bims-imseme 2026-06-21 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2026–06–21
34 papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

T Cell Exhaustion as a Regulated Differentiation Programme.
Bridging the Gap: The Emerging Role of memory CD8+ T Cells in Fibrotic Interstitial Lung Disease.
Mitochondrial transfer in the tumor microenvironment: a dynamic determinant of cancer plasticity, immune dysfunction, and therapeutic opportunity.
The gut microbiota directs vitamin A flux to regulate intestinal T cell development.
Control of naive T cell reactivity and peripheral tolerance by ascorbate and TET activity.
Mitochondrial potential reflects T cell fitness and function during cancer immunotherapy.
Single-Cell RNA Editing Identifies T Cell ADAR1 as a Key Regulator of Immune Exhaustion and Anti-PD-1 Resistance in Colorectal Cancer.
T cell dysfunction and metabolic disruption in chronic hepatitis C virus infection.
Tumor-Associated Platelets Suppress T-Cell Function and Promote Immune Evasion in TNBC via the P-selectin/ P-selectin glycoprotein ligand-1 Pathway.
Cell-autonomous co-stimulatory function of membrane-bound CD100 promotes activation and differentiation of HBcAg-specific CD8+ T cells.
Regulation of antiviral immunity by PD-1 during respiratory syncitial virus infection and upon vaccination.
DsbA-L safeguards T cell mitochondrial redox homeostasis to restrain Th17 differentiation and colitis.
The role of tumor metabolic reprogramming in acquired anti-PD-1/PD-L1 resistance.
Loss of HTLV-1-specific CD8+ T-cell immunity in virus carriers predisposed to adult T-cell leukemia/lymphoma.
The competition of amino acid among tumors, tumor-associated macrophages and T cells based on metabolic reprogramming.
CRISPR-screen informed engineered T cell therapies.
Simultaneous TCR and IL-2 agonism selectively enhances epitope-specific CD8 T-cell responses during chronic viral infection.
Metabolic reprogramming of CD4⁺ T cells by Zaprinast induces HIV-1 latency reversal ex vivo.
Immunometabolic Reprogramming: A New Frontier in Cancer Immunotherapy.
The Memory Inflation Response Against Spread-Defective CMV Requires Priming-Independent CD4+ T Cell Help.
Precise control of switchable chimeric antigen receptor T cells allows enhanced safety and less T cell exhaustion.
Immune responses in aging adults.
CD8 T lymphocytes deploy embryonic cell cycle control mechanisms for rapid cell proliferation.
Linking T Cell States to T Cell Receptors in Systemic Lupus Erythematosus.
TIM3 signaling in effector T cells acts as an immunometabolic switch in the purine degradation pathway to suppress intestinal inflammation.
Chimeric Antigen Receptor T Cells as Living Therapeutics Targeting Senescence and Age-Related Diseases.
Mitochondria and brain aging: From cell-specific dysfunction to intercellular cooperation.
A TIGIT nanotrapping-guided STING-activatable immunometabolic strategy overcomes innate immune silence and T cell exhaustion in breast cancer.
Immune checkpoint crosstalk between LAG-3 and CD39/CD73 in glioblastoma: dual-pathway regulation of metabolic exhaustion and therapeutic reversal strategies.
Follicular T cells in the ovarian cancer immune microenvironment: biological insights and translational implications.
β-Adrenergic receptors as immunomodulators in T cells: mechanisms of neuroimmune crosstalk and pathophysiological implications.
Transcriptional and functional profiling reveals unique activation of Adapter CAR T cells in acute myeloid leukemia.
The trinity of T cell engagement: navigating the molecular and clinical landscape of CAR-T, TILs, and TCEs in the war against cancer.
Profiling the molecular and physiological effects of senolytic treatment on aged mice identifies immune, fibrotic and metabolic remodeling.

Eur J Immunol. 2026 Jun;56(6): e70205

T Cell Exhaustion as a Regulated Differentiation Programme.

Marc Veldhoen, Cristina Ferreira.

T cell exhaustion is now recognised as a structured, antigen-driven differentiation programme rather than a state of cellular fatigue. Under sustained antigen exposure, CD8+ T cells progress through distinct, hierarchically organised differentiation states, initiated by progenitor exhausted cells (TPEX), which retain self-renewal, multipotency, and responsiveness to immune checkpoint blockade. Continued stimulation drives differentiation into intermediate (TEXint) and terminally exhausted (TEX term) states, with TEXint retaining greater effector capacity than TEXterm despite both exhibiting restraint relative to functional effector T cells, alongside increasingly consolidated epigenetic architecture. Rather than reflecting immunological failure, exhaustion preserves long-term antigen surveillance while limiting tissue damage. Convergence between exhaustion-associated transcriptional modules and tissue-resident memory (TRM) programmes highlights shared mechanisms of adaptation to restrictive microenvironments. Yet TRM and TEX arise in distinct contexts and are not interchangeable. Recognising exhaustion as a context-dependent differentiation process reframes therapeutic strategies, in line with current evidence indicating that immune checkpoint blockade primarily acts by expanding and redirecting the TPEX pool rather than reversing terminal exhaustion. This framework integrates insights from chronic infection, tumour immunology, and tissue adaptation.

DOI: https://doi.org/10.1002/eji.70205
Am J Respir Cell Mol Biol. 2026 Jun 19. pii: aanag129. [Epub ahead of print]

Bridging the Gap: The Emerging Role of memory CD8+ T Cells in Fibrotic Interstitial Lung Disease.

Sherly I Celada, Stefan W Ryter, Robert P Baughman, Luc Van Kaer, Lindsay J Celada.

Interstitial lung disease (ILD) disproportionately affects older adults, yet the contribution of immunosenescence to disease pathogenesis remains poorly understood. In fibrotic ILDs (fILDs), CD8 + T cells accumulate in fibrotic regions, where they may drive disease by promoting cytotoxic inflammation, impairing epithelial repair, and sustaining senescence. CD8 + T cell exhaustion (CD8 + Tex) has also emerged as a hallmark of chronic lung disease, although its relationship to immunosenescence in ILD remains unclear. Here, we highlight the heterogeneity among CD8 + T cells in fILD, including effector- and senescent-like subsets, and identify programmed death (PD)-1 as a protective "brake" limiting tissue-damaging immunopathology. Functional profiling indicates that CD8 + T cells in fILD exhibit features consistent with ex-tissue-resident and effector memory CD8 + T cell subsets. Recent evidence from severe and post-acute viral injury demonstrates that PD-1hiCD8 + T cells balance protective immunity with restraint of fibrotic sequelae while also driving maladaptive epithelial remodeling through expansion of dysplastic basal-like cells and impaired alveolar regeneration. These observations suggest that CD8 + T cells in fILD may directly regulate the balance between tissue repair and fibrosis. Our recent studies have shown that the antifibrotic effects of pirfenidone and nintedanib may arise from selective modulation of profibrotic programs in CD8+/CD4 + T cells, lymphoid endothelial cells and dendritic cells. Collectively, these findings support a paradigm shift in which fILD reflects a dysregulation of local immune networks rather an inevitable consequence of aging. Most importantly, these networks are modifiable, offering opportunities for early detection, patient stratification, and stage-specific immunomodulatory interventions, with maladaptive memory CD8 + T cell functional states serving as potential biomarkers of disease susceptibility.

DOI: https://doi.org/10.1093/ajrcmb/aanag129
Front Immunol. 2026 ;17 1871148

Mitochondrial transfer in the tumor microenvironment: a dynamic determinant of cancer plasticity, immune dysfunction, and therapeutic opportunity.

Zhenyuan Xu, Qingli Zhou, Jifei Miao.

  Intercellular mitochondrial transfer has emerged as a significant mode of communication within the tumor microenvironment (TME). We propose that this process operates as a stress-adaptive organelle economy, redistributing three biologically decisive assets (respiratory competence, redox tolerance, and stress history) among tumor, immune, and stromal cells according to local metabolic asymmetry. Cancer cells acquire healthy mitochondria from stromal and immune populations, thereby restoring oxidative phosphorylation, expanding metabolic plasticity, and driving chemoresistance. Tumor cells also engage in outward transfer that is recipient-selective. Damaged mitochondria may be exported to CD8+ T cells and fibroblasts, corrupting effector function and reprogramming the stroma, whereas functional mitochondria may be delivered to pro-tumor immune populations such as M2 tumor-associated macrophages, myeloid-derived suppressor cells, and regulatory T cells to sustain their immunosuppressive activity. Functional mitochondria therefore play a dual role in tumorigenesis. The consequences for antitumor immunity depend on donor identity, cargo quality, and recipient lineage rather than on transfer itself. The principal transport routes are tunneling nanotubes, extracellular vesicles, and cell fusion, but biological outcome is ultimately governed by a post-transfer fate checkpoint involving PINK1/Parkin-mediated mitophagy and USP30-facilitated retention. Therapeutically, the goal is not to block or enhance transfer globally but to achieve context-selective modulation within an inherently bidirectional system.

Keywords:  cancer plasticity; extracellular vesicles; mitochondrial transfer; t cell exhaustion; tumor microenvironment; tunneling nanotubes

DOI:  https://doi.org/10.3389/fimmu.2026.1871148
Cell Host Microbe. 2026 Jun 17. pii: S1931-3128(26)00212-X. [Epub ahead of print]

The gut microbiota directs vitamin A flux to regulate intestinal T cell development.

Tarun Srinivasan, Chaitanya Dende, Kelly A Ruhn, Stefanie L Moye, Ann Johnson, Cassie L Behrendt, Brian Hassell, Gonçalo Vale, Jiwoong Kim, Jake N Lichterman, Chaoying Liang, Carlos Arana, Prithvi Raj, Xiaowei Zhan, Jeffrey G McDonald, Andrew Y Koh, Lora V Hooper.

  The intestinal microbiota shapes adaptive immunity, but the mechanisms remain incompletely defined. Here, we show that the microbiota initiates movement of retinoids-dietary vitamin A derivatives including retinol and retinoic acid-through a sequential pathway from epithelial cells to myeloid cells and ultimately to T cells in the mesenteric lymph nodes (mLNs). This cellular axis is traversed over three days. Microbe-associated molecular patterns initiate retinoid flux by inducing expression of serum amyloid A proteins. These epithelial retinol-binding proteins are necessary and sufficient for epithelial-to-myeloid retinoid transfer and myeloid cell migration to the mLNs. In the mLNs, microbial antigen drives retinoid transfer from myeloid cells to developing T cells, culminating in T cell retinoid uptake and transcriptional programming. This pathway is activated during postnatal development, when gut adaptive immunity is established. These findings reveal that the microbiota programs intestinal adaptive immunity by regulating immune cell access to a nutrient-derived developmental signal.

Keywords:  CD4+ T cells; RAR; intestinal homing; mesenteric lymph nodes; microbiota; myeloid cells; postnatal development; retinoic acid receptor; retinoids; serum amyloid A; vitamin A

DOI:  https://doi.org/10.1016/j.chom.2026.05.019
Sci Adv. 2026 Jun 19. 12(25): eaeh1439

Control of naive T cell reactivity and peripheral tolerance by ascorbate and TET activity.

Xiaolei Hao, Lu Bai, Jun Li, Beisi Xu, Laura J Janke, Gustavo Palacios, Clifford Guy, Jeremy Chase Crawford, Yiping Fan, Wojciech Rosikiewicz, Julia Keith, Hoang Le, Minghong He, Darong Yang, Jacob A Steele, Shondra M Pruett-Miller, Yong Cheng, Jacob H Hanna, Terrence Geiger, Yongqiang Feng.

Peripheral tolerance depends on limiting conventional T cell responses to self-antigens. To define the contribution of nutritional factors and related epigenetic regulation, we perform in vivo CRISPR screening and identify the ascorbate transporter Slc23a2 as a key regulator of naive T cell (Tn) reactivity. T cell-specific loss of Slc23a2 reduces intracellular ascorbate, induces regional DNA hypermethylation, enhances differentiation of Tn cells into effector and memory populations, and promotes low-grade autoimmune inflammation. These phenotypes mirror those caused by ascorbate deprivation, TET dioxygenase deficiency, and aging. Mechanistically, Slc23a2 maintains TET enzymatic activity through ascorbate, dampens proximal TCR signaling, represses helper T cell lineage programs, and sustains Tcf1 expression and chromatin binding in Tn cells. Deletion of Tcf7 partially phenocopies Slc23a2 deficiency, whereas Tcf1 overexpression mitigates the effects. Together, these findings identify ascorbate and TET-dependent DNA demethylation as a checkpoint that restrains Tn cell reactivity to self-antigens, thereby maintaining peripheral tolerance, a process compromised with aging.

DOI: https://doi.org/10.1126/sciadv.aeh1439
J Immunol. 2026 Jun 07. pii: vkag120. [Epub ahead of print]215(6):

Mitochondrial potential reflects T cell fitness and function during cancer immunotherapy.

Paul L Lindau, Alex V Nesta, Caroline E Roe, Madelyn D Landis, Zaid Hatem, Allison E Sewell, Allison K Blount, Jackie E Bader, Reddy Anupama, W Kimryn Rathmell, Jonathan M Irish, Jeffrey C Rathmell, Kathryn E Beckermann.

  Checkpoint inhibitors have transformed cancer treatment, yet predicting responses remains challenging. Mitochondrial quality decreases in tumor infiltrating lymphocytes and correlates with impaired antitumor immunity in animal models. Mitochondrial membrane potential (MMP) increases with T cell activation and may also indicate cellular dysfunction. Here, we assessed the MMP of tumor-associated T cells as an indicator of cell phenotypes and immunotherapy responses in non-small cell lung carcinoma and clear cell renal cell carcinoma patients. Primary tumors were collected followed by analysis of peripheral blood mononuclear cells prior to and after 3 wk on treatment with immune checkpoint inhibitors (ICIs). Peripheral blood mononuclear T cells were analyzed for MMP using tetramethylrhodamine ethyl ester (TMRE) and sorted into high and low populations. TCRβ and single-cell RNA sequencing of primary tumors identified and characterized peripheral blood T cell clones associated with the tumor microenvironment. As anticipated, ICI therapy increased the frequency of effector T cells in patients who experienced clinical benefit. TMREhigh peripheral blood T cells with tumor-matching TCRβ sequences had elevated oxidative phosphorylation gene signatures. Gene signatures of stress and exhaustion, such as Tigit and Cmc1, were also elevated in the TMREhigh CD8 T cell populations, while gene expression patterns in TMRElow cells suggested mitochondrial fitness and cell longevity. Importantly, clinical benefit from ICIs was negatively correlated with the TMREhigh CD8 T cell gene expression signature. These findings highlight a T cell population characterized by elevated MMP that correlates with exhaustion-like transcriptional states and poor response to immunotherapy.

Keywords:  T cells; checkpoint inhibitor; kidney cancer; lung cancer; metabolism; mitochondria

DOI:  https://doi.org/10.1093/jimmun/vkag120
Adv Sci (Weinh). 2026 Jun 15. e76143

Single-Cell RNA Editing Identifies T Cell ADAR1 as a Key Regulator of Immune Exhaustion and Anti-PD-1 Resistance in Colorectal Cancer.

Da Kang, Song-Zuo Xie, Yong-Zhou Luo, Xin-Pei Deng, Xi-Rong Tan, Ze-Geng Chen, Ling-Xing Zeng, Gong Chen, Pei-Rong Ding, Zhi-Zhong Pan, Rong-Xin Zhang.

  ADAR1-mediated RNA editing has been implicated in tumor immune evasion, primarily through tumor-intrinsic interferon (IFN) signaling. However, its cell-type-specific roles within immune compartments, particularly T cells, remain unclear in colorectal cancer (CRC). RNA editing landscapes were profiled using bulk RNA sequencing and full-length single-cell RNA sequencing. ADAR1 expression and RNA editing activity were analyzed across the tumor microenvironment (TME), followed by functional validation and multi-cohort clinical evaluation. Single-cell analyses revealed elevated ADAR1 activity in tumor-infiltrating T cells, defining an exhausted and proliferative T cell state associated with immune dysfunction. Functional experiments demonstrated that ADAR1 promotes T-cell exhaustion and impairs cytotoxic activity. In vivo adoptive transfer models further confirmed that ADAR1 overexpression in T cells limits antitumor efficacy. Mechanistically, ADAR1 activated the TGF-β-SMAD signaling pathway. Clinically, elevated ADAR1 expression in T cells was associated with reduced response to anti-PD-1 therapy across immunotherapy cohorts. These findings identify ADAR1 as a key regulator of dysfunctional T cell states in CRC and suggest that targeting ADAR1 activity in T cells may represent a promising strategy for improving immunotherapy efficacy and developing predictive biomarkers.

Keywords:  ADAR1; T cell exhaustion; TGF‐β signaling pathway; colorectal cancer; immunotherapy

DOI:  https://doi.org/10.1002/advs.76143
Front Immunol. 2026 ;17 1844075

T cell dysfunction and metabolic disruption in chronic hepatitis C virus infection.

Bhavya Sajeet, Uma Ganapathi, Kiruthika Naganathan, Aarthi Parthasarathy, Pramod Darvin, Varun Sasidharan Nair.

  Hepatitis C virus (HCV) infection remains a major global health burden and a leading cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma. Despite the availability of highly effective direct-acting antivirals, sustained immune dysfunction and long-term complications continue to challenge disease management. Chronic HCV infection is facilitated by multiple viral evasion mechanisms, including rapid sequence variation, disruption of innate antiviral signaling, and altered natural killer cell function. A key feature of disease progression is the dysfunction of virus-specific CD4+ and CD8+ T cells caused by prolonged antigen exposure. These cells gradually develop an exhausted phenotype marked by reduced proliferation, impaired cytokine production, and increased expression of inhibitory receptors such as PD-1, CTLA-4, TIM-3, and TIGIT. At the same time, intrahepatic accumulation of regulatory T cells further suppresses antiviral immune responses and promotes viral persistence. Recent studies also show that chronic HCV infection induces significant metabolic and mitochondrial dysfunction including oxidative stress, impaired bioenergetics, and altered glycolytic adaptation, all of which contribute to defective T cell responses and disease progression. Notably, some of these immune defects persist even after viral eradication because of stable transcriptional and epigenetic changes in exhausted T cells. This review summarizes current understanding of how T cell dysfunction, epigenetic programming, and metabolic disruption interact in chronic HCV infection. Understanding these interconnected mechanisms may guide the development of novel therapeutic strategies that combine antiviral, immunomodulatory, and metabolic interventions to achieve durable immune restoration and improved clinical outcomes.

Keywords:  T cell exhaustion; epigenetic scarring; hepatitis C virus; mitochondrial dysfunction; regulatory T cells

DOI:  https://doi.org/10.3389/fimmu.2026.1844075
Cancer Res Commun. 2026 Jun 16.

Tumor-Associated Platelets Suppress T-Cell Function and Promote Immune Evasion in TNBC via the P-selectin/ P-selectin glycoprotein ligand-1 Pathway.

Margaret R Smith-Oliver, Deepa Gautam, Grace C Petrarca, Megan E Sullivan, Emily M Clarke, Giovanni Goggi, Milos Spasic, Natalie Kane, Jared Brown, Harvey G Roweth, Joanna Baginska, Ana C Garrido-Castro, Patricia Davenport, Sandra S McAllister, Elisabeth M Battinelli.

Tumor-associated platelets (TAPs), which are reprogrammed by tumor-derived signals to acquire immunosuppressive properties, represent an emerging mechanism of immune evasion in triple-negative breast cancer (TNBC). Although immune checkpoint inhibitors (ICIs) have shown promise, their efficacy is frequently limited by T cell exhaustion and therapeutic resistance. Here, we demonstrate that TAPs, unlike healthy circulating platelets, induce T cell dysfunction through platelet-derived P-selectin, which engages P-selectin glycoprotein ligand-1 (PSGL-1) on T cells. This interaction promotes immunosuppressive signaling, driving T cell exhaustion and impairing anti-tumor cytotoxicity. Using in vitro co-culture systems and in vivo TNBC models, we show that disruption of the P-selectin-PSGL-1 axis, including pharmacologic blockade with the FDA-approved anti-P-selectin antibody Crizanlizumab, restores T cell function and enhances responsiveness to immune checkpoint blockade. Notably, PSGL-1, traditionally recognized for its role in leukocyte trafficking and immune regulation, is co-opted by TAPs to suppress T cell activity, revealing a mechanism of platelet-mediated immune modulation. These findings establish TAPs as active regulators of anti-tumor immunity and identify the P-selectin-PSGL-1 axis as a therapeutically actionable target to overcome resistance to immunotherapy in TNBC.

DOI: https://doi.org/10.1158/2767-9764.CRC-26-0187
Front Immunol. 2026 ;17 1826036

Cell-autonomous co-stimulatory function of membrane-bound CD100 promotes activation and differentiation of HBcAg-specific CD8+ T cells.

Mengxiao Zhao, Liwei Chen, Yuhang Chen, Lu Wang, Xuecheng Yang, Kathrin Sutter, Mengji Lu, Jieliang Chen, Xin Zheng, Dongliang Yang, Liang Wang, Jia Liu.

   Background: CD100/SEMA4D functions as a critical co-stimulatory molecule in T cell responses, existing in both membrane-bound (mCD100) and soluble (sCD100) forms. Previous studies have shown that CD100 enhances CD8+ T cell responses indirectly by promoting the maturation and activation of antigen-presenting cells, thereby facilitating viral clearance. However, whether mCD100, highly expressed on resting T cells, can also directly regulate CD8+ T cell function upon ligand engagement remains unclear.
Methods: We examined the impact of CD100 deficiency on the functional phenotype and differentiation of HBcAg-specific CD8+ T cells using separate and co-culture systems in vitro. Furthermore, through adoptive transfer of CD100 knockout HBV Cor93 TCR-transgenic (CD100KO C93-TCRtg) CD8+ T cells, we investigated the early impact of mCD100 deficiency on the development of HBcAg-specific CD8+ T cell responses during HBV infection.
Results: The absence of mCD100 expression significantly decrease HBcAg-specific CD8+ T-cell proliferation, activation, effector cytokine production, and expression of Granzyme B and Eomes upon antigen stimulation in vitro. In the acute self-resolving models, the early proliferation of transferred CD100KO C93-TCRtg CD8+ T cells were impaired compared to their WT counterparts following HBV challenge. Transcriptomic data revealed that significant downregulation of gene sets associated with the PI3K-Akt, mTOR, NF-κB, and JAK-STAT signaling pathways in CD100KO CD8+ T cells.
Conclusions: Membrane CD100 expressed on resting HBcAg-specific CD8+ T cells may function as a co-stimulatory molecule by providing a direct stimulatory signal for the early proliferation and effector differentiation of T cells. The observed effects of mCD100 are associated with the PI3K-Akt-mTOR, JAK-STAT and NF-κB signaling pathways.

Keywords:  CD8+ T cells; JAK-STAT; NF-κB; PI3K-Akt-mTOR; costimulatory molecular; hepatitis B virus; membrane-bound CD100; transfer

DOI:  https://doi.org/10.3389/fimmu.2026.1826036
iScience. 2026 Jun 19. 29(6): 116157

Regulation of antiviral immunity by PD-1 during respiratory syncitial virus infection and upon vaccination.

Linmar Rodríguez-Guilarte, Constanza Méndez, M Fernanda Rojas, Patricia Pereira-Sánchez, Mariana Ríos, José T Muñoz, Mónica A Farías, Susan M Bueno, Alexis M Kalergis.

  Respiratory syncytial virus (RSV) induces a protective immune response shaped by regulatory pathways that control T cell function. The inhibitory receptor PD-1 is a central modulator of these processes. Here, we analyzed PD-1, LAG-3, and TIM-3 expression in CD8+ T cells during RSV infection and evaluated PD-1/PD-L1 modulation across different immunological contexts in mice. PD-1 expression progressively increased in lung CD8+ T cells at 5- and 9-day post-infection, accompanied by co-expression of LAG-3 and TIM-3, and elevated PD-L1 in epithelial and antigen-presenting cells. PD-1 modulation varied with context: passive immunization reduced its expression, whereas rBCG-N-RSV vaccination followed by infection increased PD-1 and cytokine production. PD-1 blockade enhanced memory T cell generation and the quality of the humoral response, whereas PD-1 deficiency impaired these responses. These findings support a context-dependent role for PD-1 in coordinating antiviral immunity and vaccine-induced immune responses.

Keywords:  Cell biology; Immunology; Molecular biology; Respiratory medicine; Virology

DOI:  https://doi.org/10.1016/j.isci.2026.116157
Cell Death Dis. 2026 Jun 13.

DsbA-L safeguards T cell mitochondrial redox homeostasis to restrain Th17 differentiation and colitis.

Jiangming Deng, Liwen Wang, Bilian Liu, Jing Wang, Qingxin Li, Yi Deng, Long Yan, Hairong Luo, Wen Meng, Feng Liu.

Pathogenic Th17 accumulation drives intestinal inflammation in inflammatory bowel disease (IBD), yet the metabolic mechanisms directing Th17 polarization remain incompletely understood. Here, we identify the mitochondrial matrix protein DsbA-L serves as a critical, cell-intrinsic metabolic checkpoint for Th17 differentiation and intestinal immune homeostasis. In mouse models, dextran sulfate sodium (DSS)-induced colitis downregulated DsbA-L expression and disrupted mitochondrial redox balance in intestinal CD4⁺ T cells. T cell-specific DsbA-L deletion exacerbated colitis and selectively promotes pathogenic Th17 differentiation by increasing mitochondrial reactive oxygen species (mtROS). Pharmacological mtROS scavenging reverses the Th17 bias, establishing mitochondrial redox imbalance as a causal driver of pathogenic polarization. Furthermore, DsbA-L is essential for the therapeutic efficacy of the PPARγ agonist rosiglitazone in colitis. Collectively, our findings position DsbA-L-mediated mitochondrial redox balance as a key regulator of Th17 pathogenicity and intestinal inflammation, offering new conceptual and therapeutic insights for precision intervention in IBD.

DOI: https://doi.org/10.1038/s41419-026-08978-6
Transl Lung Cancer Res. 2026 May 31. 15(5): 150

The role of tumor metabolic reprogramming in acquired anti-PD-1/PD-L1 resistance.

Cize Gao, Jianing Chen, Boyue Pang, Chunxia Su.

  Tumor metabolic reprogramming is a pivotal mechanism driving acquired resistance to programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) blockade therapy. Under therapeutic pressure, tumor cells undergo extensive metabolic rewiring, encompassing enhanced glycolysis, altered amino acid metabolism, and reprogrammed lipid utilization. This metabolic plasticity intensifies nutrient competition within the tumor microenvironment (TME), leading to the accumulation of immunosuppressive metabolites such as lactate and kynurenine. These metabolites collectively impair effector T cell activation, proliferation, and cytotoxicity, while simultaneously facilitating the expansion and suppressive activity of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). In parallel, T cells often exhibit metabolic exhaustion, characterized by mitochondrial dysfunction, reduced oxidative phosphorylation, and impaired metabolic flexibility, which ultimately limits their persistence and anti-tumor efficacy despite checkpoint blockade. Moreover, the intrinsic heterogeneity and adaptability of tumor metabolism promote the selection of resistant subclones during immunotherapy, further undermining treatment durability. To overcome these barriers, emerging combinatorial strategies are focusing on integrating metabolic inhibitors, such as lactate dehydrogenase A (LDHA) and IDO1 inhibitors, with immune checkpoint blockade, or on metabolically engineering T cells to enhance their fitness. Future efforts should emphasize precise patient stratification, development of highly selective metabolic modulators, and rational design of combination therapies to improve both the efficacy and long-term durability of cancer immunotherapy.

Keywords:  Programmed cell death protein 1/programmed death-ligand 1 blockade (PD-1/PD-L1 blockade); immune therapy resistance; metabolic heterogeneity; metabolic reprogramming

DOI:  https://doi.org/10.21037/tlcr-2026-1-0171
Blood Neoplasia. 2026 Aug;3(3): 100235

Loss of HTLV-1-specific CD8+ T-cell immunity in virus carriers predisposed to adult T-cell leukemia/lymphoma.

Devon A Weterings, Lisa Lam Chiou Yee, Patricia Watber, Jerico Baylon, Claire Greiller, Graham P Taylor, Lucy B M Cook, Aileen G Rowan.

Adult T-cell leukemia/lymphoma (ATL) is caused by chronic infection with human T-lymphotropic virus type 1 (HTLV-1). HTLV-1 contains highly immunogenic CD8 + T-cell epitopes that elicit high frequencies of virus-specific CD8 + T cells in most virus carriers. Despite the virus being present in the tumor, HTLV-1-specific CD8 + cells are often undetectable in ATL. To characterize HTLV-1-specific CD8 + T cells during ATL development, we studied a subgroup of people living with asymptomatic HTLV-1 infection at very high risk of developing ATL. These so-called "high-risk" carriers have suspected premalignant lesions: expanded, HTLV-1-infected "ATL-like" clones circulating in their peripheral blood. Compared to viral antigen-burden matched controls, high-risk carriers had significantly fewer Tax-specific IFN-γ + CD8 + cells in peripheral blood. Furthermore, ex vivo CD8 + T cells from high-risk carriers did not efficiently kill autologous HTLV-1-infected T cells, including premalignant ATL-like clones. We stained Tax11-19/HLA-A∗0201 pentamer + CD8 + T cells to test whether the low frequencies of functional CD8+ T cells resulted from phenotype or absolute frequency of HTLV-1-specific CD8 + T cells. High-risk carriers had significantly lower frequencies of Tax11-19/HLA-A∗0201 pentamer + CD8 + T cells than controls, but we observed no difference in effector function, memory phenotype, or expression of checkpoint control molecules. In contrast, there was no difference in the frequency of CD8 + T cells specific for other viruses (cytomegalovirus, Epstein-Barr virus, influenza virus) between high-risk carriers and controls. This is the first report of HTLV-1-specific immune dysregulation in the premalignant stage of ATL. Low frequencies of HTLV-1-specific CD8 + T cells may contribute to ATL development and may be a novel therapeutic target for ATL prevention.

DOI: https://doi.org/10.1016/j.bneo.2026.100235
iScience. 2026 Jun 19. 29(6): 116253

The competition of amino acid among tumors, tumor-associated macrophages and T cells based on metabolic reprogramming.

Chenyang Xianyu, Yuxiao Song, Ci Zhao, Qian Min, Zhixu Wang, Mingbo Zhang, Bicheng Zhang.

  Amino acids are important nutrients in the process of tumor proliferation. Dysregulated amino acid metabolism profoundly influences tumor growth and immune cell function. Within the tumor microenvironment (TME), metabolic reprogramming of amino acids modulates the polarization of tumor-associated macrophages (TAMs) and the differentiation of T cells, processes intimately linked to tumor immune evasion. Meanwhile, metabolic reprogramming leads to amino acid competition between tumor cells and immune cells, particularly TAMs and T cells. To meet their own amino acid needs, tumors carry out a series of optimized metabolic strategies by expressing specific enzymes, cytokines, and amino acid transporters, and so forth promoting the formation of an immunosuppressive microenvironment and hindering anti-tumor immunity. Notably, this metabolic competition may exhibit spatial heterogeneity and temporal dynamics. Given the central role of amino acid metabolism in tumor progression and immune evasion, targeting key metabolic pathways represents a promising therapeutic strategy for cancer treatment.

Keywords:  Cancer; Cancer systems biology; Human metabolism; Immune response

DOI:  https://doi.org/10.1016/j.isci.2026.116253
Front Immunol. 2026 ;17 1839064

CRISPR-screen informed engineered T cell therapies.

Karrie Wong, Conor Calnan, Micah J Benson.

  Adoptive T cell therapies can deliver curative responses for refractory patients with B cell malignancies, yet clinical activity in solid tumors remains inconsistent. Tumor-intrinsic barriers dominating this inconsistency include the immunosuppressive solid tumor microenvironment (TME) imposing chronic inhibitory cues to T cells and the scarcity of patient-shared and uniformly expressed tumor-restricted antigens for T cells to target. CRISPR-based forward genetics screens enable mapping of the functional genome regulating T cell anti-tumor activity. Here, we review recent insights from pooled CRISPR knockout screens in T cells to define convergent targets and pathways regulating T cell anti-tumor function and align the pharmacology of engineered T cells with sequential barriers they encounter within the TME. We additionally propose a framework for CRISPR screen-enabled target prioritization and present an example of how these principles can be applied to the functional enhancement of T cells through TIL (Tumor Infiltrating Lymphocyte) therapy, which utilizes a patient's personalized immune response against solid tumor antigens.

Keywords:  CRISPR; T cell; TIL; adoptive cell therapy; solid tumor

DOI:  https://doi.org/10.3389/fimmu.2026.1839064
J Virol. 2026 Jun 15. e0059326

Simultaneous TCR and IL-2 agonism selectively enhances epitope-specific CD8 T-cell responses during chronic viral infection.

Masao Hashimoto, Mohammad Affan Khan, Akil Akhtar, Javed N Agrewala, Gordon J Freeman, Natasha Girgis, Yu Zhang, Simon Low, Steven N Quayle, Anish Suri, Rafi Ahmed.

  Interleukin-2 (IL-2) remains an attractive cytokine for enhancing antigen-specific CD8 T-cell responses in cancer immunotherapy, but systemic toxicity hinders its broad clinical application. To address this, various IL-2-based therapeutics have been engineered with altered IL-2 receptor bias or targeted delivery to tumors, the tumor microenvironment, or immune cell populations. Ideally, IL-2 signals should be selectively delivered to antigen-specific CD8 T cells, boosting their responses and promoting effector differentiation while sparing non-targeted populations. Immuno-STAT (Selective Targeting and Alteration of T cells) is a fusion protein platform comprising a bivalent peptide-major histocompatibility complex (MHC) class I complex and an affinity-attenuated IL-2 mutein that co-stimulates T-cell receptor and IL-2 signaling in epitope-specific CD8 T cells. Here, we investigated whether a DbGP33-41-targeted Immuno-STAT enhances DbGP33-specific CD8 T-cell responses in a mouse model of chronic lymphocytic choriomeningitis virus infection. Immuno-STAT treatment selectively expanded DbGP33-specific CD8 T cells with an effector-like phenotype. Non-targeted DbGP276-specific CD8 T cells showed little to no expansion in response to DbGP33-41-targeted Immuno-STAT therapy, underscoring the selectivity of this approach. However, minor changes in phenotypic markers, including increased expression of CD25 and CX3CR1, were observed in non-targeted CD8 T cells, likely reflecting bystander IL-2 signaling. Combining Immuno-STAT with PD-1 blockade augmented DbGP33-specific CD8 T-cell responses more effectively than PD-1 blockade alone, with minor effects on the non-targeted DbGP276-specific population. These findings inform the clinical development of Immuno-STAT and other IL-2 therapeutics and highlight the value of coordinated TCR and IL-2 stimulation during chronic antigen exposure, alone or in combination with PD-1 blockade.
IMPORTANCE: Interleukin-2 (IL-2) is a key cytokine for promoting effector differentiation of antigen-specific CD8 T cells and remains an attractive agent in cancer immunotherapy, but systemic toxicity limits its clinical use. This study addresses a central challenge in IL-2-based immunotherapy: delivering IL-2 to cognate antigen-specific CD8 T cells while minimizing activation of non-targeted populations. Using a mouse model of chronic lymphocytic choriomeningitis virus (LCMV) infection, we show that the Immuno-STAT (Selective Targeting and Alteration of T cells) platform selectively expands targeted virus-specific CD8 T cells and enhances their function while limiting effects on non-targeted populations. We also show that combining Immuno-STAT with PD-1 blockade further enhances targeted virus-specific CD8 T-cell responses during chronic LCMV infection. These findings provide mechanistic and preclinical support for integrating T-cell receptor specificity with IL-2 signaling to advance cancer immunotherapy and guide next-generation IL-2 therapeutics for cancer and chronic infection.

Keywords:  CD8 T cells; IL-2; T-cell exhaustion; chronic infection; immunotherapy

DOI:  https://doi.org/10.1128/jvi.00593-26
Retrovirology. 2026 Jun 13.

Metabolic reprogramming of CD4⁺ T cells by Zaprinast induces HIV-1 latency reversal ex vivo.

V De Masson d'Autume, V LeDouce, A Dutilleul, S O'Reilly, N François, E Formiconi, M Angieladis, L Pilosio, M Bendoumou, A Garcia Leon, D Alalwan, E Moore, T McGinty, J C Valle-Casuso, A Macken, O Rohr, C Van Lint, A Sáez-Cirión, A Cotter, E Feeney, P W G Mallon, W V Gautier.

BACKGROUND: HIV-1 latency and persistence of viral reservoirs within memory CD4+ T cells remain a fundamental obstacle to achieving a cure despite suppressive antiviral treatments. HIV-1 persistence is sustained by the dynamic interactions between viral regulatory mechanisms and the host cellular environment. At the intersection between immunometabolism and virology, the quiescent metabolic profile of resting CD4+ T cells, defined as the balance between oxidative phosphorylation (OXPHOS) and aerobic glycolysis, supports the long-term maintenance of latent viral reservoirs. Existing "Shock and Kill" strategies have shown limited clinical impact, partly due to the metabolic constraints that limit robust viral reactivation. Targeting metabolic junctions to overcome this barrier may provide a complementary therapeutic avenue.
RESULTS: We evaluated Zaprinast, a mitochondrial pyruvate carrier inhibitor (MPCi), for its capacity to reprogramme CD4+ T cell metabolism and promote latency reversal. Across multiple primary T-cell based models of HIV-1 latency, Zaprinast induced a moderate yet reproducible increase in HIV-1 gene expression and viral particle production, including in circulating reservoirs from antiretroviral-treated individuals cultured ex vivo. Metabolic profiling revealed a biphasic response: an initial, transient inhibition of mitochondrial respiration followed by a shift from an OXPHOS-dominant to a more glycolytic metabolic state, while maintaining mitochondrial function. This metabolic reprogramming of resting CD4+ T cells by Zaprinast was reversible and did not impair cell viability, trigger non-specific T cell activation or proliferation, nor elevate reactive oxygen species levels.
CONCLUSIONS: These results highlight that selective targeting of the quiescent metabolic state in resting CD4+ T cells can facilitate HIV-1 reactivation without compromising cellular integrity. This study identifies host metabolic reprogramming as a promising strategy to enhance latency reversal and complement existing cure strategies. Our work provides new insights into the importance of host metabolic states in governing viral persistence and underscores the translational potential of metabolic interventions in HIV-1 eradication research.

DOI: https://doi.org/10.1186/s12977-026-00680-x
Curr Mol Med. 2026 Jun 10.

Immunometabolic Reprogramming: A New Frontier in Cancer Immunotherapy.

Saeed Mohammadi, Mahmoud Darweesh, Mina Rahmati, Moosa Al-Hamadani, Milad Ahmadaghdami, Ahmed Al-Harrasi.

  The interaction between cellular metabolism and immune function, termed immunometabolism, has been regarded as a crucial determinant of anti-tumor immunity and the efficacy of cancer immunotherapy. Understanding the metabolic dependencies and vulnerabilities of various immune cell subsets and cancer cells is enabling researchers to study novel therapeutic strategies. These strategies aim to reprogram the metabolic landscape of the TME to enhance stronger anti-tumor immune responses and overcome resistance to current immunotherapies. This review provides a comprehensive overview of the fundamental principles of immunometabolism, detailing the key metabolic pathways and regulators in immune and cancer cells. We explore the distinct metabolic profiles of various immune cell subsets and how they are altered during an anti-tumor response. Furthermore, we discuss the metabolic hallmarks of cancer cells, considering variations across different cancer types. Then, we discuss how current immunotherapies, such as checkpoint inhibitors and CAR-T cell therapy, impact and are influenced by cellular metabolism. Finally, we highlight promising therapeutic opportunities for targeting immunometabolism, including metabolic inhibitors, modulators, and combination strategies. This review aims to introduce immunometabolic reprogramming as a new frontier to enhance the efficacy of cancer immunotherapy and improve patient outcomes.

Keywords:  CAR-T engineering; Immunometabolism; cancer heterogeneity; checkpoint blockade; metabolic reprogramming; precision oncology.; tumor microenvironment

DOI:  https://doi.org/10.2174/0115665240435650260516221100
Eur J Immunol. 2026 Jun;56(6): e70225

The Memory Inflation Response Against Spread-Defective CMV Requires Priming-Independent CD4+ T Cell Help.

Jack Barton, Yeonsu Kim, Matthias T Warkotsch, Luka Cicin-Sain, Mateusz P Poltorak, Veit R Buchholz, Dirk H Busch.

  Memory inflation (MI) is a distinctive CD8+ T cell response to chronic cytomegalovirus (CMV) infection, characterized by non-contracting, functional populations that are predominantly effector differentiated. Harnessing such responses has received growing attention as a promising vaccination strategy, using spread-defective CMV-vectors. However, many underlying mechanistic aspects of CD8+ MI responses, including their dependency on CD4+ T cell help, remain unclear. Using a Rag KO transfer model, we demonstrate that CD4+ T cells enhance effector differentiation of inflationary CD8+ T cells when present during priming, or when introduced at late timepoints post-infection, indicating a continuous, priming-independent support mechanism. This helper requirement was specific to spread-defective CMV infection, whereas spread-competent virus induced MI even in the absence of CD4+ T cells. We confirmed the importance of continuous support in wild-type mice, where late CD4 depletion attenuated an established MI response. Gene set enrichment analysis implicates IFNγ, TNF, and IL-1 signaling as potential mediators of CD4+ T cell support. Our findings clarify CD4+ T cell help requirements for maintaining effector populations in MI during chronic antigen exposure. These results have particular relevance for spread-defective CMV-based vaccination strategies and T cell-based therapies in which the persistence and expansion characteristic of MI are desirable qualities.

Keywords:  CD8; T cell; antigen; biology; cytotoxic T cell ; effector; immunology; vaccination; virus

DOI:  https://doi.org/10.1002/eji.70225
J Transl Med. 2026 Jun 17.

Precise control of switchable chimeric antigen receptor T cells allows enhanced safety and less T cell exhaustion.

Zihan Anna Zhang, Logan Herring, Thuzar Hla Shwe, Yue Hu, Xiaotong Song, Wenyue Cao, Wenshe Ray Liu.

   BACKGROUND: Chimeric antigen receptor (CAR)-T cell therapies have achieved remarkable success in hematologic malignancies, yet their clinical utility remains limited by safety concerns, limited persistence, and T-cell exhaustion driven by continuous receptor signaling. While switchable CAR designs provide external control, many reported systems are irreversible, strictly binary, or compromise CAR-T potency.
METHODS: We engineered an optimized chemically switchable CAR platform (CSN CAR) that pharmacologically regulates antigen engagement by controlling the surface expression of the full-length CAR. An NS3 protease module was embedded within the CAR construct to enable drug-dependent stabilization of intact CAR on T cells. Using engineered CAR-T cells, we quantified drug-controlled activation, cytotoxicity, and cytokine release against CD19⁺ tumor cells by flow cytometry and ELISA in vitro. We further screened clinically approved NS3/4A inhibitors in CAR-HEK and CAR-T cells to identify optimal small-molecule controllers. A chronic stimulation model was established to assess CAR-T persistence and exhaustion-associated phenotypes in vitro.
RESULTS: CSN CAR-T cells enabled precise, dose-dependent regulation of CAR surface density, cytokine production, and cytotoxicity. In the OFF state, switchable CAR-T cells showed minimal basal activity, consistent with reduced antigen-driven activation and cytokine release in the absence of drug in the experimental conditions. Upon drug addition, intact surface CAR was detectable within 1 h, reaching ~ 80% of peak observed CAR expression by 4 h. Reversible suppression of CAR expression enabled attenuation of cytotoxicity toward normal CD19⁺ B cells in vitro after target-cell reduction, supporting a potential strategy to mitigate prolonged on-target/off-tumor activity. Under chronic stimulation, switchable CAR-T cells exhibited reduced exhaustion-associated markers, more stable CAR expression, and preferential differentiation toward a central memory phenotype.
CONCLUSION: Together, these findings establish CSN CAR as a reversible and tunable switchable CAR-T platform enabled by clinically approved NS3/4A inhibitors, supporting controllable modulation of CAR activity with potential applications for improving the precision and safety of CAR-T cell therapy.

Keywords:  Chimeric antigen receptor (CAR); Cytokine release syndrome; Switch; T cell exhaustion; T cell therapy

DOI:  https://doi.org/10.1186/s12967-026-08464-9
J Clin Invest. 2026 06 15. pii: e206227. [Epub ahead of print]136(12):

Immune responses in aging adults.

Cornelia M Weyand, Jörg J Goronzy.

As a widely distributed network of cells, tissues, and organs, the human immune system is profoundly vulnerable to the effects of aging. Intrinsic and extrinsic stressors progressively erode its structural integrity and functional resilience, weakening core protective responses and increasing susceptibility to infection, malignancy, and tissue degeneration. At the same time, aging heightens the risk of chronic inflammation and autoimmune disease. Hematopoietic stem cells become uniquely compromised as aging intensifies metabolic and replicative stress. Their continuous high-volume turnover results in diminished self-renewal capacity, skewed lineage output, and dominance of expanded clones. These changes undermine innate immune competence and amplify inflammatory activity. Adaptive immune function declines with age through coordinated cellular and molecular programs. T and B lymphocytes exhibit a decline in naive cells, progressive loss of stemness, shortened lifespan, and constrained clonal diversity. Aging lymphocytes reconfigure transcriptional networks, undergo widespread organelle dysfunction, develop maladaptive stress responses, and redistribute into noncanonical tissue niches. Collectively, these alterations reduce antigen specificity and precision, promote innate-like immune behavior, and confer resistance to tolerance. These mechanisms result in concurrent immunodeficiency and autoimmunity, exemplified by two autoimmune diseases disproportionately affecting older adults: rheumatoid arthritis and giant cell arteritis.

DOI: https://doi.org/10.1172/JCI206227
EMBO Rep. 2026 Jun 18.

CD8 T lymphocytes deploy embryonic cell cycle control mechanisms for rapid cell proliferation.

David A Lewis, Ananya Kar, Alice Savage, Van Kelly, David Wright, Devin Tan, Mary Tozer, Christina Rollings, Doreen A Cantrell, Rose Zamoyska, Tony Ly.

Rapid proliferation of CD8 T cells is crucial for adaptive immunity against viral infection. CD8 T cells can complete division cycles in less than 6 h, representing a physiological extreme for somatic mammalian cells. Embryonic stem cells utilize specialized cell cycle control mechanisms, including subdued periodic expression, for rapid cell division cycles. CD8 T cell cycle control remains poorly understood. Here, we test whether CD8 T cells utilize embryonic mechanisms to promote rapid cell cycles. We comprehensively measure protein abundances in G1, S, and G2&M phases in three murine cell types: CD8 T cells, embryonic stem cells, and fibroblasts. We discover striking similarities between mESC and CD8 T cells. We demonstrate that CD8 T cells express Cyclin E1 and Emi1/Fbxo5 at high levels to promote S-phase entry. Interestingly, CD8 T cells and mESCs differ in the frequency of G2&M phase cells, the abundance of DNA replication origin licensing and initiation factors, and the abundance of APC/C substrates. Thus, somatic T cells have both unique and shared cell cycle control mechanisms to promote rapid cell cycles.

DOI: https://doi.org/10.1038/s44319-026-00830-4
Arthritis Rheumatol. 2026 Jun 15.

Linking T Cell States to T Cell Receptors in Systemic Lupus Erythematosus.

Zandra E Walton, Deepak A Rao.

DOI: https://doi.org/10.1002/art.70254
Gastroenterology. 2026 Jun 17. pii: S0016-5085(26)06976-3. [Epub ahead of print]

TIM3 signaling in effector T cells acts as an immunometabolic switch in the purine degradation pathway to suppress intestinal inflammation.

Annkathrin Knauss, Michael Gabel, Cora Kaufmann, Laura Loges, Timo Rath, Raja Atreya, Daniel Radtke, Hendrik Grapp, Katharina Gerlach, Oana-Maria Thoma, Markus Eckstein, Arne Gessner, Nora Bartels, Benjamin Schmid, Philipp Tripal, Benno Weigmann, Markus F Neurath.

   BACKGROUND AND AIMS: Effector T lymphocytes have been shown to play a key role in inflammatory bowel diseases (IBD). However, the molecular pathways controlling their metabolism and functional activity remain poorly defined. We aimed to elucidate the role of the immune checkpoint receptor TIM3 for T cell signalling in IBD.
METHODS: We combined experimental colitis models in TIM3-deficient mice with analyses of human IBD and control samples. Blood and mucosal T cells were assessed using multi-colour flow cytometry, cytokine profiling, and untargeted metabolomics. Single-cell sequencing data were analysed. The TIM3 ligand galectin-9 was used to study TIM3 function.
RESULTS: TIM3 expression was higher on blood Th1 cells and mucosal Th17 cells in IBD patients compared to controls, with levels being particularly high in anti-TNF refractory patients. Mice lacking TIM3 showed exacerbated oxazolone colitis and increased effector T cell activation. Metabolome profiling and functional analyses revealed that TIM3 signaling functions as an immunometabolic regulator, suppressing adenosine deaminase and the purine degradation pathway to keep effector T cells in an exhausted PD1+ state. However, insufficient availability of the TIM3 ligand galectin-9 limited effective TIM3 signalling in chronic inflammation. Treatment with galectin-9 ameliorated experimental colitis via adenosine deaminase inhibition. Moreover, in IBD T cells, galectin-9 induced an immunometabolic switch associated with reduction of terminally exhausted Th17 cells.
CONCLUSION: TIM3 plays a key role in the immunometabolism of effector T cells in colitis by suppressing adenosine deaminase and the purine degradation pathway. Targeting the immunometabolic functions of effector T cells via TIM3 activation emerges as a promising strategy for chronic intestinal inflammation.

Keywords:  Immunometabolism; Inflammatory bowel disease (IBD); T cell exhaustion; TIM3/galectin-9 axis

DOI:  https://doi.org/10.1053/j.gastro.2026.05.027
Research (Wash D C). 2026 ;9 1326

Chimeric Antigen Receptor T Cells as Living Therapeutics Targeting Senescence and Age-Related Diseases.

Qingyi Shao, Danlei Chen, Wenxia Shao, Qing Ye.

The aging of the global population exacerbates the burden of age-related diseases; however, therapies that can intervene in fundamental aging processes are lacking. Senescent cells drive chronic inflammation and multitissue dysfunction through the secretion of proinflammatory and profibrotic senescence-associated secretory phenotype cells, making them emerging therapeutic targets. Although first-generation senolytic drugs have entered clinical trials, they face limitations such as insufficient targeting specificity and transient efficacy. The success of chimeric antigen receptor T cell (CAR T cell) therapy in cancer immunotherapy has validated its precision clearance capabilities as a "living drug". This review systematically elaborates on the paradigm shift of extending CAR T cell therapy to aging medicine, from the discovery and validation of surface targets on senescent cells to a CAR engineering design tailored to the senescent microenvironment and from evidence of reversing fibrosis and improving metabolic function in preclinical models to the challenges of specificity, safety, and manufacturing faced in clinical translation. Finally, future directions for integrating technologies such as mRNA delivery and artificial intelligence are envisioned in this article, which proposes that CAR T cell therapy may drive the evolution of medicine from "treating single diseases" to "intervening in shared aging processes", offering transformative strategies to achieve healthy aging.

DOI: https://doi.org/10.34133/research.1326
Neuron. 2026 Jun 16. pii: S0896-6273(26)00371-5. [Epub ahead of print]

Mitochondria and brain aging: From cell-specific dysfunction to intercellular cooperation.

Amandine Grimm, Undine Lang, Anne Eckert.

  Mitochondria are essential for brain energy metabolism and are increasingly recognized as key contributors to brain aging. Although neurons are exceptionally vulnerable to age-related mitochondrial decline, emerging evidence reveals that glial and vascular cells also exhibit distinct mitochondrial impairments. This review synthesizes recent advances in our understanding of mitochondrial dysfunction across specific brain regions and diverse cell types, highlighting subcellular compartmentalization and metabolic rewiring. We further explore intercellular mitochondrial transfer as a novel form of metabolic cooperation, as well as the therapeutic potential of mitochondrial transplantation. Finally, we highlight recent clinical trials evaluating mitochondria-targeted interventions aimed at preserving brain function in older adults. Together, these findings reposition mitochondria as both integrators and amplifiers of brain aging processes across diverse cell populations. By broadening the focus beyond neurons and emphasizing translational efforts, we offer a comprehensive framework for understanding and therapeutically targeting mitochondrial dysfunction in age-related cognitive decline and neurodegeneration.

Keywords:  aging; astrocytes; blood-brain barrier; brain; intercellular mitochondrial transfer; microglia; mitochondria; mitochondrial transplantation; neurons; oligodendrocytes

DOI:  https://doi.org/10.1016/j.neuron.2026.04.048
J Control Release. 2026 Jun 18. pii: S0168-3659(26)00514-6. [Epub ahead of print] 115111

A TIGIT nanotrapping-guided STING-activatable immunometabolic strategy overcomes innate immune silence and T cell exhaustion in breast cancer.

Shuai Guo, Xiaoke Wang, Huiwan Chen, Xiaopan Chen, Tianyu Li, Xueqin Shi, Baoyan Ou, Juntao Yuan, Zhilu Yang, Jun Zhou, Shaohui Deng, Yang Liu, Xing-Jie Liang, Caiwen Ou.

  Breast cancer exhibits a profoundly immunosuppressive tumor microenvironment (TME), where innate immune silence prevents antigen sensing and persistent T cell exhaustion limits effector responses, rendering most immunotherapies ineffective. Clinical profiling of 1093 The Cancer Genome Atlas (TCGA) cases identified a glucose-fueled glutathione (GSH)-glutathione peroxidase 4 (GPX4)-dihydrolipoamide S-acetyltransferase (DLAT) axis as a dominant metabolic shield that suppresses oxidative stress, and thereby enforces both stimulator of interferon genes (STING) silence and CD8+ T cell exclusion. To dismantle this barrier, we developed an immunometabolic nanotherapy, GOx/ES-CO-LDH@TIGIT-Nanotrap (TNT). In acidic tumors, proton-driven layered double hydroxide (LDH) disassembly releases glucose oxidase (GOx) and extremely small cuprous oxide (ES-CO). GOx depletes glucose and nicotinamide adenine dinucleotide phosphate (NADPH) to induce disulfidptosis, while ES-CO releases cuprous ions (Cu+) that trigger cuproptosis via binding to lipoylated mitochondrial proteins. Their mutual biochemical amplification produces a cycloacclerated disulfidptosis-cuproptosis cascade that collapses the GSH-GPX4-DLAT axis and restores STING activation. Meanwhile, the macrophage-derived T cell immunoreceptor with Ig and ITIM domains (TIGIT) Nanotrap sequesters CD155 to prevent T cell suppression. Together, this coordinated innate reactivation and adaptive rescue converts immune-cold tumors into STING-inflamed and T cell responsive lesions.

Keywords:  Cuproptosis; Disulfidptosis; Innate immune silence; STING-activable immunometabolic nanotherapy; T cell exhaustion; TIGIT nanotrap

DOI:  https://doi.org/10.1016/j.jconrel.2026.115111
J Egypt Natl Canc Inst. 2026 Jun 15. pii: 21. [Epub ahead of print]38(1):

Immune checkpoint crosstalk between LAG-3 and CD39/CD73 in glioblastoma: dual-pathway regulation of metabolic exhaustion and therapeutic reversal strategies.

Arpita Mukherjee.

  Glioblastoma (GBM) represents an immunologically "cold" and metabolically suppressive tumor characterized by profound T-cell exhaustion, hypoxia-induced adenosinergic signaling, and resistance to checkpoint blockade. Converging evidence identifies lymphocyte-activation gene 3 (LAG-3) and the CD39/CD73 ectonucleotidase cascade as cooperative regulators of immune dysfunction within the GBM microenvironment. LAG-3 attenuates TCR/CD3 signaling and disrupts mitochondrial oxidative phosphorylation, diminishing effector T-cell persistence. Concurrently, CD39/CD73-mediated ATP hydrolysis elevates adenosine levels, activating A₂A receptors that inhibit glycolysis, suppress IFN-γ, and promote Treg and M2 macrophage polarization. Spatial and single-cell omics reveal co-localization of LAG-3⁺ exhausted T cells with CD73⁺ stromal and myeloid niches, suggesting a reciprocal immunometabolic feedback loop reinforcing exhaustion. This review elucidates the molecular crosstalk between LAG-3 signaling and the adenosine pathway, emphasizing key metabolic regulators including AMPK, mTOR, and HIF-1α. It further evaluates therapeutic strategies combining LAG-3 or PD-1 blockade with adenosine receptor antagonists or CD73 inhibitors to restore T-cell bioenergetics and antitumor activity. By integrating mechanistic immunometabolism with translational insights, this review establishes a dual-pathway framework of checkpoint synergy underlying resistance in GBM and proposes rational combination immunotherapies to reverse metabolic and immune exhaustion.

Keywords:  Adenosine signaling; CD39/CD73; Glioblastoma; Immune checkpoint crosstalk; Immunotherapeutic reversal; LAG-3; Metabolic exhaustion

DOI:  https://doi.org/10.1186/s43046-026-00361-y
Front Immunol. 2026 ;17 1849305

Follicular T cells in the ovarian cancer immune microenvironment: biological insights and translational implications.

Yidan Xu, Li Li.

   Background: Ovarian cancer, particularly high-grade serous ovarian cancer (HGSOC), exhibits a generally poor response to immune checkpoint inhibitors, and its underlying mechanisms remain incompletely defined. This observation suggests that an immunological framework focused predominantly on CD8+ cytotoxic T cells is insufficient to fully explain immune resistance in ovarian cancer. Increasing evidence highlights the importance of tertiary lymphoid structures (TLS) and follicular immune responses in coordinating antitumor immunity and shaping therapeutic outcomes.
Main body: Follicular T cell subsets-including follicular helper T cells (Tfh), follicular regulatory T cells (Tfr), and CXCR5+ follicular-like cytotoxic CD8+ T cells (Tfc)-form a dynamic immunoregulatory axis that governs B-cell activation, germinal center-like structure formation, antigen presentation, and local immune microenvironment remodeling. In this review, we systematically summarize the differentiation programs and regulatory mechanisms of follicular T cells and their compartment-specific distribution and functional remodeling in ovarian cancer. We integrate current evidence regarding their interactions with TLS maturation, B-cell function, and effector CD8+ T cell responses. Attention is given to the emerging concept that dysregulation of the follicular T cell axis-especially an elevated Tfr/Tfh ratio and defective functional maturation of TLS-may contribute to immune suppression and resistance to immunotherapy in ovarian cancer. From a translational perspective, we discuss therapeutic strategies aimed at reprogramming follicular T cell responses, including immune checkpoint modulation, chemokine axis targeting, metabolic interventions, and engineered cell-based therapies. We also highlight follicular immune features as potential biomarkers for immunotherapy response prediction and patient stratification.
Conclusions: Collectively, this review proposes a follicular T cell-centered immunological framework that extends beyond conventional CD8+ T cell-centric models and identifies promising therapeutic avenues to overcome immunotherapy resistance in ovarian cancer.

Keywords:  follicular T cells; immunotherapy; ovarian cancer; tertiary lymphoid structures; tumor immune microenvironment

DOI:  https://doi.org/10.3389/fimmu.2026.1849305
Mol Med. 2026 Jun 15.

β-Adrenergic receptors as immunomodulators in T cells: mechanisms of neuroimmune crosstalk and pathophysiological implications.

Junyan Yao, Suli Zhang, Fei Sun, Mingyang Chen, Huirong Liu.

  Regulation of T cell function by the sympathetic nervous system via β-adrenergic receptors is a pivotal research focus in neuroimmunology, with most studies centered on β2-adrenergic receptors. However, the roles of other subtypes remain unclear. This review systematically summarizes differential expression and signaling of β2- and β1-adrenergic receptors across T cell subsets. While β2-adrenergic receptor bidirectionally modulates immune responsiveness through classical or non-classical pathways, β1-adrenergic receptor is predominantly expressed in regulatory and exhausted T cells, exerting immunosuppression via the cAMP-CREM axis. Furthermore, this review examines the pathophysiological roles of β-adrenergic receptor signaling in the tumor immune microenvironment, autoimmune diseases, infections and cardiovascular diseases, highlighting β1-adrenergic receptor as a candidate immune checkpoint. Ultimately, elucidating the subtype-specific mechanisms of β-adrenergic signaling provides a critical framework for understanding immune dysregulation and highlights the potential of targeting these pathways to restore immune homeostasis in various pathological contexts.

Keywords:  T cell; neuroimmune interaction; sympathetic nervous system; β-adrenergic receptor

DOI:  https://doi.org/10.1186/s10020-026-01526-0
J Transl Med. 2026 Jun 18.

Transcriptional and functional profiling reveals unique activation of Adapter CAR T cells in acute myeloid leukemia.

Nele Knelangen, Ulrika Bader, Evangelia Maniaki, Boris Engels, Luca Gattinoni, Joerg Mittelstaet.

   BACKGROUND: Chimeric antigen receptor (CAR) T cell therapy has shown great promise in treating malignant diseases, yet its efficacy is often limited by challenges such as controllability and the lack of tumor-specific antigens. Adapter CAR (AdCAR) T cells address these limitations by redirecting T cell activity through adapter molecules rather than direct interaction with tumor-associated antigens, offering an on-/off- switch mechanism and the potential for multitargeting. While functionality of AdCAR T cells has been demonstrated in various models, the underlying AdCAR T cell response to differing adapter concentration and its comparison to conventional CAR T cells remain poorly characterized.
METHODS: In this study, we systematically examined adapter-dependent AdCAR T cell responses using functional assays and single-cell RNA sequencing in an acute myeloid leukemia model.
RESULTS: Adapter concentration was found to determine AdCAR T cell activation dynamics, transcriptional states and metabolic reprogramming. At low adapter concentrations, an interferon-responsive state was observed, while high concentrations induced strong cytolytic activity, cytokine secretion, and metabolic shifts toward glycolysis and oxidative phosphorylation. Importantly, increasing adapter concentrations enhanced tumor control of sub-optimally activated AdCAR T cells, demonstrating the platform's tunability. A hallmark gene signature was identified across different adapters and target cells, comprising the interferon-responsive gene MX1 and activation-associated genes including ENO1, HSP90AB1, and RRM2.
CONCLUSIONS: Our findings provide a mechanistic framework for tuning AdCAR T cell responses and offer critical insights for optimizing adapter dosing to enhance the safety and efficacy of tunable CAR T cell therapies.

Keywords:  Adapter CAR T cell; CAR T cell; T cell activation; Universal CAR T cell

DOI:  https://doi.org/10.1186/s12967-026-08461-y
Front Immunol. 2026 ;17 1847986

The trinity of T cell engagement: navigating the molecular and clinical landscape of CAR-T, TILs, and TCEs in the war against cancer.

Qiang Yang, Shaobin Wang, Fanlin Liu, Yongli Yu, Hai Zhao.

  The advent of cancer immunotherapy has fundamentally restructured the oncological paradigm, moving away from agents that directly target tumor cell kinetics toward strategies that empower the host immune system to recognize and eliminate malignancy. Central to this revolution is the cytotoxic T lymphocyte (CTL), now harnessed as a potent "living drug" through engineered and naturally selected modalities. This review provides a critical, in-depth examination of the three dominant pillars of T cell-driven therapies: Chimeric Antigen Receptor T-cell (CAR-T) therapy, Tumor-Infiltrating Lymphocyte (TIL) therapy, and T Cell Engagers (TCEs). We dismantle the molecular mechanisms defining each approach, contrasting the synthetic, major histocompatibility complex (MHC)-independent signaling of CAR-T cells with the diverse, MHC-restricted TCR repertoire of TILs, and the transient, pharmacologic bridging provided by bispecific TCEs. While CAR-T therapy has achieved historic success in hematologic malignancies, its translation to solid tumors is severely compromised by the hostile tumor microenvironment (TME), characterized by metabolic insulation, physical exclusion, and profound immunosuppression. Conversely, TIL therapy offers a polyclonal strategy tailored for solid tumors but is hindered by complex biomanufacturing logistics and variable tumor immunogenicity. TCEs promise off-the-shelf accessibility but face challenges regarding persistence and on-target/off-tumor toxicity. Beyond clinical outcomes, we explore the pathophysiological underpinnings of resistance, including antigen escape mechanisms and T cell exhaustion programs. Finally, we posit that the future of curative regimens lies in rational combinatorial strategies-integrating advanced genetic engineering, metabolic reprogramming, and TME-modulating agents like oncolytic viruses-to overcome the multifaceted defenses of solid tumors.

Keywords:  CAR T-cells; adoptive cell therapy; antigen escape; bispecific T cell engagers; immunosuppression; synthetic biology; tumor microenvironment; tumor-infiltrating lymphocytes (TILs)

DOI:  https://doi.org/10.3389/fimmu.2026.1847986
Nat Aging. 2026 Jun;6(6): 1281-1297

Profiling the molecular and physiological effects of senolytic treatment on aged mice identifies immune, fibrotic and metabolic remodeling.

Jing Hou, Kai-Xuan Chen, Qiao-Ni Xiao, Chen Hu, Jie Wei, Yang-Zi Jiang, Ling Liu, Chen He, Mei Huang, Yu-Rui Jiao, Xiang Tang, Nan-Yu Zou, Wen-Zhen He, Yu-Chen Sun, Yue-Ying Zhou, Xi Huang, Chao Zeng, Guang-Hua Lei, Yi-Lun Wang, Chang-Jun Li.

Although senolytics such as dasatinib and quercetin (D+Q) show promise in modulating aging, their tissue-specific efficacy and optimal intervention timing remain poorly understood. Given D+Q's potential off-target effects, incomplete senescent cell clearance and associated hematologic side effects, we performed an unbiased multitissue single-cell analysis in aged mice across different aging phenotypes and tissue contexts. Here through integrative transcriptomics, single-cell technologies, histopathology and molecular profiling, we investigated the influence of D+Q treatment on aging-related phenotypes at the tissue and cellular levels. Specifically, D+Q remodeled immunity by enhancing immune cell function and maintaining population stability, alleviated tissue inflammation and improved metabolic profiles. Furthermore, intervention initiated during early aging and prolonged treatment showed a greater tendency to mitigate readouts of aging compared to shorter, late-stage treatment. Our findings reveal that D+Q systematically attenuates several aging hallmarks in a tissue- and cell-type-specific manner, and support the possibility that early-initiated, long-term intervention may amplify efficacy.

DOI: https://doi.org/10.1038/s43587-026-01130-1