Li, Jiaqi Shi, Xianjun Li, Ying Guo, Sainan Ma, Xinxin Wang, Shule Zhang, Tianyu He, Yu Hong, Shuang Li, Caiqi Liu, Lijuan Cao, Haiping Hao, Chujie Ding.

  Colorectal cancer (CRC) exhibits significant heterogeneity in response to immunotherapy that cannot be fully explained by microsatellite status alone. Although elevated bile acid levels are recognized as an important risk factor for CRC, their impact on immunotherapy responsiveness remains poorly understood. Here, we demonstrate that high bile acid levels profoundly impair anti-PD-1 efficacy in both CRC patient cohort and mouse models, accompanied by reduced infiltration and functional impairment of tumor-infiltrating CD8+ T cells. Bile acid profiling identified deoxycholic acid (DCA) as the key bile acid species mediating this immunosuppressive effect. In vitro and in vivo studies have shown that DCA not only suppressed CD8+ T cell effector function but also drove them toward terminal exhaustion, thereby limiting responsiveness to anti-PD-1. Mechanistically, DCA disrupted mitochondrial fitness in CD8+ T cells by suppressing oxidative phosphorylation and inducing excessive mitochondrial reactive oxygen species (mtROS) production. In parallel, DCA enhanced ubiquitination-dependent degradation of Parkin, thereby inhibiting mitophagy and causing the accumulation of damaged mitochondria. These convergent defects in mitochondrial homeostasis ultimately promoted CD8+ T cell dysfunction and terminal exhaustion. Notably, pharmacological reactivation of mitophagy via Urolithin A reversed these defects and restored the antitumor efficacy of anti-PD-1 in vivo. Collectively, our findings identified a DCA-Parkin-mitophagy axis that drives CD8+ T cell terminal exhaustion and compromises immunotherapy efficacy, providing a potential metabolic intervention strategy to improve immunotherapy responses in CRC patients with elevated bile acid levels.

Keywords:  Anti-PD-1 therapy; CD8(+) T cell terminal exhaustion; Colorectal cancer; Deoxycholic acid; Mitochondrial dysfunction; Mitophagy

DOI:  https://doi.org/10.1016/j.redox.2026.104322
Immunology. 2026 Jul 26.

Methionine Regulates Antitumour Function of CD8+ T Cells Through Polyamine Synthesis.

Tian Zhao, Gillian A Carleton, Sam Preshaw, Sarah MacPherson, Madison Shiyuk, Joseph Monaghan, Jun Han, Oro Uchenunu, Robert Rottapel, Ralph J DeBerardinis, Kelly M Stewart, Bo-Hyun Kim, Juan Ausió, David R Goodlett, Helena Pětrošová, Kyle D Duncan, Julian J Lum.

  Methionine is an essential amino acid critical for T cell activation. While methionine restriction (MR) combined with immune checkpoint blockade has been shown to enhance T cell function, the impact of methionine on adoptive T cell therapies remains unknown. Here, we examined the functionality of T cells under MR and pharmaceutical inhibition of the methionine cycle (MAT2Ai), using primary T cells and a murine adoptive T cell therapy model. In vitro, transient MR or MAT2Ai treatment increased interferon gamma (IFNγ) expression in CD8+ T cells, whereas sustained MR led to the upregulation of T cell exhaustion-associated markers. Mechanistically, transient MR suppressed the polyamine synthesis pathway, and supplementation with polyamines reversed MR-induced IFNγ expression. Genetic ablation of S-adenosylmethionine decarboxylase, an enzyme involved in the polyamine synthesis pathway, recapitulated the effect of MR, indicating that transient MR enhances T cell function by inhibiting polyamine synthesis. Despite this, transient MR treatment of ovalbumin (OVA)-specific (OT-I) CD8+ T cells prior to adoptive transfer did not improve antitumour efficacy against EG7-OVA tumours in vivo. In contrast, sustained dietary MR accelerated EG7-OVA tumour growth in mice treated with OT-I T cells, demonstrating that methionine availability is essential for the activity of donor T cells. Importantly, sustained dietary MR promoted terminally exhausted phenotype in tumour-infiltrating donor CD8+ T cells, but not in host T cells. These findings suggest that enhancing methionine availability in the tumour microenvironment may improve the efficacy of adoptive T cell therapies.

Keywords:  T cell; adoptive cell therapy; cancer immunology; immunometabolism

DOI:  https://doi.org/10.1111/imm.70177
Curr Opin Immunol. 2026 Jul 29. pii: S0952-7915(26)00106-8. [Epub ahead of print]102 102829

Spatial metabolic heterogeneity shapes CD8+ T cell function in cancer.

Peio Azcoaga, Ilaria Elia.

Tumors are spatially heterogeneous ecosystems in which malignant, stromal, vascular, and immune cells interact within metabolically distinct niches. These localized microenvironments are shaped by factors such as nutrient availability, hypoxia, acidosis, and immunomodulatory metabolites, all of which strongly influence CD8⁺ T cell infiltration, migration, persistence, and effector function. Growing evidence indicates that spatial metabolic heterogeneity contributes to immune exclusion, T cell dysfunction, and resistance to immunotherapy. This has been accompanied by major advances in spatial metabolomics, particularly mass spectrometry imaging, which now enable the in situ mapping of metabolites within intact tissues. Combined with transcriptomic, proteomic, and imaging-based approaches, these technologies provide unprecedented insight into how metabolism is organized across tumors and how it shapes tumor-immune interactions. In this review, we discuss how metabolic zonation shapes CD8⁺ T cell function across primary tumors and metastatic lesions. We highlight emerging evidence linking localized metabolic programs to T cell exhaustion, impaired motility, and altered immune composition, and discuss therapeutic strategies aimed at improving T cell metabolic fitness, including metabolic modulation and engineering approaches relevant to immune checkpoint blockade and adoptive cell therapies. Finally, we consider the translational potential of spatial metabolomics for biomarker discovery and the development of precision immunometabolic oncology.

DOI: https://doi.org/10.1016/j.coi.2026.102829
Proc Natl Acad Sci U S A. 2026 Aug 04. 123(31): e2608102123

Cryoelectron tomography reveals an age-related decline in mitoribosomes that contributes to T cell dysfunction in older individuals.

Jingwen Chen, Lili Su, Bangze Pan, Junhao Sang, Linlin Li, Junsong Huang, Zhao-Lan Hu, Lixin Wang, Xiaojie Zhang, Jun Jin.

  Mitochondrial dysfunction drives T cell aging in mice. Yet, due to fundamental differences in T cell aging mechanisms between species, whether human T cells exhibit similar mitochondrial alterations remains unclear, with existing evidence often conflicting. Using cryoelectron tomography, we resolved the structure and spatial organization of mitochondrial ribosomes in primary human CD8+ T cells under physiological conditions. Comparative analysis with human aging models revealed an age-related reduction in mitoribosome abundance and in higher-order mitoribosome organization, which is necessary for cooperative translation. Defective mitochondrial translation suppressed cytosolic ribosomal protein expression, thereby limiting mitochondrial biogenesis. The consequent reduction in mitochondrial mass induced an aged T cell phenotype characterized by compromised memory phenotypes and proliferative capacity. Enhancing mitochondrial translation via overexpression of the mitoribosomal component Mrps5 reversed aged T cell phenotypes in a mouse model of viral infection or tumor. Together, our findings provide nanoscale-resolution views of internal mitochondrial structures in situ, revealing an age-related loss of mitoribosomes. This loss contributes to mitochondrial dysfunction and the subsequent decline in T cell function observed in older individuals. Restoring mitochondrial translation may therefore represent a strategy for mitigating T cell dysfunction in the aging population.

Keywords:  T cell aging; cryo-electron tomography; mitoribosome

DOI:  https://doi.org/10.1073/pnas.2608102123
J Immunol. 2026 Jul 10. pii: vkag202. [Epub ahead of print]215(7):

CD8+ T-cell effector programming is epigenetically regulated by DUSP2 through BAF complex-driven chromatin remodeling.

Emilia R Dellacecca, Jacob B Hirdler, Whitney Barham, Ying Li, Joanina K Gicobi, Yiyi Yan, Haidong Dong.

  Effector gene expression in CD8+ T cells is tightly controlled at the epigenetic and transcriptional levels; however, crucial regulatory signals remain incompletely understood. In this study, we identify dual specificity phosphatase 2 (DUSP2) as a key epigenetic modulator of effector CD8+ T-cell state, by elucidating inhibition of BAF-mediated chromatin opening by DUSP2. Induced downregulation of DUSP2 in human CD8+ T cells enhances cytotoxicity and effector phenotypes by increasing chromatin accessibility through upregulation of BAF subunits, such as SMARCA4, and permitting binding of ETS1 to BAF subunit gene loci and those essential for effector programs. These findings uncover a previously unrecognized role of DUSP2 in the management of the chromatin landscape in effector CD8+ T cells and the epigenetic fine-tuning of their functionality, highlighting DUSP2 as a promising therapeutic target for T cell-based immunotherapy.

Keywords:  BAF complex; CD8+ T cells; DUSP2; cytotoxicity; effector

DOI:  https://doi.org/10.1093/jimmun/vkag202
Sci Immunol. 2026 Jul 31. 11(121): eaec5171

Dynamic expression of IL-21 in effector CD8 T cells helps control chronic infections.

Zixuan Zhao, Han Feng, Xiaohong Zhao, Bowen Xie, Tian Xie, Qinli Sun, Yongzhen Chen, Kun Wei, Birui Pan, Peng Wei, Xuan Zhong, Lei Yuan, Xue Bai, Xiaohu Wang, Chen Dong.

CD8 T cells are critical players in immune responses against pathogens. Interleukin-21 (IL-21) is predominantly produced by CD4 T cells and exerts multifaceted effects on CD8 T cell regulation and function. Using Il21-reporter and Il21-fate mapping mice, we report that a subpopulation of activated CD8 T cells also produces IL-21 in the context of lymphocytic choriomeningitis virus (LCMV) infection. During the early effector phase of both acute and chronic infections, IL-21-expressing CD8 T cells exhibit substantial proliferative and cytotoxic capacities, with higher levels of interferon-γ (IFN-γ) and granzyme B (GZMB) compared with IL-21- counterparts. Moreover, CD8 T cell-derived IL-21 played a critical protective role in chronic, but not acute, infection. IL-21 expression in CD8 T cells appeared to be largely restricted to exhausted progenitor T cells during the exhaustion phase of chronic infection. These findings identify IL-21-expressing CD8 T cells as pivotal players in the control of chronic infection.

DOI: https://doi.org/10.1126/sciimmunol.aec5171
Biochem Biophys Rep. 2026 Sep;47 102695

CEACAM5 drives psoriatic inflammation by regulating CD8+ T cell recruitment and activation.

Lifeng Wang, Xiaotao Liu, Kaina Cao, Yifei Liu, Surong Liang, Lijuan Xu, Zigang Xu.

  As a chronic relapsing immune-mediated skin disorder, psoriasis is mainly driven by CD8+ T cells during disease progression, while the molecular basis of CD8+ T cell recruitment and activation in psoriatic lesions remains largely unclear, and the function of CEACAM5 in psoriasis remains uncharacterized. Here, we report that CEACAM5 is significantly upregulated in psoriatic patient epidermal lesions and M5-induced psoriatic keratinocytes in vitro. CEACAM5 knockdown prominently inhibits chemokine expression in keratinocytes, attenuates CD8+ T cell recruitment, and downregulates pro-inflammatory cytokine production in recruited CD8+ T cells. Mechanistic studies reveal that soluble CEACAM5 directly activates the Lck/ZAP70 signaling axis to promote the inflammatory activation of CD8+ T cells. Collectively, our work identifies CEACAM5 as a critical regulator of CD8+ T cell responses in psoriasis, providing a novel potential therapeutic target for this disease.

Keywords:  CD8+ T cells; CEACAM5; Keratinocytes; Psoriasis

DOI:  https://doi.org/10.1016/j.bbrep.2026.102695
Transplant Cell Ther. 2026 Jul 31. pii: S2666-6367(26)00589-0. [Epub ahead of print]

Haploidentical hematopoietic stem cell transplantation drives time-dependent premature T cell senescence: Recipient microenvironment modulates donor T cell epigenetic aging, telomere homeostasis and SASP remodeling.

Lin Sun, Yichen Zhang, Hong Zhang, Haoran Liu, Junjie Xu, Jiaqi Liu, Chuanfang Liu, Jun Peng, Xinguang Liu.

   BACKGROUND: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) cures hematological malignancies but severely impairs long-term immune reconstitution by inducing T cell senescence. Previous studies have linked anti-tumor therapy to immune aging; however, it remains unclear whether haploidentical HSCT (haplo-HSCT) independently drives progressive premature T cell senescence beyond pre-transplant chemotherapy, and how the recipient microenvironment shapes donor T cell aging patterns.
OBJECTIVE: This study aimed to determine the independent effect of haplo-HSCT on time-dependent T cell senescence and to elucidate the bidirectional regulatory role of recipient age-associated microenvironments on phenotypic and molecular aging signatures of donor-derived T cells.
STUDY DESIGN: A total of 34 subjects were enrolled, including 24 haplo-HSCT recipients stratified by post-transplant duration (< 12 months, n = 12; ≥ 12 months, n = 12) and 10 patients receiving chemotherapy alone. Eighteen age-reciprocal donor-recipient pairs were analyzed. Multiparameter flow cytometry, multiplex cytokine assay, SASP PCR array, epigenetic clock profiling, and telomere length measurement were performed to comprehensively characterize T cell senescence features.
RESULTS: Haplo-HSCT induced robust, time-dependent senescence in both CD4⁺ and CD8⁺ T cells, accompanied by substantial T cell subset remodeling. This included a reduced CD4/CD8 ratio, contracted naive and central memory T cell compartments, and expansion of senescence-prone terminal effector memory T cells, which was particularly pronounced in the CD8⁺ compartment. Terminal senescent CD27⁻CD28⁻CD57⁺ T cells (both CD4⁺ and CD8⁺) from long-term recipients exhibited significantly upregulated canonical senescence molecules p16INK4a and γH2AX, providing solid molecular evidence for transplant-associated T cell senescence. In contrast, chemotherapy alone failed to induce comparable terminal T cell senescence phenotypes. Haplo-HSCT further established persistent peripheral inflammatory imbalance and remodeled the pro-senescent SASP transcriptional profile of circulating T cells. Notably, recipient age exerted bidirectional modulation of donor T cell epigenetic aging, telomere homeostasis, and SASP remodeling.
CONCLUSION: Haplo-HSCT serves as an independent, time-dependent driver of premature donor T cell senescence, distinct from chemotherapy-induced immune alteration. The recipient age-related microenvironment is a critical regulator of donor T cell epigenetic aging, telomere maintenance and SASP reprogramming. This study systematically delineates multi-layered signatures of post-transplant T cell senescence and provides a theoretical foundation for developing age-adapted strategies to improve long-term immune reconstitution after haplo-HSCT.

Keywords:  Epigenetic clock; Haploidentical hematopoietic stem cell transplantation; Immune reconstitution; Premature immunosenescence; Recipient microenvironment; Senescence-associated secretory phenotype; T cell senescence; Telomere attrition

DOI:  https://doi.org/10.1016/j.jtct.2026.07.026
Radiat Res. 2026 Jul 27. pii: eRADE-25-00087.1. [Epub ahead of print]

Radiation Induces Persistent Dysregulation and Functional Impairment in CD8+ T Cell Immunity.

Anika Kot, Lorreta Yun-Tien Lin, Zhinuo Jiang, Albert J Fornace, Heng-Hong Li.

In addition to immediate cell lethality, radiation exposure has long-term effects on the immune system, particularly T lymphocytes, causing persistent functional abnormalities post-exposure. Uncertainties remain regarding the long-lasting consequences on T cell immunity in survivors of the acute radiation syndrome and the underlying mechanisms of those consequences. Here, we investigated delayed effects of acute radiation exposure on CD8+ T cell immunity using the Listeria monocytogenes infection model. Impaired CD8+ T cell activation, reduced terminal effector formation upon infection, and exacerbated listeriosis were found in mice at 4 weeks postirradiation with sublethal doses. To elucidate how radiation affects the functionality of CD8+ T cells at various differentiation stages, we performed single-cell transcriptomic profiling. Radiation altered cluster distribution pre-infection and impaired terminal effector and memory precursor effector formation post-infection. Differential gene analysis highlighted radiation-induced gene expression changes, including cytokines and mitochondrial proteins, in a cluster-specific manner post-infection. The study demonstrates dysfunction of newly replenished naïve T cells, which results in impaired CD8+ T cell immunity after irradiation.

DOI: https://doi.org/10.1667/RADE-25-00087.1
bioRxiv. 2026 Jul 15. pii: 2026.07.14.738558. [Epub ahead of print]

High-Density Wild-Type IL-2 Nanoparticles Preferentially Enhance CD8⁺ T-Cell Expansion and Reprogram the Tumor Microenvironment.

Ruijie Wang, Pramod Kumar, Noah A Crumrine, Tongchatra Watcharawittayakul, Alyssa Wallstrum, Moataz Reda, Gordon Mills, Worapol Ngamcherdtrakul, Wassana Yantasee.

Low response rates to immune checkpoint inhibitors (ICIs) in solid tumors are often driven by insufficient tumor-infiltrating CD8⁺ T cells and immunosuppressive tumor microenvironment (TME). Although interleukin-2 (IL-2) potently expands and activates CD8⁺ T cells, its clinical use is limited by rapid clearance, dose-limiting toxicity, and regulatory T cell (T reg ) stimulation. Engineered IL-2 variants have not yet achieved meaningful clinical efficacy. Here, polymer-modified mesoporous silica nanoparticles displaying dense, unmodified wild-type IL-2 on their surface (IL2-NP) are developed, conferring proteolytic stability and tumor retention. IL2-NP enables avidity-mediated CD8⁺ T cell binding and enhances proliferation and effector function without increased T reg binding or proliferation. Intratumoral IL2-NP expands CD8⁺ T cells, increases CD8⁺/T reg ratios, and reprograms TME through dendritic cell activation and M1-like macrophage polarization. IL2-NP induces regression of both treated and untreated distant colorectal tumors in a CD8⁺ T cell-dependent manner. IL2-NP synergizes with ICIs and leads to complete tumor regression and immunological memory that protect against rechallenge. Treatment is well tolerated, with strong efficacy also observed in triple-negative breast and metastatic ovarian cancer models. Overall, intratumoral IL2-NP elicits robust systemic antitumor immunity, offering a promising strategy to enhance ICIs, cancer vaccines, and adoptive T-cell therapies.
Graphical abstract: This work introduces a nanoparticle platform that overcomes major shortcomings of IL-2 immunotherapy by presenting wild-type IL-2 at high density on the nanoparticle surface, thereby increasing binding avidity to effector T cells. The resulting IL-2 nanoparticles enhance cytotoxic T cell expansion, reprogram the tumor microenvironment, and augment responses to immune checkpoint blockade to achieve robust ant-tumor immune response in mouse tumor models.

DOI: https://doi.org/10.64898/2026.07.14.738558
Front Oncol. 2026 ;16 1849888

Metabolic cell competition in the glioblastoma tumour microenvironment: glucose, glutamine, and lactate as determinants of immune exclusion and targets for pharmacological reprogramming.

Egiroh Omene.

  Glioblastoma (GBM) remains the most lethal primary brain tumour, with median overall survival of 14 to 16 months despite maximal safe surgical resection, concurrent chemoradiotherapy, and adjuvant temozolomide. Treatment failure is driven in large part by a profoundly immunosuppressive tumour microenvironment (TME) in which metabolic competition between GBM cells, bone marrow-derived immunosuppressive myeloid cells, and cytotoxic T lymphocytes determines cellular dominance. This review frames the GBM TME through the lens of metabolic cell competition: a process by which differential metabolic fitness, mediated principally through glucose and glutamine consumption, establishes a suppressive hierarchy that forecloses effective anti-tumour immunity. Aerobic glycolysis in GBM cells produces lactate, which polarises tumour-associated macrophages toward immunosuppressive phenotypes via GPR81/HIF-1alpha signalling and directly impairs T cell effector function through extracellular acidification and competition for monocarboxylate transporter capacity. GBM cells and immunosuppressive myeloid cells cannot sustain their proliferative and immunosuppressive programmes without glucose and glutamine; cytotoxic memory T cells, whose effector functions are energetically but not biosynthetically demanding, retain the capacity to function through fatty acid oxidation when these substrates are restricted. Disrupting glucose and glutamine metabolism through glutamine antagonism (DON and prodrugs JHU083/JHU395), dichloroacetate (DCA)-mediated PDK inhibition, intravenous pharmacological ascorbate-mediated GAPDH inactivation and HIF-1alpha destabilisation, systemic glucose restriction (SGLT2 inhibitors), sodium phenylbutyrate-mediated glutamine depletion, and monocarboxylate transporter inhibition can invert this competitive hierarchy, reprogramming the immunosuppressive myeloid compartment while preserving T cell fitness; mebendazole is additionally reviewed as a multi-target anti-parasitic repurposing candidate with demonstrated GBM preclinical survival benefit. Pharmacological ketosis elevates beta-hydroxybutyrate, an endogenous HDAC inhibitor that further augments T cell effector function through NLRP3 inflammasome suppression. The mechanistic and clinical evidence for each intervention is reviewed, metabolic engineering strategies for increasing T cell competitive fitness are described, and principal research gaps are identified. GBM cells and immunosuppressive myeloid cells are proposed to constitute a substrate-dependent competitive coalition whose simultaneous disruption is the central therapeutic proposition reviewed. Evidence is synthesised from in vitro metabolic competition experiments, immune-competent murine GBM models, mechanistic pharmacology studies, and early-phase clinical pharmacodynamic data in human GBM.

Keywords:  fatty acid oxidation; glioblastoma; glutamine metabolism; glycolysis; metabolic cell competition; pharmacological immunometabolism; tumour microenvironment; tumour-associated macrophages

DOI:  https://doi.org/10.3389/fonc.2026.1849888
Cell Rep Med. 2026 Jul 29. pii: S2666-3791(26)00363-0. [Epub ahead of print] 102946

Persistent cytolytic CD8+ T cells recognize SARS-CoV-2 and herpesvirus epitopes in long COVID.

Tongcui Ma, Heeju Ryu, Kailin Yin, Thomas Dalhuisen, Douglas Robbins, Tyrine T Bailey, Sean A Thomas, Emily A Fehrman, J Daniel Kelly, Jeffrey N Martin, Kara L Lynch, Sulggi A Lee, Steven G Deeks, Timothy J Henrich, Michael J Peluso, Evan W Newell, Nadia R Roan.

  Viral-specific CD8+ T cells play roles in protective immunity and immunopathology including during COVID-19. Leveraging combinatorial tetramers, we profiled CD8+ T cells specific for SARS-CoV-2, as well as those for cytomegalovirus (CMV) and Epstein-Barr virus (EBV)-herpesviruses implicated in COVID-19 pathogenesis. During severe COVID-19, EBV-specific CD8+ T cells exhibit a stem-like state, whereas CMV-specific ones are terminally differentiated and cytolytic. Comparing post-acute samples from long COVID (LC) individuals to those recovered revealed that LC-associated CMV-specific CD8+ T cells are T central memory cell (Tcm)- instead of terminally differentiated memory T cell (Temra)-biased. In LC individuals, CD8+ T cells specific for SARS-CoV-2, CMV, and EBV are preferentially terminally differentiated, exhausted, and cytolytic. Cytolytic granzyme-B-expressing CD8+ T cells are particularly prominent among LC women. As granzyme B is upregulated on viral-specific CD8+ T cells during acute viremia, an inability to shut down COVID-19-induced cytolytic effector expression may drive preferential persistence of cytolytic CD8+ T cells in people with LC, which may contribute to LC pathogenesis.

Keywords:  CD8+ T cells; CMV; EBV; SARS-CoV-2; cytolytic; granzyme; long COVID

DOI:  https://doi.org/10.1016/j.xcrm.2026.102946
Zool Res. 2026 Jul 18. pii: 2095-8137(2026)04-1179-14. [Epub ahead of print]47(4): 1179-1192

IL-21 controls CD8 + T cell immunity and antibacterial defense in fish via STAT3 signaling.

Yi Cao, Wenzhuo Rao, Haokai Chen, Kang Li, Yating Zhu, Zhichao Fang, Yuying Zheng, Ming Geng, Jiansong Zhang, Jialong Yang, Xiumei Wei.

  CD8 + T cells are indispensable effectors of adaptive immunity. While cytokine-mediated regulation of CD8 + T cell responses has been extensively characterized in mammals, the underlying mechanisms in fish remain largely unexplored. Here, we identified and characterized an interleukin-21 (IL-21) gene from Nile tilapia ( Oreochromis niloticus). In vitro stimulation with IL-21 significantly upregulated the transcription and expression of key CD8 + T cell effector molecules, including Granzyme B and interferon-gamma (IFN-γ), in splenic leukocytes, indicating a crucial role of IL-21 in modulating CD8 + T cell function in teleosts. Using a monoclonal antibody (mAb) against Nile tilapia IL-21, we further demonstrated that activated CD4-1 + T cells are the primary producers of this cytokine in fish. Intraperitoneal injection of recombinant IL-21 into Edwardsiella piscicida-infected Nile tilapia enhanced both proliferation and apoptosis of CD8 + T cells. Moreover, IL-21 elevated the expression of Granzyme B, IFN-γ, and IL-2, and boosted CD8 + T cell cytotoxicity, thereby strengthening their effector functions. In contrast, blockade of IL-21 signaling with the mAb severely impaired CD8 + T cell responses. Mechanistically, Nile tilapia IL-21 strongly induced phosphorylation of signal transducer and activator of transcription 3 (STAT3), which was required for IL-21-mediated CD8 + T cell proliferation in vitro. Inhibition of STAT3 phosphorylation in vivo attenuated CD8 + T cell responses and antibacterial immunity, underscoring its functional importance. Collectively, our findings establish IL-21 as a pivotal regulator of CD8 + T cell immunity in fish and provide evolutionary insight into conserved cytokine pathways shaping adaptive immune responses.

Keywords:  CD8+ T cells; Cytokine; IL-21; Nile tilapia; STAT3

DOI:  https://doi.org/10.24272/j.issn.2095-8137.2025.438
Int J Biol Sci. 2026 ;22(12): 6689-6708

ACSL5 programs fatty acid metabolism and mitochondrial fitness to sustain pathogenic T cells and exacerbate Sjögren's syndrome.

Xinyi Ren, Junhao Yin, Xinyi Ma, Jiabao Xu, Changyu Chen, Lele He, Ruowen Zhao, Yucheng Xu, Yiping Pu, Baoli Wang, Jiayao Fu, Lingyan Zheng.

  Emerging evidence has shown that fatty acid metabolism is closely associated with autoreactive T cells in autoimmunity, but its function in Sjögren's syndrome (SS) is still unclear. Here, we identified acyl-CoA synthetase long-chain family member 5 (ACSL5) as a metabolic checkpoint that drives pathogenic T-cell responses in SS. ACSL5 was upregulated in patients with SS and positively correlated with T-cell infiltration and lipid dysregulation. ACSL5-high T cells presented hyperactive effector activity and a proinflammatory phenotype. Metabolic profiling indicated that ACSL5 increased fatty acid uptake and utilization and promoted fatty acid oxidation (FAO) through peroxisome proliferator-activated receptor alpha (PPARα) in T cells, thereby improving mitochondrial respiratory capacity. Mechanistically, ACSL5 facilitated the nuclear translocation of PPARα and subsequent Mitofusin 2 (MFN2) transcription, increasing mitochondrial elongation and the formation of mitochondria‒endoplasmic reticulum contacts (MERCs) to influence the FAO and T-cell response. Disruption of the ACSL5/PPARα/MFN2 axis attenuated effector functions and reduced the longevity of pathogenic effector T cells. Pharmacological inhibition of FAO or ACSL5 decreased inflammatory T-cell infiltration and alleviated salivary gland inflammation. Collectively, these findings reveal an ACSL5-centered metabolic program that sustains pathogenic T-cell responses in SS and suggest ACSL5/FAO as a potential therapeutic target.

Keywords:  ACSL5; MERCs; Sjögren's syndrome; T cells; T-cell memory; fatty acid oxidation

DOI:  https://doi.org/10.7150/ijbs.131033
bioRxiv. 2026 Jul 22. pii: 2026.07.19.735925. [Epub ahead of print]

A Synthetic Microbial Therapy Rewires Antitumor Immunity Across Multiple Cancer Types.

Jugal K Das, Qing-Ming Qin, Shailbala Singh, Christina James Thomas, Shreyan Gupta, Ayan Chatterjee, Sunilgowda Sunnagatta Nagaraja, Fengguang Guo, Kaylee Delgado, Anil Kumar, Esther Ryu, Bennett Flannagan, Cansu Agca, Yuksel Agca, Noah Powell, Erin Barry, Melissa M Kahl-McDonagh, Sankar P Chaki, Andre Mendes Ribeiro Correa, Seyednami Niyakan, Song-I Han, James J Cai, Xiaoning Qian, Koichi S Kobayashi, Arum Han, Arul Jayaraman, Thomas A Ficht, Leslie Garry Adams, Robert C Alaniz, Cassian Yee, Jianxun Song, Paul de Figueiredo.

Microbial immunotherapies show promise against cancer, yet broad efficacy and mechanistic insight remain elusive. Here, we introduce SPIKE 1.0 (S1.0), a metabolically engineered bacterium that converts tryptophan into immunomodulatory hydroxyindoles via tryptophan monooxygenase to remodel the tumor microenvironment (TME). A single systemic dose of S1.0 elicited potent, durable antitumor responses across multiple murine models, including humanized mice, with minimal toxicity. S1.0 enhanced inflammatory signaling, activated innate and adaptive immunity, and promoted T cell persistence, memory, and resistance to exhaustion. It outperformed checkpoint inhibitors and synergized with chemotherapy. Multi-omics profiling revealed that S1.0 rewired amino acid metabolism in tumor-infiltrating immune cells and disrupted immunosuppressive networks. These results establish S1.0 as a scalable, cost-effective microbial immunotherapy with broad translational potential for solid tumors.

DOI: https://doi.org/10.64898/2026.07.19.735925