bims-imseme 2026-08-16 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2026–08–16
33 papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Menaquinone-4 protects CD8+ T cells from ferroptosis to enhance anti-tumor immunity.
The ADAP-TRIM21-ZEB2 axis regulates CD8+ T cell effector expansion and central memory-like differentiation.
The cost of persistence: MEK and metabolic demand.
Type I interferon drives dysfunction of a distinct CD8+ HLA-DRB1+ T cell subset in systemic lupus erythematosus.
Beyond exhaustion: T cell fitness for next generation of immunotherapy for hematological cancer.
Nanoscale artificial antigen-presenting cells reveal metabolic interventions modulate clonal composition of CD8+ T cells.
Oral nano-delivery of a gut microbial metabolite enhances T cell stemness for cancer immunotherapy.
Immunosenescence shapes the tumor immune microenvironment and limits PD-1/PD-L1 blockade efficacy in older patients with cancer.
Ferroptosis in T cells: mechanisms, biology and translational opportunities.
H2AFY2 suppresses exhaustion and enhances antitumor activity of CAR-T cells through transcriptional and epigenetic modifications.
Exercise slows ovarian aging.
Cofilin1-driven cytoskeletal remodeling modulates pan-cancer CD8+ T cell immunotherapy responses.
Decade-long persistence of CD19 CAR T cells in B cell lymphomas.
In vivo genome-wide CRISPR screens of human T cells in solid tumours.
Immune Cell Dysregulation in Hindlimb Unloading Mouse Model: Implications for Space Applications.
Healthy ageing: The struggle for maintaining T cells young.
TRECing down the source: naive and memory T cell generation in dirty mice and men.
Mitochondrial Dysfunction as a Driver of Meta-Inflammation in Aging: The Emerging Role of PDK4 in Bioenergetic Reprogramming and Inflammatory Amplification.
Advances in miRNA-Mediated Bidirectional Crosstalk and Immune Evasion Mechanisms Between Lung Cancer Cells and CD8+ T Cells.
Enhancing HIV-1-specific CAR-T cell functional activity by treatment with a novel cytokine-based scaffold with IL-15 superagonist and TGF-β-neutralizing activity.
Metabolic Bottlenecks and Opportunities: Reshaping the Tumor Microenvironment for Cancer Immunotherapy.
Cellular and molecular networks governing precursor exhausted CD8+ T cells in chronic liver disease: Implications for immunotherapy.
Engineering CXCL10-enriched macrophage-derived extracellular vesicles for T cell recruitment and immune remodeling in pancreatic cancer.
Cblb Gene Editing in T Cells Sustains Expansion and Immunogenic CAR T Tumor Killing Under Chronic Antigenic Stimulation.
TIF1γ holds the line against regulatory T cell plasticity.
mRNA-based immunotherapy improves the efficacy of adoptively transferred TCR transgenic T cells in a murine solid tumour model.
Rethinking lymphodepleting preconditioning in adoptive T cell therapy for durable tumor control.
Therapeutic remodeling of the tuberculosis granuloma with 1-methyl-D-tryptophan enhances CD8+ T cell-macrophage interactions.
Adaptation of Echinococcus Multilocularis to Oxidative Stress Depends on EmPDK-Mediated Metabolic Reprogramming.
Metabolic Reprogramming at the Tumor-Immune Interface in Hepatocellular Carcinoma.
Boosting anti-leukemia cytotoxicity of CD4 and CD8 T cells through combined inhibition of MEK and HDAC.
A microRNA atlas of CD4+ T cell subsets in experimental autoimmune encephalomyelitis identifies regulators of disease pathogenesis.
Inhibiting menin attenuates high-fat diet-induced weight gain by limiting intestinal lipid absorption in mice.

Sci China Life Sci. 2026 Aug 06.

Menaquinone-4 protects CD8+ T cells from ferroptosis to enhance anti-tumor immunity.

Jiarong Wang, Wen Wang, Simiao Fan, Liyun Liang, Huaibin Hu, Zenqing Song, Yu Zhang, Jiamei Zhang, Wanying Xiao, Biyu Zhang, Yaxin Li, Liang Luo, Min Wu, Haiqin Tu, Shaoyi Huang, Qiuying Han, Yuqi Wen, Sen Li, Ailing Li, Huiyan Li.

  Tumor-infiltrating CD8+ T cells undergo aberrant lipid accumulation in the tumor microenvironment (TME), which triggers ferroptosis, drives T cell dysfunction, and impairs anti-tumor activity. However, strategies to protect the effector functions of CD8+ T cells by preventing ferroptosis in vivo remain limited. Here, we report that menaquinone-4 (MK-4), a form of vitamin K2, serves as a potent ferroptosis inhibitor that preserves CD8+ T cell function within the TME and enhances anti-tumor activity. Specifically, we demonstrated that MK-4 acts as a potent anti-ferroptotic agent in CD8+ T cells, thereby restoring their effector cytotoxic potential. RNA sequencing (RNA-seq) analysis revealed that MK-4 reprograms the transcriptional landscape of CD8+ T cells by reversing RSL3-induced ferroptosis-related gene expression, restoring effector-associated gene expression, and mitigating dysfunction and exhaustion programs. In adoptive cell transfer models, MK-4 pretreatment effectively suppressed ferroptosis in CD8+ T cells, enhanced their effector functions, and inhibited tumor growth. Similarly, intravenous injection of MK-4 attenuated ferroptosis in endogenous CD8+ T cells and strengthened their anti-tumor capacity. Furthermore, the combination of MK-4 with anti-programmed death-1 (PD-1) antibody therapy elicits a synergistic anti-tumor effect. Collectively, our findings reveal that MK-4 preserves CD8+ T cell function by inhibiting ferroptosis, boosts anti-tumor immunity, thereby highlighting its potential as a therapeutic strategy for cancer treatment.

Keywords:  CD8+ T cell; anti-tumor immunity; ferroptosis; menaquinone-4

DOI:  https://doi.org/10.1007/s11427-025-3349-0
iScience. 2026 Aug 21. 29(8): 117016

The ADAP-TRIM21-ZEB2 axis regulates CD8+ T cell effector expansion and central memory-like differentiation.

Jiajia Lu, Fan Yang, Yanli Li, Pengchao Zhang, Tengfei Jia, Hebin Liu.

  The ADAP (adhesion and degranulation-promoting adapter protein)-SKAP1 signaling module is essential for TCR-mediated activation and LFA-1-dependent adhesion; however, its role in coordinating CD8+ T cell differentiation remains unclear. Here, we show that ADAP acts as a negative regulator of CD8+ T cell response. During acute LCMV-Armstrong infection, ADAP deficiency enhances CD8+ T cell effector expansion and function, as evidenced by increased IFN-γ and granzyme B expression, and subsequently favors the formation of central memory-like CD8+ T cells (CD44Hi CD62LHi). RNA sequencing (RNA-seq) analysis identified ZEB2 as one of the most significantly upregulated transcription factors in Adap -/- CD8+ T cells. Mechanistically, ADAP interacts with the E3 ubiquitin ligase TRIM21 to facilitate K48-linked polyubiquitination and degradation of ZEB2. This, in turn, reduces the binding of ZEB2 to the Smad3 promoter. Collectively, our study identifies a previously uncharacterized ADAP-TRIM21-ZEB2 axis that regulates CD8+ T cell differentiation, providing new mechanistic insights into the control of T cell fate decisions.

Keywords:  ADAP; CD8+ T cell; ZEB2; effector function; memory

DOI:  https://doi.org/10.1016/j.isci.2026.117016
Immunity. 2026 Aug 11. pii: S1074-7613(26)00311-0. [Epub ahead of print]59(8): 2058-2060

The cost of persistence: MEK and metabolic demand.

Ewelina Sobierajska, Christopher B Medina.

The metabolic mechanisms linking chronic TCR stimulation to T cell exhaustion remain incompletely understood. Mitra and colleagues show that sustained MEK signaling drives the bioenergetic demands of chronic activation to promote terminal exhaustion, whereas MEK inhibition maintains progenitor-like T cells.

DOI: https://doi.org/10.1016/j.immuni.2026.07.012
Arthritis Rheumatol. 2026 Aug 10.

Type I interferon drives dysfunction of a distinct CD8+ HLA-DRB1+ T cell subset in systemic lupus erythematosus.

Huizhong Long, Elio Carmona, Mikhail G Dozmorov, Amr H Sawalha.

OBJECTIVE: Systemic lupus erythematosus (SLE) is characterized by type I interferon (IFN) signaling and adaptive immune dysregulation. We previously identified hypomethylation of HLA-DRB1 and STAT1 in SLE CD8+ T cells, enabling aberrant IFN-driven HLA-DRB1 expression and expansion of a distinct CD8+ T cell subset. This study characterized CD8+ HLA-DRB1+ T cells in lupus.
METHODS: Peripheral blood CD8+ T cells from 11 SLE patients and 12 healthy controls were analyzed by flow cytometry. Single-cell RNA sequencing and TCR sequencing, with and without IFN-α stimulation, in 6 SLE patients and 6 matched healthy controls assessed transcriptional heterogeneity, exhaustion, senescence, and cytotoxicity.
RESULTS: CD8+ HLA-DRB1+ T cells were enriched within effector memory, CD45RA+ effector memory, and proliferative CD8+ T cells, and were significantly expanded within the effector memory and proliferative compartment in SLE compared to healthy controls. These cells displayed paradoxical features of cytotoxicity, proliferation, exhaustion, and senescence. Compared to healthy controls, lupus CD8+ HLA-DRB1+ T cells exhibited increased exhaustion, reduced cytotoxicity, and impaired antiviral pathways. IFN-α enhanced IFN-γ responses in lupus CD8+ HLA-DRB1+ T cells and exacerbated exhaustion and senescence. Despite upregulation of cytotoxic gene expression, IFN-α reduced CD107a surface mobilization, indicating impaired degranulation. Analysis of lupus nephritis datasets revealed that most kidney-infiltrating CD8+ T cells are HLA-DRB1+. HLA-DRB1 expression on peripheral CD8+ T cells from SLE patients positively correlated with SLEDAI scores.
CONCLUSION: CD8+ HLA-DRB1+ T cells represent a dysfunctional effector memory and proliferative population expanded in SLE. Type I IFN drives this paradoxical state by promoting exhaustion and impaired degranulation.

DOI: https://doi.org/10.1002/art.70292
Front Immunol. 2026 ;17 1895434

Beyond exhaustion: T cell fitness for next generation of immunotherapy for hematological cancer.

Xiaoshuang Kong, Yuanhui Su, Hanxue Zheng, Zuxi Feng, Jianxia Huang, Liansheng Zhang, Lijuan Li.

  T cell-directed immunotherapies have transformed the treatment of hematological malignancies, but durable benefit remains limited by relapse, poor persistence, incomplete immune reconstitution and infection. These outcomes depend not only on target-antigen expression but also on the functional quality of the T cell compartment. In this Review, we define T cell fitness as a multidimensional capacity that includes cellular availability, memory reserve, proliferative competence, cytotoxic function, metabolic resilience, resistance to chronic stimulation and persistence. We distinguish exhaustion, senescence and terminal differentiation as overlapping but non-equivalent states and propose a measurable, modality-specific assessment framework rather than reliance on a single marker. We then compare how these states arise in multiple myeloma, lymphoma, acute lymphoblastic leukemia and acute myeloid leukemia, emphasizing the effects of age, tissue niche, disease burden and prior therapy. We critically appraise evidence from CAR-T cell therapy, bispecific antibodies and checkpoint blockade, including the limitations of predominantly retrospective, correlative and disease-specific datasets. Finally, we translate the fitness framework into clinical questions: when to collect cells, how to select bridging therapy, which biomarkers merit prospective testing, how treatment duration and sequencing may preserve immune competence, and where gene-edited products, CAR-NK cells and metabolic interventions may reduce dependence on compromised autologous T cells. A fitness-based approach may support more precise biomarker development and safer treatment selection, but prospective validation and modality-specific thresholds are still required.

Keywords:  CAR-T cell therapy; T cell fitness; T cell senescence; biomarkers; bispecific antibodies; hematological malignancies; t cell exhaustion; treatment sequencing

DOI:  https://doi.org/10.3389/fimmu.2026.1895434
Cell Biomater. 2026 Jul 21. pii: 100368. [Epub ahead of print]2(7):

Nanoscale artificial antigen-presenting cells reveal metabolic interventions modulate clonal composition of CD8+ T cells.

Joseph Choy, Sydney R Shannon, Yicheng Zhang, Si-Sim Kang, Yining Zhu, Kenneth M Adusei, Shaelyn R Marx, Milan Patel, Benjamin A Biggs, Hai-Quan Mao, Jonathan P Schneck.

  In response to pathogens, CD8+ T cells reprogram their metabolism to fuel a proliferative burst of antigen-specific T cells. Engineering metabolism can augment CD8+ T cell responses, yet mechanistic studies understanding the direct impact of metabolic programming on T cell phenotype and TCR receptor (TCR) repertoire selection remains unknown. Here, using nanoparticle-based artificial antigen presentation cells (aAPCs) as a model of endogenous expansion to stimulate primary murine CD8+ T cells, we show that glutamine antagonism modulates epitope-specific T cell phenotype by upregulating self-renewal markers and serves a new function as a "clonal filter," enriching high-affinity CD8+ T-cell clones. Moreover, the effect of glutamine inhibition skews towards cells with high-affinity TCRs and enhances their ability to kill in vivo. Collectively, these findings introduce metabolic blockade as a rapid, non-genetic strategy to pre-select durable, high-affinity T cells, providing an easily implementable add-on for adoptive cell therapy.

Keywords:  TCR repertoire; aAPC; immunoengineering; immunometabolism; nanomaterials

DOI:  https://doi.org/10.1016/j.celbio.2026.100368
Nat Nanotechnol. 2026 Aug 10.

Oral nano-delivery of a gut microbial metabolite enhances T cell stemness for cancer immunotherapy.

Kai Han, Young Seok Cho, Mariko Takahashi, Xingwu Zhou, Hannah E Dobson, Kim Hutchings, Yuesong Wu, Youngseo Na, Fang Xie, Julia Crowther, Jinmei Wu, Jin Xu, Chuan Lee, Himani Jasewicz, Yujin Kim, Minal Nenwani, Olamide Animasahun, Fulei Wuchu, Anthony Andren, Harrison Wong, Emma Camp, Ziye Wan, Qi Wu, Li Zhang, Cheng Xu, Katherine Dong, Yao Xu, Anna Schwendeman, Grace Y Chen, Yuying Xie, Costas A Lyssiotis, Martin Clasby, Deepak Nagrath, Yu Leo Lei, James J Moon.

Gut microbial metabolites play crucial roles in regulating systemic immunity, but their mechanisms and limited drug-like properties remain unresolved. Here we report an oral nano-formulation that leverages gut microbial metabolites to modulate T cell metabolism and amplify antitumour immunity. Through an in vitro screening of gut microbial metabolites, we identified 3,4-dihydroxybenzoic acid that improved adoptive T cell therapy and enhanced CD8+ T cell stemness by suppressing glycolysis and regulating the Akt-mTORC1-Myc pathway. To harness the potency of 3,4-dihydroxybenzoic acid for systemic cancer immunotherapy, we engineered a 3,4-dihydroxybenzoic acid prodrug nano-emulsion, significantly increasing its oral absorption and half-life. In multiple murine tumour models, the oral nano-emulsion enhanced the expansion of antigen-specific, stem-like CD8+ T cells, sensitizing tumours to anti-PD-1 blockade and exerting robust antitumour efficacy. By integrating nanotechnology with microbial-metabolite-based immunotherapy, this study establishes a mechanistic link between the gut microbiota and T cell immunity, offering a promising approach for cancer immunotherapy.

DOI: https://doi.org/10.1038/s41565-026-02235-9
Front Immunol. 2026 ;17 1781004

Immunosenescence shapes the tumor immune microenvironment and limits PD-1/PD-L1 blockade efficacy in older patients with cancer.

Xiaoyu Niu, Ziwaregul Nur, Wenkang Xie, Yang Sun, Longhao Wang, Yuanyuan Zheng.

  As the global population ages, immunosenescence is emerging as a critical determinant of cancer outcomes in older adults. Although programmed cell death protein 1/protein programmed death-ligand 1 (PD-1/PD-L1) blockade has significantly improved the treatment of multiple malignancies, its efficacy in older patients is highly heterogeneous, and the biological basis for this variability remains incompletely understood. Current evidence indicates that immunosenescence reshapes antitumour immunity through thymic involution, reduced T cell receptor diversity, chronic low-grade inflammation, and expansion of immunosuppressive cell populations, thereby impairing antigen presentation, weakening T cell activation and effector function, promoting terminal T cell exhaustion, and reinforcing suppressive tumour microenvironments. Together, these changes form an important mechanistic basis for the limited benefit of PD-1/PD-L1 blockade in older patients. Meanwhile, potentially targetable processes, including metabolic dysregulation, mitochondrial dysfunction, defective autophagy-mitophagy, redox imbalance, and gut microbiota dysbiosis, are increasingly recognized as modifiable contributors to age-associated resistance to immunotherapy. In this Review, we discuss how immunosenescence remodels antitumour immunity and constrains responses to PD-1/PD-L1 blockade in older patients, and we summarize potential strategies to improve immunotherapeutic efficacy in this population. These insights may inform future mechanistic studies, biomarker discovery, and the development of age-adapted therapeutic strategies.

Keywords:  PD-1/PD-L1 blockade; gut microbiome; immunosenescence; inflammaging; metabolic reprogramming; myeloid-derived suppressor cells

DOI:  https://doi.org/10.3389/fimmu.2026.1781004
Nat Rev Immunol. 2026 Aug 10.

Ferroptosis in T cells: mechanisms, biology and translational opportunities.

Jingshu Song, Qian Wu, Douglas R Green, Fudi Wang, Junxia Min.

Ferroptosis is an iron-dependent form of regulated cell death driven by disrupted iron homeostasis and uncontrolled lipid peroxidation. Various metabolites and enzymes regulate cellular sensitivity to ferroptosis by affecting iron, lipid and redox metabolism. These pathways not only signal ferroptotic cell death but also affect the biology of T cells. The pathways include mechanisms by which iron metabolism regulates T cell activation via transferrin receptor 1-mTOR signalling, mechanisms by which lipid peroxidation drives vulnerability to ferroptosis in tumour-infiltrating CD8+ T cells, and mechanisms by which redox networks are balanced to maintain T cell survival. Here, we highlight the T cell subset-specific effects of ferroptosis-related pathways and ferroptosis susceptibility, and the implications for immunotherapy. We also discuss the emerging therapeutic strategies, including ferroptosis-resistant adoptive T cell therapy and ferroptosis-inducing approaches, that enhance the efficacy of immune checkpoint blockade for cancer treatment. Finally, we propose a framework for precision T cell-based immunotherapies, positioning ferroptosis as a tunable node linking T cell biology to clinical innovations.

DOI: https://doi.org/10.1038/s41577-026-01337-8
Cancer Immunol Res. 2026 Aug 11.

H2AFY2 suppresses exhaustion and enhances antitumor activity of CAR-T cells through transcriptional and epigenetic modifications.

Congcong Li, Qian Wang, Qitai Zhao, Qianfeng Cai, Siyang Wang, Yu Ping, Xuan Zhao, Xinfeng Chen, Chunyi Shen, Haiming Qin, Guohui Qin, Jiqi Shan, Zhen Zhang, Yi Zhang.

Chimeric antigen receptor (CAR)-T cell exhaustion constitutes a critical barrier to sustained antitumor efficacy. Through transcriptomic analysis of CAR-T cells from patients with lymphoma, we identified the histone variant macroH2A2 (H2AFY2) as a critical regulator of T cell exhaustion-a finding consistently observed across multiple tumor models. In mice, T cell-specific knockout of H2afy2 promots the expression of inhibitory receptors by activating the nuclear factor kappa-B pathway and increasing chromatin accessibility at the Rela locus, as demonstrated by single-cell RNA-sequencing and assay for transposase-accessible chromatin sequencing. H2AFY2 overexpression in CD8+ T cells induces prominent epigenetic remodeling, characterized by increased H3K27me3 enrichment. Mechanistically, H3K27me3 enrichment at the Rela locus suppresses p65-mediated transcriptional activation, leading to downregulation of the exhaustion-associated transcription factor TOX and consequent amelioration of T cell exhaustion. Furthermore, H2AFY2-overexpressing CAR-T cells sustain lower levels of inhibitory receptors and suppressed tumor recurrence. Collectively, these results define an epigenetic pathway through which H2AFY2 counteracts T cell exhaustion and support the therapeutic potential of H2AFY2-engineered CAR-T cells across tumor types.

DOI: https://doi.org/10.1158/2326-6066.CIR-25-1334
Nat Aging. 2026 Aug 14.

Exercise slows ovarian aging.

DOI: https://doi.org/10.1038/s43587-026-01176-1
Cell Rep Med. 2026 Aug 12. pii: S2666-3791(26)00401-5. [Epub ahead of print] 102984

Cofilin1-driven cytoskeletal remodeling modulates pan-cancer CD8+ T cell immunotherapy responses.

Le Li, Zheng Chao, Junbo Li, Chao Ma, Ren Zhang, Jie Zhang, Jing Luo, David Horne, Yanan Wang, Xiaodong Hao, Chunyu Zhang, Xiangdong Guo, Sheng Ma, Hao Peng, Zhiquan Hu, Bertram Yuh, Gong-Hong Wei, Xiangping Yang, Qiang Zhang, Baojun Wang, Xu Zhang, Zheng Liu, Zhihong Zhang, Peixiang Lan, Zhihua Wang.

  Tumor immunotherapies enhance CD8+ T cell function, yet heterogeneous responses in "cold" and "hot" tumors remain a challenge. Although biomechanical cues modulate T cell cytotoxicity, strategies to harness these forces for broad antitumor potentiation remain elusive. Here, integrating pan-cancer single-cell RNA sequencing data, we identify cofilin 1 (CFL1) as a determinant of immunotherapy response. CFL1 overexpression synergizes with CD8+ T cell-targeted immunotherapy across tumor types, driving intratumoral T cell expansion while rendering tumors physically vulnerable. Mechanistically, CFL1 hyperactivation induces F-actin bundling and actin rod accumulation, elevating cytoskeletal tension to facilitate immunological synapse formation. Conversely, CFL1 inactivation through phosphorylation or our newly identified lactylation correlates with poor outcomes. Combination therapy using adeno-associated virus delivering constitutively active CFL1 and PD-1 blockade achieves near-complete tumor eradication. Together, our findings position CFL1 as a biomechanical checkpoint governing tumor vulnerability to CD8+ T cells through immunological synapse licensing, offering a strategy to overcome immunotherapy resistance.

Keywords:  CD8(+) T cells; CFL1; PD-1 blockade; actin remodeling; biomechanical checkpoint; cofilin 1; immunological synapse; immunotherapy resistance; lactylation; single-cell RNA sequencing; tumor microenvironment

DOI:  https://doi.org/10.1016/j.xcrm.2026.102984
Nat Med. 2026 Aug 10.

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

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

Chimeric antigen receptor (CAR) T cell therapy induces durable remissions in lymphoid malignancies, yet the extent and biology of long-term CAR T cell persistence in B cell lymphoma remain unclear. Here we report the persistence and characteristics of 4-1BB-costimulated anti-CD19 CAR T cells (CART19) up to 10 years after infusion in 38 patients with non-Hodgkin lymphoma. Beyond year five, the CAR19 transgene was detectable in five of eight long-term responders (7.0-10.1 years), with three patients maintaining B cell aplasia, which is consistent with sustained functional activity. In one patient with a progression-free survival of 10.1 years, CART19 cells comprised 1.2% of circulating T cells 9.3 years after infusion. Long-term persisting CART19 cells exhibited a predominant double-negative (CD4-CD8-), effector-memory-like phenotype associated with increased aerobic metabolism and T cell activation programs. Longitudinal profiling revealed a progressive transition from CD8+ to double-negative CAR T cells over time. Persisting CART19 shared transcriptional features with long-term CAR T cells described in acute and chronic leukemias. T cell receptor sequencing demonstrated oligoclonal persistence at 9.3 years, with a dominant clone (70% of CART19 cells) already detectable at low frequency (<0.1%) at day 14. Lentiviral integration-site analysis identified a predominant integration within PACS1 without evidence of known drivers of CAR T cell expansion. These findings demonstrate that CART19 cells can persist for more than 10 years in lymphoma and identify phenotypic, transcriptional and clonal features associated with exceptionally long-term persistence. ClinicalTrials.gov registration: NCT02030834.

DOI: https://doi.org/10.1038/s41591-026-04578-1
Nature. 2026 Aug 12.

In vivo genome-wide CRISPR screens of human T cells in solid tumours.

Qi Liu, Peixin Amy Chen, Esha Urs, Shimin Zhang, Maya M Arce, Charlotte H Wang, Jun Yan, Vinh Q Nguyen, Zhongmei Li, Jin Seo, Nupura Kale, Fanglue Peng, Yikai Luo, Laine Goudy, Taylor N LaFlam, Haixia Zhong, Chandrima Modak, Emma Dann, Jae Hyung Jung, Amanda Kirane, Allison Betof Warner, Boi Bryant Quach, Zinaida Good, Brian R Shy, Eric Shifrut, Sagar P Bapat, Greg M Allen, Justin Eyquem, Katherine Fuh, Stacie E Dodgson, Jason G Cyster, Alexander Marson, Julia Carnevale.

Large-scale CRISPR screening in human T cells holds significant promise for identifying genetic modifications that enhance cellular immunotherapy. Yet, many regulators of T cell performance in solid tumours are not revealed in vitro1,2. In vivo screening in tumour-bearing mice is more physiological but has been limited by low intratumoural T cell recovery. Here we developed an in vivo model that efficiently recovers human T cells from solid tumours, permitting genome-wide CRISPR screens with few mice. Tumour-infiltrating T cells from this model exhibit hallmarks of dysfunction compared with splenic T cells, creating an ideal screening context. We performed two genome-wide CRISPR knockout screens to identify regulators of intratumoural T cell abundance and effector function. The abundance screen revealed the P2RY8-Gα13 GPCR signalling axis as a negative regulator of T cell tumour infiltration. The effector function screen identified GNAS as a key driver of T cell dysfunction in tumours, whose product, Gαs, acts as a convergent node downstream of multiple GPCRs sensing distinct suppressive ligands. Knockout of GNAS rendered T cells resistant to multiple suppressive cues and significantly improved efficacy across diverse solid tumour models in chimeric antigen receptor (CAR) and T cell receptor (TCR) systems. Combinatorial knockout of P2RY8-GNAS further enhanced tumour control, demonstrating that complementary in vivo screens can identify orthogonal targets whose combined editing improves therapeutic potency. This flexible, scalable platform can be adapted for systematic discovery of genetic strategies to improve solid tumour T cell therapies.

DOI: https://doi.org/10.1038/s41586-026-10906-9
J Biomed Phys Eng. 2026 Aug;16(4): 343-352

Immune Cell Dysregulation in Hindlimb Unloading Mouse Model: Implications for Space Applications.

Sadegh Masoudi, Mehdi Kalani, Ali Alavianmehr, Mohammad Amin Mosleh-Shirazi, Seyed Mohammad Javad Mortazavi, Shirin Farjadian.

   Background: Hindlimb unloading (HU) mice is a ground-based model that simulates the effects of microgravity. Since microgravity significantly affects the immune system, understanding immune cell function under these conditions is crucial for developing strategies to protect astronauts from infections and malignancies during long space missions.
Objective: To evaluate how microgravity affects neutrophils and T cells as the key components of innate and adaptive immunity, the activity of these cells in HU mice was compared with untreated control mice.
Material and Methods: In this experimental study, 10 HU male BALB/c mice and 10 untreated control mice were included. Neutrophil-to-lymphocyte ratio (NLR) was evaluated and neutrophil function was assessed using the DHR assay. T cell proliferation was evaluated using the CFSE-dilution assay. IL-4 and IFN-ɣ production by T cell subsets was determined by intracellular cytokine staining with flow cytometry.
Results: The capacity for reactive oxygen species (ROS) production in neutrophils did not differ between HU mice and control mice however, NLR was higher in HU mice. The proliferation of both CD4+ and CD8+ T cells was slightly reduced in HU mice. More notably, IL-4 production by CD4+ T cells and IFN-ɣ production by both CD4+ and CD8+ T cells were significantly decreased in HU mice.
Conclusion: Hindlimb unloading, simulating microgravity, impairs immune cell functions by reducing cytokine production and T cell proliferation. The increased NLR in HU mice could indicate a heightened inflammatory response. These insights are essential for advancing space biology and medicine, ensuring astronaut health during prolonged space travel.

Keywords:   Astronauts; Cytokines; Hindlimb Unloading; Immune System; Microgravity; Neutrophils; Space; T-Lymphocytes

DOI:  https://doi.org/10.31661/jbpe.v0i0.2406-1776
Int Immunol. 2026 Aug 13. pii: dxag042. [Epub ahead of print]

Healthy ageing: The struggle for maintaining T cells young.

David Frieser, Noemie Gensous, Victor Appay.

  Recent pandemics, the increasing incidence of cancer and an inversion of the age pyramid towards an older society fuels the need for an in depth understanding of the field of inflammaging and changes in the immune system, in particular of the T cell compartment, which is the most impacted during ageing. Starting from quantitative and qualitative changes that occur in T cells during ageing, this review discusses pathophysiological factors that lead to or accelerate these processes. Furthermore, it highlights emerging strategies aimed at overcoming age-related T-cell dysfunction, with a focus on recent advances in the field. Together, these insights may contribute to a better understanding of how healthy ageing can be promoted through the preservation or rejuvenation of T-cell "youthfulness", which is central for healthy ageing.

Keywords:  co-morbidities; dysfunction; rejuvenation

DOI:  https://doi.org/10.1093/intimm/dxag042
J Immunol. 2026 Aug 04. pii: vkag216. [Epub ahead of print]215(8):

TRECing down the source: naive and memory T cell generation in dirty mice and men.

Lyanne Y Derksen, Elena S de Dios Panal, Tamara M J Brouwers, Erdem Sanal, Anouk B Schuren, Liset Westera, Sara P H van den Berg, Debbie van Baarle, Rob J de Boer, Stephan P Rosshart, Kiki Tesselaar, José A M Borghans.

  Healthy aging relies on the maintenance of a diverse T cell pool. This diversity is ensured by balancing thymic output, differentiation of naive into memory T cells, T cell proliferation and cell death. For naive T cells, the balance of these processes differs between standard laboratory mice and humans. This may be a true species difference or, alternatively, result from the vastly different amounts of antigens to which standard laboratory mice and humans are exposed. Using wildlings, that is, laboratory mice born to wild mice, we studied the impact of antigen-exposure through a natural microbiome on naive and memory T cell maintenance. We found that standard laboratory mice and wildlings maintain their naive T cell pools similarly: naive T cells rarely divide and are replaced by thymic emigrants at similar rates. The daily replacement rate of memory T cells, on the other hand, is about 50% faster in wildlings than in standard laboratory mice. In both types of mice, about 20% of newly produced memory T cells originate from recruitment of naive T cells, while the remaining cells are produced by their clonal expansion and by self-renewal. In older mice, this drops to 5%. In humans, a similarly large fraction of memory cells originate from recruitment of naive T cells. Unlike in mice, most naive T cells in human adults are formed by naive T cell proliferation. Thus, while both types of mice mimic the maintenance mechanisms of the memory T cell pool in humans, even wildlings fall short as a model for human naive T cell maintenance.

Keywords:  T cells; cell proliferation; memory; thymus

DOI:  https://doi.org/10.1093/jimmun/vkag216
Cells. 2026 Aug 03. pii: 1404. [Epub ahead of print]15(15):

Mitochondrial Dysfunction as a Driver of Meta-Inflammation in Aging: The Emerging Role of PDK4 in Bioenergetic Reprogramming and Inflammatory Amplification.

Md Riad Chowdhury, Gui-Hwa Jeong, In-Kyu Lee.

  Aging is accompanied by a progressive decline in mitochondrial quality, bioenergetic flexibility, and stress resilience. Aging mitochondria are increasingly recognized as active inflammatory signaling platforms rather than passive targets of cellular damage. Excess mtROS, leaked mtDNA, defective mitophagy, altered NAD+ metabolism, and impaired pyruvate oxidation together create a cellular environment that favors persistent inflammatory activation. These signals engage NF-κB, NLRP3 inflammasome, cGAS-STING, and SASP pathways, allowing mitochondrial stress to spread from organelle dysfunction to tissue-level inflammation. Within this framework, pyruvate dehydrogenase kinase 4 (PDK4) is of particular interest because it directly controls mitochondrial pyruvate entry through inhibition of the pyruvate dehydrogenase complex. By phosphorylating and inhibiting the pyruvate dehydrogenase complex, PDK4 limits mitochondrial pyruvate oxidation and favors lactate accumulation, fatty acid utilization, and redox-inflammatory signaling. Recent work in senescent cells links PDK4-dependent lactate accumulation to NOX1-derived ROS and SASP activity, suggesting a direct route by which altered fuel handling may reinforce inflammation. Here, we review mitochondrial dysfunction as the organizing principle of age-associated meta-inflammation, discuss PDK4 as a central metabolic checkpoint, examine tissue-specific consequences in muscle, adipose tissue, brain, and kidney, and evaluate therapeutic strategies aimed at restoring mitochondrial function to suppress chronic inflammation and preserve healthspan.

Keywords:  NLRP3; PDK4; SASP; aging; inflammaging; meta-inflammation; mitochondrial dysfunction; mitophagy; mtROS; pyruvate dehydrogenase

DOI:  https://doi.org/10.3390/cells15151404
Int J Mol Sci. 2026 Aug 01. pii: 6918. [Epub ahead of print]27(15):

Advances in miRNA-Mediated Bidirectional Crosstalk and Immune Evasion Mechanisms Between Lung Cancer Cells and CD8+ T Cells.

Xinyi Zhou, Tao Pang, Zhe Ge.

  Lung cancer ranks first in both incidence and mortality among all malignancies, and tumor microenvironment (TME)-induced CD8+ T cell exhaustion is a critical factor driving immune evasion and compromising the efficacy of immunotherapy. MicroRNAs (miRNAs), as key post-transcriptional regulators, shuttle between lung cancer cells and CD8+ T cells via extracellular vesicles (EVs), serving as critical communication hubs that reshape the TME. This review systematically synthesizes recent literature to summarize the regulatory patterns of miRNAs on functions of lung cancer cells and CD8+ T cells, and dissect the molecular mechanisms underlying miRNA-mediated bidirectional crosstalk between these two cell types. This review focuses on the dual-pronged immune evasion strategy employed by lung cancer cells to counteract CD8+ T cells. On the one hand, lung cancer cells aberrantly express endogenous miRNAs, such as miR-20a, miR-149-5p, and miR-326, to remodel their surface ligands and establish immune camouflage. On the other hand, they actively secrete EVs enriched in specific miRNAs, including miR-7108-3p, miR-651-5p, and miR-24-3p, which directly suppress CD8+ T cell function. Furthermore, lung cancer cells secrete additional miRNAs, notably miR-6794-5p, miR-708-5p, and miR-1234-3p, to reprogram other TME components, namely tumor-associated macrophages (TAMs), natural killer (NK) cells, and myeloid-derived suppressor cells (MDSCs). These reprogrammed cells, in turn, indirectly attenuate CD8+ T cells through a relay-like mechanism via immunosuppressive cytokines or surface checkpoint molecules produced by these cells. In addition, competing endogenous RNA (ceRNA) networks formed by long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) in lung cancer cells regulate miRNA activity at multiple levels, further impairing the immune effector functions of CD8+ T cells. Conversely, activated CD8+ T cells also secrete miRNA-containing EVs, which deliver these miRNAs to tumor cells, thereby inhibiting tumor progression. Elucidation of this miRNA-based bidirectional communication network will not only advance our understanding of immune evasion mechanisms in lung cancer but also provide novel insights into cell-free immunotherapeutic approaches based on CD8+ T cell-derived vesicles.

Keywords:  CD8+ T cells; extracellular vesicles; immune evasion; lung cancer; miRNAs

DOI:  https://doi.org/10.3390/ijms27156918
J Virol. 2026 Aug 14. e0005126

Enhancing HIV-1-specific CAR-T cell functional activity by treatment with a novel cytokine-based scaffold with IL-15 superagonist and TGF-β-neutralizing activity.

Sara Lamcaj, Erin Cole, Christopher Hiner, Marta Santos Bravo, Jian Hua Zheng, Niraj Shrestha, Gregory Sowd, Ying Xiong, Zhongyu Zhu, Boro Dropulic, Hing C Wong, Harris Goldstein.

  Chimeric antigen receptor T cell (CAR-T cell) therapy targeting and eliminating HIV-infected cells offers a promising approach to provide people living with HIV (PLWH) with a functional cure by preventing the recurrence of viremia caused by reactivation of latent HIV-1-infected cells. We previously described a bispecific CAR-T cell targeting two highly conserved gp120 epitopes (duoCAR-T cell) with potent anti-HIV-1 activity that is currently in clinical trials. However, elevated levels of transforming growth factor β (TGF-β) present in many PLWH may hinder the activity of both infused HIV-1-specific CAR-T cells, such as duoCAR-T cells and endogenous HIV-1-specific CD8+ T cells, thereby limiting their effectiveness to achieve a functional HIV-1 cure. We hypothesized that HCW9218, a novel bifunctional immunomodulatory protein composed of TGF-βRII and IL-15/IL-15Rα, would enhance anti-HIV-1 immunity by TGF-βRII binding and neutralizing TGF-β, while IL-15/IL-15Rα would stimulate effector cells and reactivate latent HIV-1-infected cells. We used duoCAR-T cells generated from CD4+ and CD8+ T cells from people without HIV (PWoH) and PLWH donors to demonstrate the in vitro capacity of HCW9218 to block TGF-β activity, and enhance duoCAR-T cell proliferation, cytotoxicity, and anti-HIV-1 activity. HCW9218 also functioned as a latency-reversing agent, stimulating HIV-1 production by CD4+ T cells from ART-suppressed PLWH. Production of HIV-1 by HCW9218-treated CD4+ T cells from ART-suppressed PLWH donors was suppressed by co-culture with autologous duoCAR-T cells. Together, these findings highlight the potential of HCW9218 to augment T cell and CAR-T-based therapies and contribute to strategies aimed at achieving a functional cure for HIV-1.IMPORTANCEThe persistence of HIV-1 reservoirs remains the primary barrier to an HIV-1 cure because antiretroviral therapy (ART) suppresses viral replication but does not eliminate latent HIV-1-infected cells. Treatment with anti-HIV-1 duoCAR-T cells is a potential strategy to target and eliminate HIV-1-infected cells, but their activity may be impaired by the immunosuppressive environment in lymphoid tissues of people living with HIV (PLWH). Transforming growth factor β (TGF-β), a pleiotropic cytokine elevated in PLWH, is a key mediator of this immunosuppression. Here, we show that HCW9218, a bifunctional fusion protein with TGF-β-neutralizing activity and IL-15 superagonist activity, preserves duoCAR-T cell function in the presence of TGF-β and reactivates HIV-1 production by latent HIV-1-infected cells in ART-suppressed CD4+ T cells from PLWH. These findings highlight HCW9218 as a unique dual-function immunotherapy that may enhance the efficacy of duoCAR-T cells while facilitating clearance of the HIV reservoir.

Keywords:  CAR-T cells; DuoCAR-T cells; HIV cure strategy; HIV-1; IL-15; TGF-β; capsid; gp120/gp41; immune modulation; immune suppression; immunotherapy; p24

DOI:  https://doi.org/10.1128/jvi.00051-26
Cells. 2026 Aug 05. pii: 1422. [Epub ahead of print]15(15):

Metabolic Bottlenecks and Opportunities: Reshaping the Tumor Microenvironment for Cancer Immunotherapy.

Jianing Zhang, Zimei Tang, Yiran Wang, Jiaying Wan, Yajing Zhou, Jiexiao Li, Jie Ming.

  Metabolic reprogramming constitutes a fundamental hallmark of malignancy, orchestrating a hostile tumor microenvironment (TME) that severely compromises anti-tumor immunity. Despite the transformative success of immune checkpoint blockade and adoptive cell therapies, clinical efficacy is frequently curtailed by the metabolic barriers imposed by the TME. This review systematically elucidates the complex metabolic interplay between tumor cells and infiltrating T cells, highlighting two defining mechanisms driving immune evasion: the competitive sequestration of essential nutrients and the accumulation of immunosuppressive oncometabolites. We detail how the depletion of glucose and critical amino acids (glutamine, arginine, methionine, etc.) imposes a state of "metabolic siege" on T cells, impairing their bioenergetics and effector functions. Concurrently, we explore how accumulated metabolites-such as lactate, succinate, 2-hydroxyglutarate, kynurenine, and lipids-function as non-canonical signaling molecules to subvert immune surveillance via epigenetic remodeling and oxidative stress. Furthermore, we synthesize emerging therapeutic strategies designed to dismantle this metabolic barrier, including targeting metabolic enzymes (IDO1 and FASN) and transporters, repurposing metabolic waste, and genetically engineering T cells with enhanced metabolic fitness and resilience. By integrating the latest insights into the "metabolism-epigenetics-immunity" axis, this review provides a theoretical foundation for developing next-generation immunotherapies that target metabolic vulnerabilities to overcome resistance in cancer treatment.

Keywords:  T cell exhaustion; epigenetic remodeling; immunotherapy; metabolic reprogramming; oncometabolites; tumor microenvironment

DOI:  https://doi.org/10.3390/cells15151422
Int Immunopharmacol. 2026 Aug 13. pii: S1567-5769(26)01129-X. [Epub ahead of print]188 117283

Cellular and molecular networks governing precursor exhausted CD8+ T cells in chronic liver disease: Implications for immunotherapy.

Ruoyu Gao, Ziyan Pan, Wen Zhang, Hong Li, Caihong Wang, Wenyue Wu, Haodong Ma, Zhi Chen, Qiushuang Ji, Jingjie Zhao, Hong You, Wei Chen.

  Chronic liver diseases of diverse etiologies, along with primary liver cancers, represent major global health burdens with limited curative options. CD8+ T-cell exhaustion is a central barrier to effective immune control in these pathological settings. However, precursor exhausted CD8+ T cells (Tpex), a stem-like subset with self-renewal and proliferative potential, retain the ability to generate effector-like progeny and sustain long-term immune surveillance. In this review, we first provide a definition of Tpex to distinguish them from other related CD8+ T-cell states, including terminally exhausted, effector-like exhausted, tissue-resident memory, and conventional memory T cells, in chronic liver diseases and liver cancer. We then summarize current knowledge on the fundamental biology, etiological dynamics, and therapeutic relevance of Tpex in both benign and malignant liver diseases. Specifically, we examine the transcriptional, metabolic, and microenvironmental networks that govern Tpex fate, with particular emphasis on how distinct etiologies, including viral hepatitis, metabolic dysfunction-associated steatotic liver disease, and autoimmune hepatitis, differentially shape Tpex abundance and functional state. In chronic viral hepatitis, Tpex dynamics are critically influenced by viral persistence, metabolic context, and co-infections, which in turn have direct implications for the responsiveness to immune checkpoint blockade. In hepatocellular carcinoma and intrahepatic cholangiocarcinoma, Tpex signatures are not only correlated with clinical outcomes but also modulated by tumor genetic landscapes and the composition of the immune microenvironment. Finally, we highlight emerging Tpex-targeted therapeutic strategies, including co-stimulatory agonists, metabolic reprogramming, vaccines, CAR-T cell engineering, and gut microbiota modulation, as promising avenues to overcome immunotherapy resistance.

Keywords:  Chronic liver disease; Hepatocellular carcinoma; Immune checkpoint blockade; Immunotherapy; Intrahepatic cholangiocarcinoma; Precursor exhausted CD8 (+) T cells

DOI:  https://doi.org/10.1016/j.intimp.2026.117283
Nanoscale Adv. 2026 Aug 04.

Engineering CXCL10-enriched macrophage-derived extracellular vesicles for T cell recruitment and immune remodeling in pancreatic cancer.

Shiyao Yin, Ming Li, Yanan Li.

CXCL10-enriched macrophage-derived extracellular vesicles were engineered to reprogram the pancreatic tumor microenvironment. CXCL@MEVs enabled bioactive CXCL10 presentation, drove M2-to-M1 macrophage repolarization, recruited and activated CD8+ T cells, and suppressed PANC02 tumor growth with minimal systemic toxicity.

DOI: https://doi.org/10.1039/d6na00396f
Cells. 2026 Aug 03. pii: 1407. [Epub ahead of print]15(15):

Cblb Gene Editing in T Cells Sustains Expansion and Immunogenic CAR T Tumor Killing Under Chronic Antigenic Stimulation.

Daniel Schreiber, Sebastian Peer, Christina Lutz-Nicoladoni, Jiří Koutník, Viktor Lang, Viana Wille, Isabel Hölzl, Dominik Humer, Nino Tokic, Dorothee Freimark, Mario Kuttke, Alexander Dohnal, Romana Gugenberger, Thomas Gruber, Nikolaus Thuille, Dominik Wolf, Victoria Klepsch, Kerstin Siegmund, Gottfried Baier.

  CBL-B is an intracellular E3 ubiquitin ligase that acts as a T cell checkpoint by raising activation thresholds and limiting effector function. Here, genetic targeting of CBL-B enhances the performance of adoptively transferred T cells and CAR T cells under tumor microenvironment-like stress. In fully immunocompetent mouse models, Cblb deficiency or transient Cblb silencing improves control of MC-38 colon carcinoma and autochthonous mammary tumors, demonstrating that CBL-B restrains anti-tumor immunity. Cblb-deficient T cells show enhanced expansion and effector/effector-memory differentiation during an in vivo mixed lymphocyte reaction, confirming a cell-intrinsic brake function of CBL-B during sustained antigenic challenge. In a syngeneic Panc02-EpCAM model, Cblb-deficient anti-EpCAM CAR T cells show superior tumor control, enhanced infiltration, prolonged survival, and preserved effector function despite chronic antigen exposure and TGF-β. Mechanistically, Cblb targeting maintains granzyme B and IFN-γ production and is associated in vitro with increased GSDME-linked pyroptotic tumor cell death, consistent with features of immunogenic cell death. These findings extend previous CBL-B CAR T work from lymphocyte-deficient to immunocompetent settings and support CBL-B inhibition as a strategy to engineer CAR T cells that resist suppressive tumor microenvironments while promoting a more inflammatory mode of tumor killing.

Keywords:  CAR T cells; Cblb gene; chronic antigenic stimulation; immunogenic cell death; solid tumor microenvironment

DOI:  https://doi.org/10.3390/cells15151407
Nat Immunol. 2026 Aug 14.

TIF1γ holds the line against regulatory T cell plasticity.

Fotini Gounari, Khashayarsha Khazaie.

DOI: https://doi.org/10.1038/s41590-026-02620-5
Sci Rep. 2026 08 08. pii: 24539. [Epub ahead of print]16(1):

mRNA-based immunotherapy improves the efficacy of adoptively transferred TCR transgenic T cells in a murine solid tumour model.

Janna Krueger, Janne J Ruotsalainen, Johannes Lutz, Regina Heidenreich.

  Adoptive T cell therapy (ACT) has shown remarkable clinical success in treating haematological malignancies; however, its efficacy against solid tumours remains limited. This is largely due to poor persistence and functionality of transferred T cells, restricted tumour infiltration, and the presence of an immunosuppressive tumour microenvironment. Here, using the MC38-OVA murine tumour model, we tested whether combining Transgenic T cell receptor (TCRtg) T cell therapy with an adjunctive mRNA-based immunotherapy could address these challenges and drive effective and long-lasting anti-tumour response. Tumour-bearing mice were treated with different numbers of in vivo-activated, ovalbumin (OVA)-specific TCRtg CD8+ T cells harvested from OT-I mice, either alone or in combination with lipid nanoparticle (LNP)-encapsulated mRNA encoding OVA. Tumour progression was monitored, and analyses were performed to assess survival, T cell expansion, phenotype, infiltration, and effector function. The combination therapy of a low dose of TCRtg T cells and mRNA immunotherapy led to robust and durable anti-tumour responses, significantly improving survival compared to monotherapies. Notably, transferred TCRtg T cells expanded only following mRNA immunotherapy, and circulating TCRtg T cells exhibited a memory precursor and effector memory phenotype. These cells infiltrated tumours effectively and displayed more potent cytotoxic activity, resulting in regression of large tumours-even without prior lymphodepletion. Overall, our findings demonstrate that mRNA immunotherapy can substantially enhance the efficacy of TCRtg T cell therapy in a solid tumour model. This combinatorial approach holds promise for overcoming key limitations of ACT by boosting T cell expansion, persistence, infiltration, and functional capacity within the tumour microenvironment.

Keywords:  Adoptive T cell therapy—ACT; Cancer immunotherapy; Cancer vaccine; Immunotherapy; Transgenic T cell receptor (TCR); mRNA

DOI:  https://doi.org/10.1038/s41598-026-65120-4
Mol Ther Oncol. 2026 Sep 17. 34(3): 201293

Rethinking lymphodepleting preconditioning in adoptive T cell therapy for durable tumor control.

Diego Figueroa, Vincenzo Borgna, Alvaro Lladser.

DOI: https://doi.org/10.1016/j.omton.2026.201293
Proc Natl Acad Sci U S A. 2026 08 18. 123(33): e2528104123

Therapeutic remodeling of the tuberculosis granuloma with 1-methyl-D-tryptophan enhances CD8+ T cell-macrophage interactions.

Erin F McCaffrey, Alea C Delmastro, Bindu Singh, Annu Devi, Caden W Munson, Priyanka, Nadia A Golden, Shabaana A Khader, Michael Angelo, Deepak Kaushal, Smriti Mehra.

  Granulomas, the hallmark of tuberculosis (TB) disease, can both restrict Mycobacterium tuberculosis (Mtb) dissemination and impede its clearance. Recent studies indicate that indoleamine 2,3-dioxygenase (IDO1), an immunosuppressive metabolic enzyme, limits infiltration of activated T cells and can contribute to TB disease progression. Treatment with 1-methyl-D-tryptophan (D-1MT), a small molecule inhibitor that restores mTOR signaling, has been shown to reduce IDO1 activity and improve immune responses in Mtb-infected rhesus macaques. Here, we investigated the impact of D-1MT treatment on TB granuloma architecture using 30-plex high-dimensional issue imaging in rhesus macaques. By spatially mapping 13 distinct cell populations, we found D-1MT treatment corresponded with significantly increased infiltration CD8+ T cells into granulomas compared to untreated controls. Notably, these CD8+ T cells expressed markers of cell proliferation and cytotoxicity. D-1MT enhanced CD8+ T cell infiltration throughout the granuloma, with particularly pronounced effects in the myeloid core, where we observed significantly enhanced spatial interactions between macrophages and CD8+ T cells, but not CD4+ T cells. Our results demonstrate that: i) effective intragranulomatous Mtb control is associated with the close spatial proximity between CD8+ T cells and macrophages, a feature less abundant in uncontrolled pulmonary TB; ii) IDO1 induction blocks CD8+ T cell infiltration and reduces T cell activation and proliferation; and iii) therapeutic strategies, including D-1MT, that improve intragranulomatous killing hold strong translational potential.

Keywords:  Mycobacterium tuberculosis; granuloma; macaque; multiplexed imaging

DOI:  https://doi.org/10.1073/pnas.2528104123
Adv Sci (Weinh). 2026 Aug 13. e76829

Adaptation of Echinococcus Multilocularis to Oxidative Stress Depends on EmPDK-Mediated Metabolic Reprogramming.

Huijuan Wang, Zhijian Xu, Ye Tian, Yao Zhang, Zhe Cheng, Yanhai Wang.

  Alveolar echinococcosis (AE), a lethal disease caused by the parasite Echinococcus multilocularis, is characterized by tumor-like growths in a host-derived oxidative microenvironment. The mechanisms that enable the parasite to adapt its central carbon metabolism to the host's oxidative microenvironment remain poorly understood. Here, we report that oxidative stress serves as a key environmental cue that induces a profound metabolic rewiring. We identified pyruvate dehydrogenase kinase (EmPDK) as the central regulator governing this metabolic adjustment, favoring glycolysis and lactate production over oxidative phosphorylation (OXPHOS). Suppressing EmPDK activity enhances oxidative metabolism and impairs metacestode proliferation, whereas augmenting its function (via H2O2-induced upregulation) promotes glycolysis and growth. Reactive oxygen species (ROS) drive this metabolic reprogramming through the transcription factor EmHIF1α, forming an axis of ROS/EmHIF1α/EmPDK that modulates parasite metabolic plasticity. Our findings define EmPDK as a critical mediator of oxidative stress adaptation in E. multilocularis and support its further exploration as a candidate target for AE intervention.

Keywords:  Echinococcus multilocularis; metabolic reprogramming; oxidative stress; pyruvate dehydrogenase kinase

DOI:  https://doi.org/10.1002/advs.76829
Cells. 2026 Jul 28. pii: 1357. [Epub ahead of print]15(15):

Metabolic Reprogramming at the Tumor-Immune Interface in Hepatocellular Carcinoma.

Weiming Zhao, Ping Li.

  Hepatocellular carcinoma (HCC) arises predominantly in chronic liver disease with a uniquely tolerogenic microenvironment. Immune checkpoint inhibitors (ICIs) have improved the prognosis of advanced HCC, yet most patients exhibit low response rates or therapeutic resistance due to the highly immunosuppressive tumor microenvironment. Metabolic reprogramming is not only a core hallmark of HCC but also a key regulatory axis connecting tumor cells and the immune system. HCC cells exhibit pronounced Warburg glycolysis, upregulated glutaminolysis, aberrant lipid storage and oxidation, enhanced ketone metabolism, and altered polyamine flux. These metabolic alterations lead to nutrient competition, lactate accumulation, amino acid depletion, and oncometabolite signaling, resulting in T cell exhaustion, macrophage polarization, T cell expansion, and impaired dendritic cell function, thereby influencing tumor progression, immune escape, and therapeutic resistance. Targeting metabolic-immune crosstalk represents a promising strategy for reversing immunosuppression and enhancing the efficacy of immunotherapy. In this review, we systematically summarize the core patterns of metabolic reprogramming in HCC, dissect the molecular mechanisms of metabolic crosstalk at the tumor-immune interface, and discuss the role of immunometabolic remodeling in therapeutic resistance. This review aims to provide a comprehensive theoretical basis and new research directions for improving the efficacy of HCC treatment by targeting the metabolic-immune regulatory axis.

Keywords:  hepatocellular carcinoma; immune; interface; metabolic reprogramming

DOI:  https://doi.org/10.3390/cells15151357
Blood. 2026 Aug 04. pii: blood.2026033417. [Epub ahead of print]

Boosting anti-leukemia cytotoxicity of CD4 and CD8 T cells through combined inhibition of MEK and HDAC.

Meher Bolisetti Gayatri, Bei Jia, Anthony J Veltri, Vysakh Anandan, Maoshuo Yang, Jing Li, Kenneth Man Hei Chan, Sophie Verbeke, Jiangchen Yao, Sarah E Granozio, Yun Jiang, Esra'a Keewan, Jacqueline Ann Cook, Xiaolan Zhu, Erik A Ranheim, Zhe Wang, Chih-Hsing Chou, Kalyan V Nadiminti, H Leighton Grimes, Marulasiddappa Suresh, Hong Zheng, Xiaona You, Jing Zhang.

Acute myeloid leukemia (AML) is an aggressive blood cancer with a 5-year overall survival rate of ~30%. Although immunotherapies engaging T cells demonstrate remarkable success in treating many solid tumors and blood cancers, they show little to no efficacy in treating AML. Therefore, immunotherapies are traditionally underappreciated and underdeveloped in AML. Through a drug re-purpose screen, we identified and validated that combined MEK and HDAC inhibitions via trametinib and quisinostat (TQ) potently inhibited the growth of mouse and human NRAS;ASXL1-AML (NA-AML), MLLr, and NPM1 mutated AML cells in vitro. In NA-AML mice, TQ drastically slowed down AML progression and prolonged their survival. The survival benefits of TQ largely relied on T cell functions. We show that TQ synergized to downregulate immune checkpoint ligands and upregulate STAT1- and CIITA-mediated expression of MHC-I and MHC-II in NA-AML cells. In addition, TQ treatment significantly reprogrammed transcriptome and epigenetic landscape of T cells, activated STAT1 signaling, and upregulated genes and pathways promoting activation, survival, and cytotoxicity of CD4 and CD8 T cells. A cytotoxic cluster was thus expanded in central memory and effector memory T cells in TQ-treated NA-AML mice. More importantly, TQ directly acted on AML-associated mouse and human T cells, reverting them from a dysfunctional state to an active state. In leukemia:T cell co-cultures, TQ-treated T cells demonstrated greatly improved MHC-dependent leukemia killing. Our findings suggest that the dual actions of TQ on NA-AML and T cells enhance leukemia recognition and anti-leukemia killing of endogenous T cells, leading to effective AML clearance.

DOI: https://doi.org/10.1182/blood.2026033417
PLoS Biol. 2026 Aug 10. 24(8): e3003271

A microRNA atlas of CD4+ T cell subsets in experimental autoimmune encephalomyelitis identifies regulators of disease pathogenesis.

Carolina Cunha, Daniel Inácio, Paula Vargas Romero, Ana Teresa Pais, Catarina Pelicano, Marina Costa, Sofia Mensurado, Natacha Gonçalves-Sousa, Pedro H Papotto, Daniel Neves, Daniel Sobral, Francisco Enguita, Bruno Silva-Santos, Anita Q Gomes.

MicroRNAs (miRNAs) are key regulators of CD4+ T cell differentiation, but how they contribute to the course of an autoimmune disease in vivo remains poorly studied. Given the known roles in autoimmunity of pro-inflammatory T helper 1 (Th)1 and Th17 cells, and anti-inflammatory Foxp3+ regulatory cells, we established a triple reporter mouse for Ifng, Il17 and Foxp3, and subjected it to experimental autoimmune encephalomyelitis (EAE) to characterize the miRNomes of the corresponding CD4+ T cell subsets. We identified 110 miRNAs differentially expressed between the pro-inflammatory (Th1 and Th17 cells) and the Treg cell subsets. Among these, we found novel functions for miR-122-5p and miR-1247 as regulators of Th17 cell proliferation and Th1 cell differentiation, thus impacting the course or severity of EAE, respectively. Importantly, their expression patterns suggest miR-122-5p and miR-1247 act as peripheral brakes to CD4+ T cell pathogenicity that are subverted in the inflamed central nervous system.

DOI: https://doi.org/10.1371/journal.pbio.3003271
J Clin Invest. 2026 Aug 11. pii: e202709. [Epub ahead of print]

Inhibiting menin attenuates high-fat diet-induced weight gain by limiting intestinal lipid absorption in mice.

Xiaoru Cao, Pingping Zhou, Haiyue Meng, Zhitao Guo, Yan Cao, Chenghao Wang, Lulu Liu, Yinghao Guo, Yue Wang, Guoshun Xin, Dabin Liu, Feng Geng, Jian Ma.

  Intestinal lipid metabolism is essential for systemic energy homeostasis, and its modulation is emerging as a therapeutic strategy for obesity. Menin, a scaffold protein that regulates chromatin remodeling and gene expression, is abundantly expressed in intestinal epithelial cells (IECs), but its metabolic role remains underexplored. Here, we generated IEC-specific Men1 knockout mouse and found that Men1 deficiency protected against high-fat diet-induced obesity, accompanied by elevated carboxylesterase 1 (CES1) expression in IECs. Increased CES1 promoted triglyceride (TG) hydrolysis and reduced intracellular TG storage, thereby limiting the lipid substrate pool required for ApoB48-dependent chylomicron assembly. Although lipid hydrolysis was enhanced, steady-state free fatty acid levels were not increased; instead, Men1 deficiency activated fatty acid β-oxidation programs and increased etomoxir-sensitive fatty acid-dependent mitochondrial respiration, supporting enhanced fatty acid catabolism. Mechanistically, menin recruited histone deacetylase 1 and interacted with the nuclear receptor LXRβ to suppress Ces1g transcription, thereby sustaining efficient intestinal lipid absorption. Pharmacological inhibition of menin with MI-463 recapitulated the metabolic effects of inducible Men1 deletion. In a human gut organoid-on-chip system, MI-463 dose-dependently increased CES1 expression and markedly reduced lipid accumulation. Collectively, our findings identify menin as a regulator of intestinal lipid metabolism and suggest menin inhibition as a potential therapeutic strategy for obesity-related metabolic disorders.

Keywords:  Gastroenterology; Metabolism; Obesity

DOI:  https://doi.org/10.1172/JCI202709