bims-imseme 2025-12-21 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2025–12–21
thirty papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Regulation of T cell exhaustion and stemness: molecular mechanisms and implications for cancer immunotherapy.
Autophagy-regulated mitochondrial inheritance controls early CD8+ T cell fate commitment.
PD-1 blockade during T cell priming enhances long-term protection against metastatic tumors by epigenetically tuning T cell exhaustion.
HHLA2 promotes immune evasion in EGFR-mutant lung cancer by inhibiting CD8+ T cell glutamine metabolism via KIR3DL3 interaction.
Bcl-2 protein Noxa is required for metabolic reprogramming to glutamine dependence and for apoptosis in stimulated human CD8 + T cells.
Mitochondrial complex II orchestrates divergent effects in CD4+ and CD8+ T cells.
Dysfunctional CD4 T cells in an oncovirus-specific TCR-transgenic in vivo model.
Stress to exhaustion: Proteotoxicity in T cells.
PCK1 deficiency promotes MASH-HCC progression by 12-HETE-induced CD8+ T cell dysfunction.
Progenitor-Predominant Exhaustion in CIKs Reveals TIM-3 as a Superior Target for Enhancing CIK Cytotoxicity.
A Conserved Landscape of Chemokine Receptor Co-expression Defines the Functional States of CD8+ T Cells in Melanoma.
IL-27 effects on HIVGag-specific CD4 and CD8 T cell function.
PD-1 regulates CD4 + T cell-mediated CD8 + T cell responses in the brain to balance viral control and neuroinflammation.
Correction for Wang et al., Engineering bacteria for cancer immunotherapy by inhibiting IDO activity and reprogramming CD8+ T cell response.
"Dissecting the role of T cell exhaustion in cancer progression: a multifaceted approach".
Can therapies against cellular aging help treat metabolic diseases?
Pomalidomide enhances CAR-T cell therapeutic efficacy and remodels immune microenvironment in lymphoid malignancies.
Aging-associated transcriptional programs in T cells signify constituents of TGF-β signaling for immunosenescence.
Targeting OxLDL-mediated CD36 + CAF reprogramming potentiates PD-1 immunotherapy in osteosarcoma.
Potential strategies to improve the therapeutic efficacy of oncolytic viruses for cancer through T and NK cells targeting.
Transient hepatic reconstitution of trophic factors enhances aged immunity.
SP140 limits type I interferon-driven pathology, preserving T cell motility and promoting resistance in tuberculosis.
Potentiating immunotherapy in "immune-cold" solid tumors through orchestrating T cell immunity via tumor-specific genetic engineering.
VISTA+ follicular regulatory T cells modulate the function of effector immune cells: implications for ovarian cancer immune escape.
Afg3l2 couples mitochondrial vitamin B12 trafficking to amino acid metabolism to safeguard hematopoietic stem cell homeostasis.
The Diverse Roles of Lipid Metabolism Reprogramming in Shaping the Tumor Immune Microenvironment.
Tumor cell-derived microparticles induced by methotrexate reprogram neutrophil antitumor response via lysosomal ROS mediated degranulation.
An innovative engineered IL-10 monomer strengthens T cell-mediated anti-tumor responses through anti-PD-1 cis-delivery.
The role of miR-3188-mediated transcriptional activation of IL-7Rα in tumor immunotherapy research.
Sympathetic-parasympathetic system deregulation theory of aging.

Cell Mol Immunol. 2025 Dec 19.

Regulation of T cell exhaustion and stemness: molecular mechanisms and implications for cancer immunotherapy.

Zeyu Chen, Ziang Zhu, Taidou Hu, Chen Yao, Tuoqi Wu.

  T cells are central components of the adaptive immune system and play key roles in antitumor and antiviral responses. The diverse cell fates of T cells enable them to respond to different durations and strengths of antigen stimulation and various cytokine milieus in a context-dependent manner. During acute infection or vaccination, T cells differentiate into effector cells and later develop into memory cells after antigen clearance, which mediate immune protection against the same antigen. In contrast, during cancer and chronic infection, T cells fail to enter the canonical effector or memory cell differentiation path. Instead, antigen-specific T cells enter a dysfunctional, partially responsive state called exhaustion. Exhausted T cells are heterogeneous. A subset of exhausted T cells exhibits stem cell-like properties. These stem-like T cells sustain immunity through self-renewal and repopulation of terminally differentiated progenies. Stem-like properties are critical for T cell immunity induced by immunotherapy. This review summarizes recent advances in understanding the molecular mechanisms controlling the exhaustion and stemness of T cells and explores the potential of rewiring these circuits to increase the efficiency of T-cell-based immunotherapy.

Keywords:  Cancer immunology; Chronic infection; Immunotherapy; Stem-like T cells; T cell exhaustion

DOI:  https://doi.org/10.1038/s41423-025-01378-4
Nat Cell Biol. 2025 Dec 19.

Autophagy-regulated mitochondrial inheritance controls early CD8+ T cell fate commitment.

Mariana Borsa, Ana Victoria Lechuga-Vieco, Amir H Kayvanjoo, Edward Jenkins, Yavuz Yazicioglu, Ewoud B Compeer, Felix C Richter, Simon Rapp, Robert Mitchell, Tom Youdale, Hien Bui, Emilia Kuuluvainen, Michael L Dustin, Linda V Sinclair, Pekka Katajisto, Anna Katharina Simon.

T cell immunity deteriorates with age, accompanied by a decline in autophagy and asymmetric cell division. Here we show that autophagy regulates mitochondrial inheritance in CD8+ T cells. Using a mouse model that enables sequential tagging of mitochondria in mother and daughter cells, we demonstrate that autophagy-deficient T cells fail to clear premitotic old mitochondria and inherit them symmetrically. By contrast, autophagy-competent cells that partition mitochondria asymmetrically produce daughter cells with distinct fates: those retaining old mitochondria exhibit reduced memory potential, whereas those that have not inherited old mitochondria and exhibit higher mitochondrial turnover are long-lived and expand upon cognate-antigen challenge. Multiomics analyses suggest that early fate divergence is driven by distinct metabolic programmes, with one-carbon metabolism activated in cells retaining premitotic mitochondria. These findings advance our understanding of how T cell diversity is imprinted early during division and support the development of strategies to modulate T cell function.

DOI: https://doi.org/10.1038/s41556-025-01835-2
bioRxiv. 2025 Nov 29. pii: 2025.11.25.690601. [Epub ahead of print]

PD-1 blockade during T cell priming enhances long-term protection against metastatic tumors by epigenetically tuning T cell exhaustion.

Teresa Dinter, Sebastian Mackowiak, Zachary J Rogers, Vidit Bhandarkar, Molly Y Carney, Yiming J Zhang, Duncan Morgan, Lorelai Pop, Fiona Chatterjee, Emi Lutz, Yajit Jain, Adityanarayanan Radhakrishnan, Eric Lander, K Dane Wittrup, J Christopher Love, Alexander Meissner, Stefani Spranger.

In cancer, CD8 + T cell responses are dominated by exhausted T cells, which can be reinvigorated using immune checkpoint blockade therapy and can control large tumors. However, it remains unclear which T cell fate best supports long-term immunity following tumor regression or clearance and a period of minimal antigen load. This question is particularly relevant following surgical tumor resection, when tuning the immune system could prevent recurrence. To determine which T cell fate provides durable protection following surgery and metastatic rechallenge, we modulated T cell priming using anti-PD-1, IFN-β or agonistic anti-CD40 and assessed effects on CD8 + T cell differentiation and overall survival. IFN-β and anti-CD40 promoted effector and memory-like T cell states, respectively, whereas anti-PD-1 did not markedly alter T cell differentiation, yet conferred the greatest survival benefit against metastatic tumors. Notably, anti-PD-1 induced epigenetic remodeling, which was detectable upon metastatic recall, consistent with the maintenance of a circulatory intermediate-exhausted T cell state. Thus, while effector and memory precursor-like T cells could be generated with IFN-β and agonistic anti-CD40, only the intermediate-exhausted T cell state driven by anti-PD-1 supported durable anti-tumor immunity.
Summary: This study shows that PD-1 blockade during T cell priming promotes a circulatory intermediate-exhausted CD8⁺ T cell state that uniquely supports durable anti-tumor immunity after surgical resection and metastatic challenge, outperforming effector or memory-like T cell responses generated by IFN-β or CD40 agonist treatment, respectively.

DOI: https://doi.org/10.1101/2025.11.25.690601
Cancer Lett. 2025 Dec 12. pii: S0304-3835(25)00791-8. [Epub ahead of print]639 218219

HHLA2 promotes immune evasion in EGFR-mutant lung cancer by inhibiting CD8+ T cell glutamine metabolism via KIR3DL3 interaction.

Fei Wu, Jiannan Shen, Zhiting Zhao, Yan Chen, Binhui Ren, Ming Li, Rong Yin, Yanyan Zhang, Shaorong Yu.

  Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality, and EGFR-mutant tumors show limited response to current immunotherapy. The immunosuppressive tumor microenvironment, particularly metabolic constraints on effector T cells, is increasingly recognized as a major barrier to effective anti-tumor responses. HHLA2, a B7 family member frequently elevated in EGFR-mutant NSCLC, has an incompletely defined role in immune escape. In this study, we demonstrate that tumor-derived HHLA2 engages the inhibitory receptor KIR3DL3 on CD8+ T cells, driving T cell exhaustion through metabolic reprogramming of amino acid utilization. HHLA2-KIR3DL3 signaling suppresses glutamine utilization through ERK/MAPK-dependent repression of SLC1A5, SLC38A2, and ADHFE1, key glutamine transporters and metabolic enzymes, thereby inducing metabolic insufficiency and dysfunctional cytokine production in CD8+ T cells, including reduced IFN-γ, TNF-α, and increased IL-10. Disruption of this axis-via HHLA2 deletion or antibody blockade-restored T cell metabolism and effector function, leading to attenuated tumor progression in humanized mouse models. Notably, HHLA2/KIR3DL3 inhibition synergized with EGFR tyrosine kinase inhibitors to enhance anti-tumor immunity and suppress tumor progression. Together, these findings identify HHLA2-KIR3DL3 as a key immunosuppressive pathway in EGFR-mutant NSCLC and may provide a rationale for therapeutic targeting to improve clinical outcomes.

Keywords:  CD8(+) T cell exhaustion; EGFR-Mutant lung cancer; ERK/MAPK signaling pathway; Glutamine metabolism; HHLA2

DOI:  https://doi.org/10.1016/j.canlet.2025.218219
bioRxiv. 2025 Dec 10. pii: 2025.12.08.692849. [Epub ahead of print]

Bcl-2 protein Noxa is required for metabolic reprogramming to glutamine dependence and for apoptosis in stimulated human CD8 + T cells.

Tingyuan Yang, Himani Sharma, Jenna M Benson, William J Valente, Rebecca LaRue, Beau Webber, Branden Moriarity, Christopher A Pennell, Stephen C Jameson, Ameeta Kelekar.

Naïve or memory T cells reprogram their metabolism upon antigenic stimulation. They increase their glucose uptake, relying on aerobic glycolysis for generating biomass while switching to glutamine to fuel energy production. Here we have identified a requirement for human Bcl-2 family, Noxa, in the metabolic switch to glutamine dependence in activated CD8 + T cells, that is independent of its canonical role in apoptosis at the end of the immune response. Using an in vitro co-stimulation model, we demonstrate that Noxa is induced in CD8 + T cells and remains elevated during the proliferative and differentiation phases of the response and through the onset of apoptosis. Noxa protein induction requires glutamine, is mediated via mTOR, and is independent of glutaminolysis. Glutamine, in turn, requires Noxa to facilitate its conversion to glutamate. CD8 + T cells lacking Noxa showed reduced levels of intracellular glutamate but no impairment of mitochondrial or effector function, and decreased dependence on glutamine for both respiration and growth during the proliferative phase. NOXA knockout CD8⁺ T cells also displayed significantly higher viability in the apoptotic phase of the immune response. CD8 + T cells from a human NOXA gene-replacement mouse responded normally to in vitro stimulation and in vivo acute infection. However, human Noxa-expressing murine CD8 + T cells displayed a distinctly proliferative gene signature in their transcriptome following activation, supporting an early growth-promoting role for this BH3-only protein. Our studies suggest that knocking out NOXA in human CD8 + T cells to increase their lifespan as well as their ability to survive and function in glutamine-poor microenvironments could be a promising immunotherapeutic strategy.

DOI: https://doi.org/10.64898/2025.12.08.692849
J Clin Invest. 2025 Dec 15. pii: e194134. [Epub ahead of print]135(24):

Mitochondrial complex II orchestrates divergent effects in CD4+ and CD8+ T cells.

Keisuke Seike, Shih-Chun A Chu, Yuichi Sumii, Takashi Ikeda, Meng-Chih Wu, Laure Maneix, Dongchang Zhao, Yaping Sun, Marcin Cieslik, Pavan Reddy.

  Mitochondrial metabolism orchestrates T cell functions, yet the role of specific mitochondrial components in distinct T cell subsets remains poorly understood. Here, we explored the role of mitochondrial complex II (MC II), the only complex from the electron transport chain (ETC) that plays a role in both ETC and metabolism, in regulating T cell functions. Surprisingly, MC II exerts divergent effects on CD4+ and CD8+ T cell activation and function. Using T cell-specific MC II subunit, succinate dehydrogenase A-deficient (SDHA-deficient) mice, we integrated single-cell RNA-seq and metabolic profiling, with in vitro and in vivo T cell functional assays to illuminate these differences. SDHA deficiency induced metabolic changes and remodeled gene expression exclusively in activated T cells. In CD4+ T cells, SDHA loss dampened both oxidative phosphorylation (OXPHOS) and glycolysis, impaired cytokine production, proliferation, and reduced CD4+ T cell-mediated graft-versus-host disease after allogeneic stem cell transplantation (SCT). In contrast, SDHA deficiency in CD8+ T cells reduced OXPHOS but paradoxically upregulated glycolysis and demonstrated enhanced cytotoxic functions in vitro and in vivo. This metabolic reprogramming endowed SDHA-KO CD8+ T cells with superior in vivo antitumor efficacy after immune checkpoint inhibitor therapy and allogeneic SCT. These findings reveal MC II as a bifurcation point for metabolic and functional specialization in CD4+ and CD8+ T cells.

Keywords:  Bone marrow transplantation; Hematology; Immunology; Metabolism; Mitochondria; T cells

DOI:  https://doi.org/10.1172/JCI194134
Nat Commun. 2025 Dec 18.

Dysfunctional CD4 T cells in an oncovirus-specific TCR-transgenic in vivo model.

Felicia S Spitzer, Marcel G M Camps, Cedrik M Britten, Sandra Vloemans, Hester J T van Zeeburg, Cornelis J M Melief, Tsolere Arakelian, Ferry Ossendorp.

T cell exhaustion has been implicated in cancer and infectious diseases. In this study, we report a novel mouse model, "MolT-II", with T cells expressing a transgenic T cell receptor (TCR) specific for a Moloney virus envelope-derived, MHC class II-presented peptide epitope. Characterization of MolT-II CD4 T cells revealed that they are dysfunctional, showing severely impaired effector functions, reduced proliferation and increased baseline expression of co-inhibitory receptors such as PD-1, LAG-3 and CTLA-4, likely due to chronic exposure to a self-antigen. We further show that epitope-specific peptide vaccination combined with immune checkpoint blockade is able to restore the function of MolT-II CD4 T cells in vivo, associated with enhanced tumor control in mice. The MolT-II mouse strain thus represents an in vivo model for reversible CD4 T cell dysfunction, allowing the study of the role of CD4 T cell regulation in cancer, mechanisms underlying CD4 T cell dysfunction and exhaustion, and novel immunomodulatory therapies aiming to rescue dysfunctional T cells.

DOI: https://doi.org/10.1038/s41467-025-67588-6
Mol Cell. 2025 Dec 18. pii: S1097-2765(25)00933-5. [Epub ahead of print]85(24): 4490-4491

Stress to exhaustion: Proteotoxicity in T cells.

Ting Zhang, Chen Dong.

In a recent Nature paper, Yi et al.1 uncover that a noncanonical proteotoxic stress response (PSR) in exhausted T cells (Tex), termed "Tex-PSR," drives T cell exhaustion. This response is characterized by sustained global protein synthesis, accumulation of protein aggregate, and selective upregulation of chaperone proteins.

DOI: https://doi.org/10.1016/j.molcel.2025.11.016
Gut. 2025 Dec 17. pii: gutjnl-2024-334562. [Epub ahead of print]

PCK1 deficiency promotes MASH-HCC progression by 12-HETE-induced CD8+ T cell dysfunction.

Kang Wu, Luo Li, Yi Liu, Kai Wang, Jianghong Zheng, Huijun Liang, Fengli Xu, Renming Liu, Chang Chen, Luyi Huang, Haijun Deng, Xiaojian Han, Shi Chen, Zhirong Zhang, Xinyu Liu, Qiang He, Xiaosong Li, Aishun Jin, Ailong Huang, Ni Tang.

   BACKGROUND: Metabolic dysfunction-associated steatohepatitis-related hepatocellular carcinoma (MASH-HCC) has been reported to be less responsive to immune checkpoint inhibitors, which may be associated with metabolic reprogramming of tumour cells and abnormal tumour microenvironment.
OBJECTIVE: Here, we aim to investigate the role of gluconeogenic enzyme phosphoenolpyruvate carboxykinase 1 (PCK1) in MASH-HCC and its interplay with the tumour microenvironment.
DESIGN: Hepatocyte-specific phosphatase and tensin homologue (Pten) and Pck1 biallelic knockout mice were established to induce MASH-HCC. Single-cell RNA sequencing and multiparametrical flow cytometry were performed to analyse the immune landscape alterations. Untargeted metabolomics was conducted to elucidate the hepatic metabolism dysregulation.
RESULTS: PCK1 is downregulated in tumour tissues compared with adjacent non-cancerous tissues from patients with MASH-HCC. Hepatocyte-specific Pck1 knockout mice exhibited markedly increased tumorigenesis in dietary models and genetic models of spontaneous MASH-HCC, together with inhibited effector function of tumour-infiltrating CD8+ T cells. Mechanistically, PCK1 deficiency induces the accumulation of endogenous metabolite 12-hydroxyeicosatetraenoic acid (12-HETE), which can be taken up by CD8+ T cells and activate the p38 mitogen-activated protein kinase pathway by directly interacting with the BTB and CNC homology 1 transcription factor, ultimately leading to CD8+ T cells dysfunction. Notably, PCK1 restoration or 12-HETE inhibition combined with anti-PD-1 treatment increases the antitumour capability of CD8+ T cells and suppresses MASH-HCC development.
CONCLUSION: This study reveals the pivotal role of the hepatic cell-intrinsic enzyme PCK1 in mediating CD8+ T cell dysfunction via 12-HETE-p38 signalling in MASH-HCC. PCK1 could be a metabolic checkpoint to enhance the efficacy of anti-PD-1 immunotherapy in MASH-HCC.

Keywords:  CARCINOGEN METABOLISM; FATTY LIVER; HEPATOCELLULAR CARCINOMA

DOI:  https://doi.org/10.1136/gutjnl-2024-334562
J Leukoc Biol. 2025 Dec 19. pii: qiaf180. [Epub ahead of print]

Progenitor-Predominant Exhaustion in CIKs Reveals TIM-3 as a Superior Target for Enhancing CIK Cytotoxicity.

Jian Wang, Qin Wang, Jiahui Zhou, Li Zhou, Xiubao Ren, Feng Wei.

  Precursor exhausted and terminally exhausted T cells (Tpex and Tex) are associated with immune checkpoints, T-cell checkpoint blockade may improve patient survival. We assessed cytotoxic activity and PD-1/TIM-3 expressions of CD3+CD8+CD56+ T cells (NK-like T) in cytokine-induced killer (CIK) cells across exhaustion states. We grouped the NK-like T cells into three based on TOX and TCF1 expressions: TOX-TCF1+ (memory-like NK-like T), TOX+TCF1+ (NK-like Tpex), and TOX+TCF1- (NK-like Tex). The proportion of NK-like Tpex cells among the CIK cells was the highest （>90%) after culture. TIM-3 and PD-1 expression were high in NK-like Tpex but low in NK-like Tex cells. However, TIM-3 expression was higher than PD-1 expression in CIK cells, suggesting that combining CIK cells and TIM-3 inhibitors may have better effects. Perforin, granzyme B, DNAM-1, and NKG2D, which are cytotoxicity biomarkers, were more expressed in NK-like Tpex than in NK-like Tex cells, which implies that NK-like Tpex may still has a strong cytotoxic effect. The CD4⁺ T cell counts and TIM-3 expression level in the NK-like Tpex cells were positively correlated. CD4⁺ T cells may actively sustain progenitor exhaustion, but the mechanisms are unknown. In vitro cytotoxicity assays confirmed that CIK cell-mediated tumor cytotoxicity was significantly enhanced by TIM-3 than by PD-1 blockade. Furthermore, tumor cytotoxicity was greater for CIK cell cultures with higher than those with lower CD4⁺ T cell counts following TIM-3 blockade. This work demonstrates CD4⁺T cell modulation of progenitor exhaustion in CIK cells and positions TIM-3 blockade to rescue their anti-tumor potential.

Keywords:  CIK cells; Cytotoxicity; Immune checkpoint; Progenitor exhaustion (NK-like Tpex); Transcription factor (TOX/TCF1)

DOI:  https://doi.org/10.1093/jleuko/qiaf180
bioRxiv. 2025 Dec 16. pii: 2025.12.10.693486. [Epub ahead of print]

A Conserved Landscape of Chemokine Receptor Co-expression Defines the Functional States of CD8+ T Cells in Melanoma.

Rodney Macedo, David W Harle, Kevin Hoffer-Hawlik, Ximi K Wang, Thomas McMahon-Skates, Alexandra Matschiner, Kirubel Belay, Yvonne M Saenger, Benjamin Izar, Elham Azizi, Ran Reshef.

Cancer immunotherapies, from checkpoint blockade to adoptive cell therapies like tumor-infiltrating lymphocytes (TILs), have revolutionized cancer treatment but are limited by variable efficacy and significant toxicities. A central challenge is identifying ideal T-cell populations that effectively eliminate tumors without causing off-target damage, a distinction not captured by existing biomarkers. We show that co-expression patterns of chemokine receptors (CRs) CXCR3, CCR5, and CXCR6 on CD8 + T cells provide a functional "code" defining subsets with divergent roles in on-target immunity versus off-target inflammation. In mouse and human melanoma, a triple-positive (CXCR3 + CCR5 + CXCR6 + ) T-cell subset is essential for tumor control, and its genetic signature correlates with positive clinical response, while a distinct CCR5 + CXCR6 + subset drives liver immune-related adverse events (IRAEs). Crucially, this CR code reveals that immunotherapy actively reshapes T-cell trafficking patterns, uncovering profound heterogeneity within conventional populations and distinguishing potent anti-tumor progenitors from cells predisposed to exhaustion or off-target migration. This work establishes CR co-expression as a practical tool, providing a surface marker-based strategy to identify and enrich optimized T cells for adoptive therapies, thereby offering a framework to uncouple efficacy from toxicity.

DOI: https://doi.org/10.64898/2025.12.10.693486
Front Virol. 2025 ;pii: 1600802. [Epub ahead of print]5

IL-27 effects on HIVGag-specific CD4 and CD8 T cell function.

Maryam Abdussamad, Grace Katz, Jie Cheng, Chinmayee Mehta, Fernando Andres-Martin, Danial Mahmood, Princy Kumar, Marta Catalfamo.

   Background: In people with HIV (PWH) and suppressed viral replication by antiretroviral therapy persistent T cell activation and inflammation are important contributors of the increased risk of morbidity and mortality. CD8 T cells express checkpoint receptors and are dysfunctional. IL-27, a member of the IL-6/IL-12 family has shown anti-viral properties against various human viruses, including HIV. The role of IL-27 on HIV-specific T cells remains unclear. We hypothesized that IL-27 will enhance the function of HIV-specific T cells.
Methods: IL-27 effects on T cell function was evaluated by measuring cytokine secretion, proliferation, and cytotoxicity.
Results: Our findings show that IL-27 upregulates cytokine secretion and cytotoxic potential, and trafficking of proliferating HIV-specific CD8 T cells expressing checkpoint receptors TIGIT and PD-1. Unbiased clustering analysis showed that IL-27 may have differential effects on distinct populations of HIV-specific T cells.
Conclusion: Altogether these results suggest that IL-27 may enhance T cell function in the setting of chronic HIV infection.

Keywords:  HIV; HIV-specific T cells; IL-27 effects on T cells; IL27; T cell immune activation

DOI:  https://doi.org/10.3389/fviro.2025.1600802
bioRxiv. 2025 Dec 01. pii: 2025.11.26.690770. [Epub ahead of print]

PD-1 regulates CD4 + T cell-mediated CD8 + T cell responses in the brain to balance viral control and neuroinflammation.

Arrienne B Butic, Elia Afanasiev, Samantha A Spencer, Mofida Abdelmageed, Anirban Paul, Kalynn M Alexander, Katelyn N Ayers, Todd D Schell, Matthew D Lauver, Ge Jin, Samantha M Borys, Laurent Brossay, Jo Anne A Stratton, Vonn Walter, Aron E Lukacher.

Programmed cell death protein 1 (PD-1) is expressed by T cells during progressive multifocal leukoencephalopathy (PML), a life-threatening brain disease caused by the human-only JC polyomavirus. Why PD-1 blockade finds variable success in PML patients is unclear. Brain CD4 + and CD8 + T cells are PD-1 high during mouse polyomavirus (MuPyV) encephalitis. Here, we show that PD-1 loss during MuPyV infection acts in a brain-autonomous manner to increase the magnitude of brain-infiltrating CD4 + and CD8 + T cells and the function of virus-specific CD8 + T cells; in concert, brain virus levels decline and neuroinflammation increases. Deletion of PD-1 in CD4 + T cells, but not CD8 + T cells, recapitulates effects of global PD-1 loss. Single-cell RNA sequencing shows that PD-1-deficient CD8 + T cells cluster as effectors while transcripts associated with proliferation and function are upregulated with loss of PD-1. Thus, CD4 + T cell-intrinsic PD-1 signaling balances antiviral defense against neural injury during polyomavirus CNS infection.

DOI: https://doi.org/10.1101/2025.11.26.690770
Proc Natl Acad Sci U S A. 2025 Dec 23. 122(51): e2533734122

Correction for Wang et al., Engineering bacteria for cancer immunotherapy by inhibiting IDO activity and reprogramming CD8+ T cell response.

DOI: https://doi.org/10.1073/pnas.2533734122
Front Immunol. 2025 ;16 1646292

"Dissecting the role of T cell exhaustion in cancer progression: a multifaceted approach".

Xinyang Li, Shiwen Song.

  This article thoroughly explores the crucial role of T cell exhaustion in the process of tumor immune escape, comprehensively explaining its key characteristics, such as dynamic plasticity, heterogeneity, and epigenetic reprogramming. The article first elaborates on the complex interaction between immune surveillance and tumor escape, and then clarifies the core position of T cells in anti-tumor immunity and the evolution of the "exhaustion" concept, covering various research fields from chronic infections to the tumor microenvironment (TME). It provides a detailed analysis of the origin, differentiation pathways, and dynamic plasticity of exhausted T cells, revealing the possibility of functional recovery under specific conditions. At the same time, the article analyzes the profound influence of various factors in the TME (such as metabolic stress, immune suppression networks, and stromal interaction interfaces) on the process of T cell exhaustion. It conducts in-depth research on the molecular characteristics of exhausted T cells (including surface marker characteristics, transcriptional regulatory networks, and metabolic reprogramming characteristics), providing potential therapeutic targets for precision medicine. In the clinical translation aspect, this study clarifies the cutting-edge exploration achievements of diagnostic biomarkers, such as the exhausted subtypes defined by single-cell multi-omics technology, the prognostic value of TCR clonal dynamics, and the innovation of treatment strategies, including the "re-mobilization window" theory in PD-1 blockade, the synergistic effect of epigenetic drugs, the temporal and spatial selection in metabolic intervention, and the application of engineered cell therapies. This study systematically integrates the latest progress in the field of T cell exhaustion, providing comprehensive and profound theoretical support and innovative ideas for addressing challenges in tumor immunotherapy.

Keywords:  T cell exhaustion; TME; clinical translation; epigenetic reprogramming; immune escape; immunotherapy

DOI:  https://doi.org/10.3389/fimmu.2025.1646292
Saudi Med J. 2025 Dec;46(12): 1567

Can therapies against cellular aging help treat metabolic diseases?
Cancer Immunol Immunother. 2025 Dec 18. 75(1): 9

Pomalidomide enhances CAR-T cell therapeutic efficacy and remodels immune microenvironment in lymphoid malignancies.

Yi Zhou, Yan Yu, Linzhi Xie, Liwen Wang, Yuhan Yan, Qian Cheng, Jing Liu, Chang Zhang, Xin Li.

   BACKGROUND: Chimeric antigen receptor T cell (CAR-T) therapy achieves high remission rates in lymphoid malignancies, but its long-term efficacy is limited by poor persistence and T cell exhaustion. Pomalidomide, an immunomodulatory drug (IMiD), demonstrates clinical synergy with CAR-T therapy, yet the underlying mechanisms driving this potentiation remain poorly defined. This study aimed to elucidate how pomalidomide enhances CAR-T cell function and remodels the immune microenvironment to overcome therapeutic limitations.
METHODS: In vitro assays (CCK-8, LDH, qPCR, ELISA, flow cytometry) and bulk RNA-seq assessed pomalidomide's effects on human CAR-T cells. In vivo efficacy was evaluated in myeloma xenograft models. Single-cell RNA sequencing (scRNA-seq) of PBMCs from a lymphoma patient post-CAR-T/pomalidomide assessed immune microenvironment remodeling.
RESULTS: Pomalidomide significantly enhanced CAR-T cell proliferation and cytotoxicity in an activation-dependent manner. It upregulated effector molecules (IL-2, IFN-γ) and chemokines (CXCL9-CXCL11), promoted central memory T cells (Tcm), and induced metabolic reprogramming while reducing exhaustion markers. In xenografts, combination therapy induced tumor regression and extended survival vs. CAR-T alone. scRNA-seq revealed pomalidomide-driven remodeling, characterized by increased T/NK cell proportions/activity and reduced myeloid-derived suppressor cell (MDSC) signatures.
CONCLUSIONS: Pomalidomide synergizes with CAR-T by directly enhancing CAR-T function (memory, cytokine/chemokine production, metabolic fitness, and reduced exhaustion) and remodeling the suppressive immune microenvironment (increased cytotoxic effectors, diminished MDSC activity). These findings provide a crucial mechanistic rationale for optimizing pomalidomide-CAR-T combinations in refractory lymphoid malignancies.

Keywords:  CAR-T therapy; Immune microenvironment; Lymphoid malignancies; Memory T cell; Pomalidomide

DOI:  https://doi.org/10.1007/s00262-025-04247-1
BMC Biol. 2025 Dec 15.

Aging-associated transcriptional programs in T cells signify constituents of TGF-β signaling for immunosenescence.

Renke He, Chanchan Xiao, Wen Lei, Guobing Chen, Yangqiu Li, Oscar Junhong Luo.

   BACKGROUND: Immunosenescence, particularly the altered ratio of naïve and memory T cells, contributes to a diminished immune reserve and impaired adaptive immunity in aging and frail populations. The role of TGF-β signaling pathway-a critical hallmark of organismal senescence and T-cell exhaustion-in terminally differentiated effector memory T (Temra) cells remains elusive. We devised single-cell and bulk-cell RNA sequencing (RNA-seq) datasets to identify age-group-specific transcriptional regulatory networks in T cells and elucidate the roles of TGF-β signaling constituents associated with immunosenescence in Temra.
RESULTS: Analysis of scRNA-seq data from peripheral T cells across healthy human age groups revealed young-specific regulons controlled by FOXP1, TCF7, LEF1, and IKZF1 and old-specific regulons governed by EOMES, TBX21, RUNX3, and NFATC2. Transcription factor (TF)-binding-motif enrichment analysis implicated TGF-β signaling pathway components ZEB2 and TGFBR3 as pivotal target genes coregulated by multiple TFs, potentially facilitating T-cell terminal differentiation and exhaustion. Pseudotime analysis and bulk-cell RNA-seq further corroborated these regulons, validating their association with T-cell self-renewal capacity (young-specific) or effector/terminal differentiation (old-specific). In terms of aging, multiple TGF-β signaling activation components, including TGFB1, TGFBR1, SMAD3, ZEB2, and TGFBR3, were significantly upregulated in CD8 + Temra cells relative to CD8 + naïve T cells.
CONCLUSIONS: Our study used systematic approaches for delineating age-dependent transcriptional networks for T-cell-associated immunosenescence. We identified multiple components of the TGF-β signaling pathway as potential biomarkers of Temra, which are strongly associated with senescence features including impaired differentiation plasticity, high cytotoxicity, and inflammatory chemotaxis capacity.

Keywords:  Immunosenescence; TGF-β signaling pathway; TGFBR3; Temra; ZEB2

DOI:  https://doi.org/10.1186/s12915-025-02484-5
Mol Cancer. 2025 Dec 18.

Targeting OxLDL-mediated CD36 + CAF reprogramming potentiates PD-1 immunotherapy in osteosarcoma.

Anyu Zeng, Hongmin Chen, Tianqi Luo, Weiqing Chen, Yihui Song, Yanyang Xu, Zhihao Chen, Qinglian Tang, Xiaojun Zhu, Chuangzhong Deng, Huaiyuan Xu, Anqi Wang, Hao Wu, Guohui Song, Jinchang Lu, Jin Wang.

   BACKGROUND: Osteosarcoma demonstrates limited responsiveness to PD-1 blockade, largely due to its immunosuppressive tumor microenvironment (TME). The specific mechanisms by which cancer-associated fibroblasts (CAFs) contribute to immunosuppression in osteosarcoma are not fully understood.
METHODS: We performed single-cell RNA sequencing (scRNA-seq) on osteosarcoma tissues from patients treated with neoadjuvant chemotherapy and anti-PD-1 therapy to investigate the tumor microenvironment. Cellular composition, gene expression programs, and signaling pathways were analyzed. Functional assays, pull-down and PLA-flow binding validation, and in vivo mouse models were used to dissect the mechanisms by which CAF-derived factors influence CD8⁺ T cell function and contribute to immunotherapy response.
RESULTS: We identified a subpopulation of CD36⁺ CAFs, characterized by adaptive uptake of oxidized low-density lipoprotein (OxLDL) and activation of the PPARG-FABP4 axis. This metabolic program promoted ANGPTL4 secretion, which bound integrin on CD8⁺ T cells and activated the JAK2-STAT3 pathway, leading to T cell exhaustion and impaired effector function. In vivo, administration of VitE effectively scavenged OxLDL, reprogrammed the TME, enhanced CD8⁺ T cell infiltration, and synergized with PD-1 blockade to improve tumor control.
CONCLUSIONS: CD36⁺ CAFs drive immunosuppressive metabolic reprogramming via the OxLDL-PPARG-ANGPTL4 axis, promoting CD8⁺ T cell exhaustion and resistance to immunotherapy in osteosarcoma. Targeting this pathway with VitE alleviated CAF-mediated immune suppression and enhanced PD-1 blockade responses in preclinical models, providing a rationale for metabolism-based combinatorial strategies in osteosarcoma.

Keywords:  Cancer-associated fibroblasts; Immune checkpoint blockade; Immunotherapy resistance; Lipid metabolism reprogramming; Osteosarcoma

DOI:  https://doi.org/10.1186/s12943-025-02516-2
Crit Rev Oncol Hematol. 2025 Dec 14. pii: S1040-8428(25)00474-3. [Epub ahead of print]218 105086

Potential strategies to improve the therapeutic efficacy of oncolytic viruses for cancer through T and NK cells targeting.

Chuanjian Wu, Hanzhang Liu, Yujie Shi, Jie Tang, Rong Sun, Xudong Han, Yihui Fan.

  Oncolytic viruses (OVs) elicit potent tumor lysis and remodel the tumor microenvironment (TME) to activate adaptive and innate immunity, yet their efficacy depends critically on T and NK cell responses. Here, we review recent advances in the characterization and engineering of OVs to enhance lymphocyte-mediated tumor control. CD8⁺ cytotoxic T cells and CD4⁺ helper T cells drive durable antitumor immunity through OV-enhanced antigen presentation, memory formation, and modulation of Tregs, whereas T cell exhaustion and checkpoint interactions remain key barriers. Arming OVs with cytokines, chemokines, bispecific engagers, or metabolic modulators enhances effector T-cell expansion, infiltration, and cytotoxicity in solid tumors. In parallel, NK cells-whose efficacy is often limited by poor intratumoral activity and antiviral competition-are increasingly harnessed by OV platforms expressing immune stimulators or checkpoint modulators. Combination strategies with targeted therapies, checkpoint blockade, or adoptive NK/T cell transfer further potentiate therapeutic efficacy. Importantly, although OVs may inadvertently amplify dominant antiviral responses at the expense of antitumor activity, strategies incorporating tumor antigen encoding and TME reprogramming can overcome this limitation. Collectively, these findings underscore the central role of T and NK cells in OV-based immunotherapy and highlight rational arming and combination approaches to improve tumor control and long-term protection.

Keywords:  Cancer vaccine; Immune checkpoint inhibitors; Metabolism; Oncolutic virus; Tumor immunotherapy

DOI:  https://doi.org/10.1016/j.critrevonc.2025.105086
Nature. 2025 Dec 17.

Transient hepatic reconstitution of trophic factors enhances aged immunity.

Mirco J Friedrich, Julie Pham, Jiakun Tian, Hongyu Chen, Jiahao Huang, Niklas Kehl, Sophia Liu, Blake Lash, Fei Chen, Xiao Wang, Rhiannon K Macrae, Feng Zhang.

Ageing erodes human immunity, in part by reshaping the T cell repertoire, leading to increased vulnerability to infection, malignancy and vaccine failure1-3. Attempts to rejuvenate immune function have yielded only modest results and are limited by toxicity or lack of clinical feasibility1,3-5. Here we show that the liver can be transiently repurposed to restore age-diminished immune cues and improve T cell function in aged mice. These immune cues were found by performing multi-omic mapping across central and peripheral niches in young and aged animals, leading to the identification of Notch and Fms-like tyrosine kinase 3 ligand (FLT3L) pathways, together with interleukin-7 (IL-7) signalling, as declining with age. Delivery of mRNAs encoding Delta-like ligand 1 (DLL1), FLT3L and IL-7 to hepatocytes expanded common lymphoid progenitors, boosted de novo thymopoiesis without affecting haematopoietic stem cell (HSC) composition, and replenished T cells while enhancing dendritic cell abundance and function. Treatment with these mRNAs improved peptide vaccine responses and restored antitumour immunity in aged mice by increasing tumour-specific CD8+ infiltration and clonal diversity and synergizing with immune checkpoint blockade. These effects were reversible after dosing ceased and did not breach self-tolerance, in contrast to the inflammatory and autoimmune liabilities of recombinant cytokine treatments6,7. These findings underscore the promise of mRNA-based strategies for systemic immune modulation and highlight the potential of interventions aimed at preserving immune resilience in ageing populations.

DOI: https://doi.org/10.1038/s41586-025-09873-4
bioRxiv. 2025 Dec 09. pii: 2025.12.05.692491. [Epub ahead of print]

SP140 limits type I interferon-driven pathology, preserving T cell motility and promoting resistance in tuberculosis.

Maxime Caouaille, Léa Fromont, Tomoyo Shinkawa, Marion Faucher, Aizat Iman Abdul Hamid, Serge Mazères, Yaël Duvergé, Yohan Lorreyte, Emmanuelle Näser, Samuel M Behar, Emma Lefrançais, Olivier Neyrolles, Denis Hudrisier.

CD8 + T cells are robustly activated during tuberculosis but how their responses differ in susceptible hosts remains unclear. Using mice lacking the transcriptional repressor Sp140, we assessed the magnitude and diversity of pulmonary CD8⁺ T cell responses to Mycobacterium tuberculosis infection. We show that control mice develop a robust CD8 + T cell response following infection, characterized by a diverse pool of effector and memory subsets and strong TNF and IFNγ production, whereas Sp140 -/- mice display a profound reduction in T cell numbers across all subsets. Single-cell RNA sequencing revealed redistribution and skewing of CD8 + T cell clusters in Sp140 -/- mice, with overrepresentation of gene expression programs associated with exhaustion and type I interferon (IFN-I) signaling. Blockade of the IFN-I receptor (IFNAR) restored CD8 + T cell numbers, diversity, cytokine production, spatial localization, and coincided with substantially reduced bacterial burden and lung pathology. Similarly, CD4 + T cell numbers were also rescued. Intravital microscopy of infected lungs further showed that T cell dynamics and motility within lesions were restricted under exuberant IFN-I signaling but fully restored by IFNAR blockade. Together, these findings reveal that SP140 sustains host resistance in mice by restraining IFN-I-driven pathology, coinciding with preserved T cell immunity and lesion surveillance.

DOI: https://doi.org/10.64898/2025.12.05.692491
Cell Rep Med. 2025 Dec 16. pii: S2666-3791(25)00583-X. [Epub ahead of print]6(12): 102510

Potentiating immunotherapy in "immune-cold" solid tumors through orchestrating T cell immunity via tumor-specific genetic engineering.

Jiaqi He, Chunguang Zhang, Chao Liang, Wenchi Xue, Yongheng Li, Lili Dai, Chunyuan Liu, Wan-Ru Zhuang, Xianbin Ma, Ran Cheng, Yao Lei, Weidong Nie, Hai-Yan Xie.

  We engineer a tumor-targeted genetic plasmid vector (PαCD3&LIGHT) to systematically modulate T cell immunity. The tumor-specific telomerase reverse transcriptase (TERT) promoter drives simultaneous expression of tumor necrosis factor superfamily member 14 (LIGHT) and membrane-anchored anti-CD3 single-chain variable fragment (αCD3), which are important immunomodulators with closely clinical relevance. Secreted LIGHT induces high endothelial venule formation and chemokine secretion to recruit circulating lymphocytes, while remodeling extracellular matrix to facilitate immune cell penetration into tumor parenchyma. αCD3 establishes artificial immunological synapses between tumor cells and T lymphocytes. This dual mechanism synergistically establishes tertiary lymphoid structures de novo even within deep tumor regions, harboring stem cell-like CD8+ T cells and driving sustained immunity. Concurrently, αCD3-mediated T cell redirection not only amplifies TCR signaling but also reverses exhausted T cells. The orchestrated T cell immunity significantly potentiates checkpoint inhibitor and chimeric antigen receptor (CAR)-T cell therapies in "immune-cold" tumors without obvious side effects and also remarkably enhances the outcome of human CAR-T cells, demonstrating translational potential in solid tumor immunotherapy.

Keywords:  LIGHT; T cell immunotherapy; anti-CD3 scFv; chimeric antigen receptor T cell; immune checkpoint inhibitor; tumor-specific genetic engineering; “immune-cold” solid tumor

DOI:  https://doi.org/10.1016/j.xcrm.2025.102510
Front Immunol. 2025 ;16 1704048

VISTA+ follicular regulatory T cells modulate the function of effector immune cells: implications for ovarian cancer immune escape.

Yan Ma, Yidan Xu, Chunxia Yu, Huatuo Wu, Li Li.

   Background: As key regulatory cells, the impact of follicular regulatory T (Tfr) cells, whose function is regulated by V-domain Ig suppressor of T cell activation (VISTA), on downstream immune cells remains unclear. These cellular-level regulatory mechanisms are closely associated with the development of immune escape in ovarian cancer, a disease characterized by severe effector immune cell dysfunction in the tumor microenvironment. This study aims to elucidate the regulatory effects of VISTA+ Tfr cells on the functions of CD8+ T cells, CD4+CD25- T cells, and B cells, and to reveal their significance in the immune escape of ovarian cancer.
Methods: VISTA-overexpressing and silenced Tfr cell models were constructed in vitro. Through co-culture experiments, CFSE proliferation assays, ELISA, and flow cytometry were employed to investigate the effects of VISTA+ Tfr cells on CD8+ T cell proliferation, effector cytokine secretion, and activation status; their regulation of CD4+CD25- T cell proliferation, cytokine secretion, and Th cell differentiation; and their impact on B cell proliferation and antibody secretion.
Results: VISTA+ Tfr cells significantly inhibited CD8+ T cell proliferation, secretion of effector cytokines (IL-2, IFN-γ), and expression of the activation marker CD69, while upregulating their exhaustion molecules (PD-1, CTLA-4). They skewed the differentiation of CD4+CD25- T cells toward a Th2 phenotype and suppressed Th1 and Th17 cell differentiation. Furthermore, they specifically inhibited IgE secretion by B cells, with no significant effect on other antibodies.
Conclusion: VISTA+ Tfr cells multi-dimensionally suppress the function of effector immune cells, providing experimental evidence for the potential role of VISTA-targeted strategies in improving anti-tumor immune responses in ovarian cancer.

Keywords:  B cells; CD8+ T cells; T helper cells; VISTA+ follicular regulatory T cells; immune escape; ovarian cancer

DOI:  https://doi.org/10.3389/fimmu.2025.1704048
Cell Rep. 2025 Dec 17. pii: S2211-1247(25)01507-4. [Epub ahead of print]45(1): 116735

Afg3l2 couples mitochondrial vitamin B12 trafficking to amino acid metabolism to safeguard hematopoietic stem cell homeostasis.

Meng Zhang, Xiashiyao Zhang, Yandan Chen, Mengmeng Li, Qingwei Ding, Liang Zheng, Junke Zheng, Jun Wan, Bin Guo.

  Mitochondrial proteostasis is essential for hematopoietic stem cell (HSC) maintenance, yet how proteolytic regulation coordinates with metabolic pathways remains unclear. Here, we identify Afg3l2 as a key regulator of cobalamin metabolism and amino acid homeostasis in HSCs through its mediation of Mmadhc degradation. Loss of Afg3l2 leads to Mmadhc accumulation, driving excessive mitochondrial cobalamin import and its conversion to adenosylcobalamin. Elevated adenosylcobalamin levels hyperactivate methylmalonyl-CoA mutase, diverting branched-chain amino acid catabolism toward excessive succinyl-CoA production. This overstimulates the tricarboxylic acid cycle and creates a compensatory dependency on anaplerotic amino acid replenishment. Consequently, Afg3l2-deficient HSCs exhibit increased oxidative stress due to mitochondrial hyperactivation and reactive oxygen species accumulation, ultimately impairing their maintenance and engraftment capacity. Remarkably, Mmadhc overexpression phenocopies these defects, whereas Mmadhc knockdown partially restores HSC function in Afg3l2-deficient models. Our work defines a proteostatic-metabolic circuit in which Afg3l2-mediated Mmadhc degradation regulates cobalamin flux to maintain amino acid and energy balance in HSCs.

Keywords:  CP: Metabolism; CP: Stem cell research; TCA cycle; amino acid metabolism; cobalamin metabolism; hematopoietic stem cell; mitochondrial protease

DOI:  https://doi.org/10.1016/j.celrep.2025.116735
Cancer Res. 2025 Dec 15.

The Diverse Roles of Lipid Metabolism Reprogramming in Shaping the Tumor Immune Microenvironment.

Jiin Lee, Jacinth Wing-Sum Cheu, Carmen Chak-Lui Wong.

Lipid metabolism reprogramming modulates the tumor microenvironment (TME) and alters the function of immune cells, including tumor-infiltrating lymphocytes (TILs). While lipids can enhance general T cell activity, high lipid content in the TME may restrain the anti-tumor function of effector T cells and augment immunosuppression by regulatory T cells. In addition, lipid metabolism reprogramming greatly influences the crosstalk between TILs and other immune cells in the TME, including dendritic cells, macrophages, and myeloid-derived suppressor cells. By discussing potential therapeutic strategies to target lipid metabolism in TILs, along with combination approaches with chemo-immunotherapy, nanomedicine, and adoptive cell transfer therapy, we aim to lay the groundwork for advancing effective treatments for cancer patients.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-2568
Mol Cancer Res. 2025 Dec 15.

Tumor cell-derived microparticles induced by methotrexate reprogram neutrophil antitumor response via lysosomal ROS mediated degranulation.

Pingwei Xu, Xiaojie Zhang, Kai Chen, Meng Zhu, Siyu Gao, Junyi Wang, Xingyu Si, Ru Jia, Chenghao Jin, Junhong Ding, Xingyi Hu, Haobing Li, Yunfeng Huang, Meilin Yi, Ebrahim Abdo, Keqing Shi, Ke Tang.

Neutrophils are one of the most important immune cells in the tumor microenvironment, and they affect the immunosuppression status by directly supporting the tumor progression or indirectly impairing T cell antitumor response. Although recent evidence indicates that neutrophils determine the success of tumor immunotherapy, how to activate the innate immune system antitumor response still lags out. Here, we provide evidence that the methotrexate packaged tumor cell-derived microparticles (MTX-MP) activate neutrophil antitumor response by directly releasing tumor cytotoxic microparticles, increasing tumor-infiltrated CD8+ T cells, and promoting CD8+ T cell antitumor response. Strikingly, mitochondrial-lysosomal membrane contacts mediate NADH translocation to lysosomal compartments. Within lysosomes, ENOX2 catalyzes NADH oxidation to generate lysosomal reactive oxygen species (ROS), which induce Ca2+ efflux via lysosomal channels. This calcium surge triggers neutrophil degranulation, thereby promoting cytotoxic microparticle release. By performing the combination of MTX-MP-activated neutrophils and OT-1 CD8+ T cells transfer, we found that the long-term survival rate improved in OVA-expressing Lewis lung carcinoma (LLC-OVA) models. Implications: Our findings revealed a new way by which activated-neutrophils release microparticles to kill tumor cells and provided a potential combinatorial therapeutic strategy for tumor immunotherapy.

DOI: https://doi.org/10.1158/1541-7786.MCR-25-0615
Cell Rep Med. 2025 Dec 16. pii: S2666-3791(25)00588-9. [Epub ahead of print] 102515

An innovative engineered IL-10 monomer strengthens T cell-mediated anti-tumor responses through anti-PD-1 cis-delivery.

Ce Gu, Jian Guo, Chang Zhou, Peipei Hu, Xiaodong Wu, Jiaojiao Ding, Xinxin Zhou, Liao Zeng, Wen Yu, Yingye Ou, Linhui Ye, Mengying Liang, Yue Huang, Jiatian Li, Zhe Zhang, Wentao Deng, Baiguang Ren, Yingpei Zhang, Li Wang, Xuejiao Chen, Yingxing Duan, Zhe Han, Yang Leng, Hongxin Li, Kongzhen Hu, Yongting Huo, Di Lu.

  Immune checkpoint blockade (ICB) therapy exerts anti-tumor efficacy mainly by activating intratumoral CD8+ T cells but fails to re-activate terminally exhausted CD8+ T cells. Interleukin-10 (IL-10) has been shown to directly expand and activate these cells and to exert a synergistic effect when combined with ICB. Nevertheless, the clinical application of IL-10 for cancer immunotherapy is restricted by severe hematological toxicity. Here, we design FP008 (anti-PD-1×IL-10M), a clinical-stage fusion protein composed of an anti-PD-1 antibody and an attenuated IL-10 monomer (IL-10M). Mechanistically, the activity and toxicity of IL-10M are significantly reduced, while its therapeutic benefits are enhanced through anti-PD-1-targeted enrichment and cis-activation. Anti-PD-1×IL-10M therapy displays robust anti-tumor activity in various mouse models, including those resistant to anti-PD-1 therapy, and exhibits promising safety in GLP toxicology studies in cynomolgus monkeys. Altogether, reinvigorating exhausted CD8+ T cells in the tumor microenvironment through anti-PD-1×IL-10M represents a promising therapeutic strategy for overcoming anti-PD-1/L1-refractory solid tumors.

Keywords:  ICB; IL-10 monomer; anti-PD-1; anti-tumor activity; cis-activation; fusion protein; hematological toxicity; terminally exhausted CD8⁺ T

DOI:  https://doi.org/10.1016/j.xcrm.2025.102515
Mol Immunol. 2025 Dec 16. pii: S0161-5890(25)00290-1. [Epub ahead of print]189 142-152

The role of miR-3188-mediated transcriptional activation of IL-7Rα in tumor immunotherapy research.

Dan Wan, Xiao Liang, Fanfan Liang, Mengchen Zhu, Chongyu Zhang, Shaoying Zhang.

   BACKGROUND: Adoptive cell therapy (ACT) utilizing tumor-infiltrating lymphocytes (TIL) is a promising immunotherapeutic approach for disseminated malignancies. However, ex vivo-expanded tumor-infiltrating lymphocytes (TIL) often rapidly progress to a state of functional exhaustion or suppression within the tumor microenvironment. Interleukin-7(IL-7) not only supports the survival of T-lymphocyte in vivo but also induces vigorous expansion of naïve and memory T lymphocytes in vitro. Upregulating the expression of interleukin-7 receptor alpha (IL-7Rα) helps T cells restore their responsiveness to IL-7 signaling, aids in their survival, and enables them to regain anti-tumor activity.
METHODS: Firstly, we utilized databases to analyze the expression changes of CD127 in different tumor tissues, clarifying the correlation between its expression changes and patient prognosis. Subsequently, we collected clinical patient samples to validate the expression changes of CD127 in tumor-infiltrating T cells. We also simulated the tumor microenvironment through in vitro co-culture to explore the impact of tumor cells on the expression of CD127 on the surface of T cells. After then, we screened for miRNAs that are complementary to the sequence of the TATA box region in the CD127 promoter and employed a CD127 promoter driven dual-luciferase reporter system to identify the specific miRNA capable of upregulating CD127 expression. Finally, we analyzed the effects of miRNA-mediated upregulation of CD127 on T cell function.
RESULTS: Bioinformatics analysis and clinical validation both confirmed decreased IL-7Rα expression in tumors. Moreover, in clinical samples, IL-7Rα and miR-3188 expression levels showed concordant changes and a positive correlation. miR-3188 can upregulate the expression level of IL-7Rα by specifically targeting the TATA-box region of CD127 promoter. Utilizing miR-3188 to upregulate IL-7Rα expression can facilitate T cell survival, promote the development of memory T cells and enhance the secondary response and tumor-killing capacity of T cells.
CONCLUSION: Our findings reveal a novel mechanism of IL-7Rα regulation and propose a potential strategy to improve the persistence and functionality of T cells for ACT.

Keywords:  IL-7Rα; MiR-3188; TIL; Tumor

DOI:  https://doi.org/10.1016/j.molimm.2025.12.007
NPJ Aging. 2025 Dec 16. 11(1): 100

Sympathetic-parasympathetic system deregulation theory of aging.

Joseph P Errico, Benneth Ben-Azu, Makenna Gargus, M Karen Newell Rogers, Marie-Ève Tremblay.

The central nervous system, comprised of the brain, spinal cord, and nerves, includes the autonomic nervous system (ANS) that regulates involuntary functions. Within the ANS, the sympathetic and the parasympathetic nervous systems (SNS and PNS, respectively) control the same bodily functions, but in opposing directions. For example, the sympathetic nervous system elicits our "fight or flight" response, while the parasympathetic system supports "rest and repair" mechanisms in the broadest possible sense. With age, changes occur in how information is transmitted, in energetic requirements and expenditures, and in the ability to respond to change. These alterations with age result in the "hallmarks of aging", specifically including genomic instability, telomere attrition, epigenetic changes, loss of proteostasis, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and chronic inflammation. Understanding these age-dependent changes is essential for promoting healthy aging and longevity. We propose that, at the core of aging, there is an imbalance between the SNS and PNS, which provides opportunities for therapeutic intervention.

DOI: https://doi.org/10.1038/s41514-025-00293-2