bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2025–11–02
twenty-one papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Exhausted CD8+ T Cell in HIV Infection Exhibits an Impaired Bioenergetic Metabolism Driven by Mitochondrial Dysfunction.
  2. Transcriptional regulator SATB1 limits CD8+ T cell population expansion and effector differentiation in chronic infection and cancer.
  3. Re-evaluating CD57 as a marker of T cell senescence: implications for immune ageing and differentiation.
  4. Great "Tex"-pectations.
  5. Glutamine synthetase deficiency enhances CD8 T cell survival and stress resilience in the tumor microenvironment.
  6. Epigenetic regulation of T cell exhaustion in cancer.
  7. Next-generation T cell immunotherapy: overcoming exhaustion, senescence, and suppression.
  8. Loss of Bcl6 promotes antitumor immunity by activating glycolysis to rescue CD8 T-cell function.
  9. Cancer suppresses mitochondrial chaperone activity in macrophages to drive immune evasion.
  10. CD8+ T cells against extracellular pathogens: more than just a cytotoxic cell.
  11. Quercetin-derived microbial metabolite DOPAC potentiates CD8+ T cell anti-tumor immunity via NRF2-mediated mitophagy.
  12. Immunometabolism at the crossroads of infection: mechanistic and systems-level perspectives from host and pathogen.
  13. Installation of dominant-negative mutations in FAS and TGFβR2 via base editing in primary T cells.
  14. Thymopentin Enhances Antitumor Immunity Through Thymic Rejuvenation and T Cell Functional Reprogramming.
  15. Analysis of immune cell remodeling and functional alterations induced by aging and obesity in mice.
  16. Stem-like tissue-resident memory T cells control functional heterogeneity and reactivation of T cell memory in the intestine.
  17. STAT3 S727 phosphorylation drives pathogenic Th17 differentiation and neuroinflammation in autoimmune disease.
  18. Stage-specific roles of clonally expanded CD8+ T cells in regulating amyloid pathology in Alzheimer's disease models.
  19. Targeting PTPN2 enhances human CAR T cell efficacy and the development of long-term memory in mouse xenograft models.
  20. Small-molecule control of CAR T cells.
  21. Can NaCl predict or even enhance responses to immunotherapy in cancer?
  1. Immunology. 2025 Oct 28.
    Exhausted CD8+ T Cell in HIV Infection Exhibits an Impaired Bioenergetic Metabolism Driven by Mitochondrial Dysfunction.
    Yee Teng Chan, Kar Min Loh, Zhi Ying Phong, Ting Fang Tang, Chun Howe Ng, Alireza Saeidi, Heng Choon Cheong, Yi Ying Cheok, Rong Xiang Ng, Raja Iskandar Shah Raja Azwa, Kian-Kai Cheng, Chung Yeng Looi, Adeeba Kamarulzaman, Reena Rajasuriar, Won Fen Wong.
      In people living with HIV (PLWH), persistent viral replication and antiretroviral therapy (ART)-associated toxicity contribute to T cell exhaustion, characterised by significant metabolic reprogramming that negatively impacts cellular function and longevity. Understanding the metabolic dysregulation in exhausted T cells could unveil novel therapeutic strategies to rejuvenate immune responses in PLWH. This study investigated the prevalence and metabolic gene expression profiles of exhausted CD8+ T cells across three PLWH cohorts: viremic treatment-naïve (TN), viremic treatment-failure (TF) and aviremic treatment-responders (TR). Our analysis revealed that the proportion of exhausted CD8+ T cells (PD1+CD107a-) was markedly higher in viremic TN (5.1%) and TF (4.2%) groups compared to the aviremic TR cohort (2.2%, p < 0.05). Similarly, the percentage of terminally differentiated TEMRA cells (CCR7-CD45RA+) was elevated in TN (38.0%) and TF (44.7%) compared with TR (21.5%, p < 0.05), indicating a higher prevalence of late-stage differentiation and exhaustion in viremic individuals. NanoString analysis revealed a broad downregulation of metabolic genes in exhausted CD8+ T cells from viremic individuals, suggesting a shift toward a metabolically quiescent state akin to naïve T cells. Seahorse analysis revealed impaired mitochondrial respiration in CD8+ T cells from viremic PLWH, characterised by reductions in both ATP-linked respiration and proton leak. Furthermore, we reported that combined treatment with MitoTEMPO and N-acetyl-l-cysteine (NAC) improved mitochondrial function but failed to restore the effector capacity of CD8+ T cells. In summary, this study highlights the defective metabolic programming of exhausted CD8+ T cells in viremic PLWH, underscoring potential metabolic targets for therapeutic intervention.
    Keywords:  CD8+ T cell; HIV; T cell exhaustion; metabolic pathways; mitochondria; people living with HIV (PLWH)
    DOI:  https://doi.org/10.1111/imm.70054
  2. Nat Immunol. 2025 Oct 27.
    Transcriptional regulator SATB1 limits CD8+ T cell population expansion and effector differentiation in chronic infection and cancer.
    Leonie Heyden, Lisa Rausch, Michael H Shannon, Lachlan Dryburgh, Marcela L Moreira, Aleksej Frolov, Christina M Scheffler, Marit J van Elsas, Junming Tong, Olivia Hidajat, Sharanya K M Wijesinghe, Sining Li, Helena Horvatic, Nhat Truong Huynh-Anh, Catarina Gago da Graça, Carlson Tsui, Maren Köhne, Daniel Sommer, F Thomas Wunderlich, Bianca von Scheidt, Simone L Park, Laura K Mackay, Daniel T Utzschneider, Jan Schröder, Stephen J Turner, Phillip K Darcy, Marc D Beyer, Zeinab Abdullah, Axel Kallies.
      CD8+ T cells are major mediators of antiviral and antitumor immunity. During persistent antigen stimulation as in chronic infection and cancer, however, they differentiate into exhausted T cells that display impaired functionality. Precursors of exhausted T (TPEX) cells exhibit stem-like properties, including high proliferative, self-renewal and developmental potential, and are responsible for long-term CD8+ T cell responses against persistent antigens. Here we identify the chromatin organizer and transcriptional regulator SATB1 as a major regulator of exhausted CD8+ T cell differentiation. SATB1 was specifically expressed in TPEX cells where it limited population expansion and effector differentiation while preserving functionality of CD8+ T cells. SATB1 downregulation was required for TPEX cell-to-effector cell differentiation in chronic infection and contributed to coordinated effector and memory differentiation in acute viral infection. DNA binding of SATB1 regulated gene expression both dependent and independent of chromatin accessibility. Finally, SATB1 limited antitumor CD8+ and chimeric antigen receptor T cell immunity. Overall, our results identify SATB1 as a central regulator of precursor fate and effector differentiation of CD8+ T cells both in infection and in cancer.
    DOI:  https://doi.org/10.1038/s41590-025-02316-2
  3. Immun Ageing. 2025 Oct 31. 22(1): 47
    Re-evaluating CD57 as a marker of T cell senescence: implications for immune ageing and differentiation.
    Gaëlle Autaa, Daniil Korenkov, Josine van Beek, Isabelle Pellegrin, Béatrice Parfait, Debbie van Baarle, Odile Launay, Eric Tartour, Victor Appay.
      Ageing is accompanied by a decline in immune function, associated with susceptibility to infections and malignancies, and reduced vaccine efficacy. These immunological changes, affect multiple components of the immune system, particularly T lymphocytes, which exhibit altered subset distributions and accumulate senescent features. CD57, a surface glycoprotein expressed on T cells, has emerged as a potential marker of terminal differentiation and senescence used for immunomonitoring in infection or cancer contexts. However, the use of CD57 as a marker of T cell senescence remains unclear. To investigate this, we analyzed CD57 expression on CD8+ and CD4+ T cells in healthy donors from two independent cohorts, considering cellular differentiation, age, cytomegalovirus status, and other senescence markers. Our findings reinforce the association between CD57 expression, T cell differentiation, and CMV seropositivity, but not with chronological age. Although CD57 is associated with altered proliferation and survival in all T cell differentiation subsets, it does not fully align with a senescent phenotype. Therefore, we propose that CD57 may be better appreciated as a marker of immunological age. Moreover, the interpretation of CD57 expression must account for CMV serostatus to avoid misleading conclusions, especially in oncology and ageing research.
    Keywords:  Ageing; Cytomegalovirus; Differentiation; Senescence; T lymphocytes
    DOI:  https://doi.org/10.1186/s12979-025-00542-8
  4. J Immunol. 2025 Oct 01. 214(10): 2489-2491
    Great "Tex"-pectations.
    Grace A Ward, Ben Youngblood.
      
    Keywords:  CD8 T cell; Immunotherapy; PD-1; T-cell Exhaustion
    DOI:  https://doi.org/10.1093/jimmun/vkaf163
  5. J Immunol. 2025 Oct 31. pii: vkaf250. [Epub ahead of print]
    Glutamine synthetase deficiency enhances CD8 T cell survival and stress resilience in the tumor microenvironment.
    Emilie L Fisher-Gupta, Emma S Hathaway, Jeffrey M Perera, Erin Q Jennings, Channing Chi, Allison E Sewell, Spenser H Stone, Jason E Muka, Rachael C Sinard, Joseph A DeCorte, Heidi Chen, John T Wilson, Jens Meiler, Jeffrey C Rathmell.
      Cellular immunotherapy has revolutionized the treatment of hematologic malignancies yet has had limited success in the solid tumor microenvironment (TME). While insufficient nutrients can lead to T cell metabolic stress in the TME, the glutamine antagonist DON can paradoxically enhance antitumor immunity. Because DON inhibits both essential and nonessential enzymes whose impairment may contribute to dose-limiting toxicities, mechanisms underlying DON-induced antitumor activity have remained unclear. Here, we aimed to identify specific DON targets that increase T cell antitumor activity and test if more selective inhibition of glutamine metabolism could replicate the effects of DON with reduced toxicity. CRISPR screening in the TME of DON-relevant glutamine metabolizing enzymes identified some targets that were essential in tumor-infiltrating CD8 T cells, but that tumor-infiltrating CD8 T cells lacking the DON target glutamine synthetase (GS) were enriched. Upon adoptive T cell transfers, GS-deficient CD8+ T cells displayed improved survival, a higher proportion TCF-1+ Tox- stem-like cells, and greater antitumor and memory function. GS converts glutamate to glutamine and GS-deficient cells exhibited increased intracellular glutamate and reduced glutathione levels, which correlated with enhanced mitochondrial respiration and resistance to reactive oxygen species. Pharmacological inhibition of GS reduced tumor burden in multiple orthotopic murine tumor models in a manner dependent on adaptive immunity. Our findings establish GS as a key metabolic regulator of CD8+ T cells stress resilience in the TME. By preserving intracellular glutamate, GS inhibition reprograms T cells for improved survival and function, offering a promising therapeutic strategy to enhance immune-based cancer treatments.
    Keywords:  T cell; antitumor immunity; glutamine; glutamine synthetase; immunometabolism
    DOI:  https://doi.org/10.1093/jimmun/vkaf250
  6. Nat Rev Cancer. 2025 Oct 27.
    Epigenetic regulation of T cell exhaustion in cancer.
    Tae Gun Kang, Jordan T Johnson, Caitlin C Zebley, Ben Youngblood.
      Current T cell-based immunotherapy strategies, including immune checkpoint blockade (ICB) and chimeric antigen receptor (CAR) T cells, have revolutionized cancer care. However, many patients with cancer who are treated with these approaches fail to respond or do not achieve durable protection against disease relapse, highlighting the need for further optimization of such strategies. The advent of cancer immunotherapy has ushered in an era of research centred on immune oncology with a specific focus on defining T cell-intrinsic mechanisms that delineate therapeutic responders and non-responders. Among the major barriers limiting immunotherapy efficacy, T cell exhaustion - which is characterized by repression of the effector functions and proliferative potential of T cells - has emerged as a common mechanism among various cancers. Here, we review transcriptional and epigenetic mechanisms that control T cell exhaustion. We discuss how T cell subset-specific gene regulatory programmes limit immunotherapy success and theorize on the development of next-generation strategies for increasing the clinical breadth, efficacy and durability of T cell immunotherapy.
    DOI:  https://doi.org/10.1038/s41568-025-00883-y
  7. Front Immunol. 2025 ;16 1662145
    Next-generation T cell immunotherapy: overcoming exhaustion, senescence, and suppression.
    Guangmei Li, Dengju Li, Xiaojian Zhu.
      T-cells are a core component of tumor immunotherapy because of their potent ability to identify and kill cancer cells. Yet efficacy is limited by exhaustion, senescence, metabolic dysregulation, an immunosuppressive tumor microenvironment (TME), and limited persistence. This review analyzed these key issues and proposed targeted improvement strategies. Emerging approaches encompass pharmacological modulation of T cell activation and survival pathways, epigenetic reprogramming to reverse exhaustion and senescence, metabolic engineering, combinatorial targeting of immunosuppressive TME components and advanced genetic tools, notably CRISPR-Cas9-based CAR-T optimization, which exemplifies how precise genome editing can enhance therapeutic efficacy. We review the progress and prospects of T-cell improvement strategies in tumor immunotherapy, emphasizing the need for further exploration to enhance the broader application and long-term efficacy of T-cell therapies. This review highlights recent advances and future directions in T-cell engineering, metabolic modulation, and microenvironment targeting, aiming to translate innovations into effective cancer immunotherapies.
    Keywords:  T-cell enhancement; T-cell exhaustion and aging; metabolic regulation; microenvironment optimization; tumor immunotherapy
    DOI:  https://doi.org/10.3389/fimmu.2025.1662145
  8. Life Sci Alliance. 2026 Jan;pii: e202503335. [Epub ahead of print]9(1):
    Loss of Bcl6 promotes antitumor immunity by activating glycolysis to rescue CD8 T-cell function.
    Fangkun Luan, Yunqiao Li, Jia Ning, Jenny Tuyet Tran, Tanya R Blane, Raag Bhargava, Zhe Huang, Changchun Xiao, David Nemazee.
      T cells are one of the most powerful weapons to fight cancer; however, T-cell exhaustion and dysfunction restrict their long-lasting function in antitumor immunity. B-cell lymphoma 6 (BCL6) has many functions in CD8 T cells; however, it is unclear how it regulates the effector function and exhaustion of CD8 cells. Overall, a low level of BCL6 mRNA in human cancer samples is associated with better outcomes, but high expression of BCL6 is specifically observed in cytotoxic CD8 T cells. We found that BCL6 deficiency in activated CD8 T cells enhanced tumor repression in multiple mouse models. More IL-2-expressing CD8 T cells and reduced proportions of exhausted or dysfunctional CD8 T cells were detected within tumors when Bcl6 was knocked out upon T-cell activation. Glycolysis was promoted, and GLUT3 expression was derepressed in BCL6-deficient CD8 T cells. The BCL6 inhibitor Fx1 promoted antitumor immunity in a T cell-dependent manner. These findings suggest a novel pathway to restore effector function of CD8 T cells by changing their energy use pathways to facilitate long-term tumor resistance.
    DOI:  https://doi.org/10.26508/lsa.202503335
  9. Nat Immunol. 2025 Oct 29.
    Cancer suppresses mitochondrial chaperone activity in macrophages to drive immune evasion.
    Haoxin Zhao, Jaeoh Park, Yuzhu Wang, Yi-Ju Chou, Lemin Li, Lydia N Raines, Michael Hsu, Ching-Cheng Lin, Wei Cao, Yuli Ouyang, Heng-Yi Chen, Linghua Zheng, Zihai Li, Alex Y Huang, Ping-Chih Ho, Chan-Wang Jerry Lio, Stanley Ching-Cheng Huang.
      Contrary to tumor-infiltrating T cells with dysfunctional mitochondria, tumor-associated macrophages (TAMs) preserve their mitochondrial activity in the nutrient-limited tumor microenvironment (TME) to sustain immunosuppression. Here we identify TNF receptor-associated protein-1 (TRAP1), a mitochondrial HSP90 chaperone, as a metabolic checkpoint that restrains oxidative respiration and limits macrophage suppressive function. In the TME, TRAP1 is downregulated through TIM4-AMPK signaling, and its loss enhances immunoinhibitory activity, limits proinflammatory capacity and promotes tumor immune escape. Mechanistically, TRAP1 suppression augments electron transport chain activity and elevates the α-ketoglutarate/succinate ratio, remodeling mitochondrial homeostasis. The resulting accumulation of α-ketoglutarate further potentiates JMJD3-mediated histone demethylation, establishing transcriptional programs that reinforce an immunosuppressive state. Restoring TRAP1 by targeting TIM4 and JMJD3 reprograms TAMs, disrupts the immune-evasive TME and bolsters antitumor immunity. These findings establish TRAP1 as a critical regulator integrating metabolic and epigenetic control of suppressive TAM function and position the TRAP1 pathway as a promising target for cancer immunotherapy.
    DOI:  https://doi.org/10.1038/s41590-025-02324-2
  10. Immunol Cell Biol. 2025 Oct 28.
    CD8+ T cells against extracellular pathogens: more than just a cytotoxic cell.
    Rafael Cardoso Maciel Costa Silva.
      The role of CD8+ T cells, as cytotoxic cells, being critical against intracellular pathogens is well known. Through the killing of infected (target) cells, CD8+ T cells impair intracellular pathogens' replication. However, extracellular pathogens are not directly targeted by CD8+ T cells, since these pathogens do not express MHC-I-peptides, responsible for the activation of the cytotoxic activity of CD8+ T cells. In this sense, how CD8+ T cells affect the course of extracellular infections is discussed in this review, underscoring the important regulatory functions of CD8+ T cells, killing phagocytes and other cells that are able to cross-present extracellular antigens. In addition, the role of CD8+ T cells in the modulation of immune responses through the secretion of cytokines, such as gamma interferon (IFNγ), is also discussed in the context of extracellular infections.
    Keywords:  CD8+ T cells; cytotoxicity; extracellular pathogens; immune regulation; infectious disease
    DOI:  https://doi.org/10.1111/imcb.70064
  11. Cell Metab. 2025 Oct 24. pii: S1550-4131(25)00395-X. [Epub ahead of print]
    Quercetin-derived microbial metabolite DOPAC potentiates CD8+ T cell anti-tumor immunity via NRF2-mediated mitophagy.
    Penghu Han, Shuzheng Chu, Jing Shen, Lixiang Li, Yan Zhang, Shiguan Wang, Yatai Chen, Yangchun Ma, Xiaolong Tang, Chao Gao, Xiangyun Zheng, Bowen Xu, Qiong Wang, Detian Yuan, Shiyang Li.
      Quercetin, a dietary flavonol, shows promise in cancer prevention, though its effects on the immune compartment within the tumor microenvironment are not fully understood. Here, we identify 3,4-dihydroxyphenylacetic acid (DOPAC), a microbial metabolite of quercetin, as a critical mediator of its anti-tumor effects in a CD8+ T cell-dependent manner. Mechanistically, DOPAC directly binds to Kelch-like epichlorohydrin-associated protein 1 (KEAP1), disrupting its interaction with nuclear factor erythroid 2-related factor 2 (NRF2) and preventing KEAP1-mediated degradation of NRF2 in CD8+ T cells. Elevated NRF2 transcriptionally enhances the expression of B cell lymphoma 2-interacting protein 3, promoting mitophagy and mitochondrial functionality, which improves CD8+ T cell fitness within the tumor microenvironment. Furthermore, DOPAC synergizes with immune checkpoint blockade to suppress tumor growth. Our findings underscore the role of microbial metabolites of dietary nutrients in modulating anti-tumor immune responses, positioning DOPAC as a promising candidate for cancer immunotherapy.
    Keywords:  BNIP3; CD8(+) T cells; DOPAC; NRF2; anti-tumor immunity; microbiota; mitophgagy; quercetin
    DOI:  https://doi.org/10.1016/j.cmet.2025.09.010
  12. Immunometabolism (Cobham). 2025 Oct;7(4): e00069
    Immunometabolism at the crossroads of infection: mechanistic and systems-level perspectives from host and pathogen.
    Sunayana Malla, Nabia Shahreen, Rajib Saha.
      The emerging field of immunometabolism has underscored the central role of metabolic pathways in orchestrating immune cell function. Far from being passive background processes, metabolic activities actively regulate key immune responses. Fundamental pathways such as glycolysis, the tricarboxylic acid cycle, and oxidative phosphorylation critically shape the behavior of immune cells, influencing macrophage polarization, T cell activation, and dendritic cell function. In this review, we synthesize recent advances in immunometabolism, with a focus on the metabolic mechanisms that govern the responses of both innate and adaptive immune cells to bacterial, viral, and fungal pathogens. Drawing on experimental, computational, and integrative methodologies, we highlight how metabolic reprogramming contributes to host defense in response to infection. These findings reveal new opportunities for therapeutic intervention, suggesting that modulation of metabolic pathways could enhance immune function and improve pathogen clearance.
    Keywords:  adaptive immune cells; bacteria; fungi and pathogens; innate immune cells; virus
    DOI:  https://doi.org/10.1097/IN9.0000000000000069
  13. Mol Ther Oncol. 2025 Dec 18. 33(4): 201063
    Installation of dominant-negative mutations in FAS and TGFβR2 via base editing in primary T cells.
    Bryce J Wick, Mitchell G Kluesner, Nicholas J Slipek, Joseph G Skeate, Ethan M Niemeyer, Beau R Webber, Branden S Moriarity.
      Adoptive cell transfer (ACT) of engineered T cells is effective against B cell malignancies but has faltered against solid tumors due to the immunosuppressive tumor microenvironment (TME). FAS ligand (FASL) and transforming growth factor β (TGF-β) are key mediators of T cell dysfunction in the TME and overexpressing dominant negative (dn) forms of their receptors in T cells increases anti-tumor efficacy in solid tumor models. However, an approach that directly targets the endogenous genes would be more amenable to multiplex editing and reduce competition with WT alleles. Here, we employ base editing (BE) in primary human T cells to install naturally occurring dominant negative FAS and TGFβR2 mutations. In vitro survival and proliferation assays demonstrate that BE T cells are resistant to pro-apoptotic and anti-proliferative effects of FAS and TGF-β signaling. Chimeric antigen receptor (CAR)-T cells with BE-installed dn TGFβR2 or dn FAS exhibit improvements in cytotoxicity, while dn TGFβR2 CAR T demonstrate increased persistence and reduced expression of phenotypic markers of exhaustion compared to controls. Moreover, BE-engineered dn CAR T outperform lentiviral-engineered cDNA over expression counterparts in several functional assays. Considering the efficiency of BE and its amenability for multiplex editing, our approach lends itself to engineering strategies necessary to overcome T cell dysfunction in solid tumors.
    Keywords:  CAR-T; MT: Regular Issue; T cells; base editors; cancer immunotherapy; dominant-negative mutations
    DOI:  https://doi.org/10.1016/j.omton.2025.201063
  14. Biomedicines. 2025 Oct 13. pii: 2494. [Epub ahead of print]13(10):
    Thymopentin Enhances Antitumor Immunity Through Thymic Rejuvenation and T Cell Functional Reprogramming.
    Md Amir Hossain, Ye Zhang, Li Ji, Yumei Chen, Yue Luan, Yaxuan Si, Yuqing Fang, Junlan Qiu, Zhuo Wang, Guilai Liu.
      Background/Objectives: T cell dysfunction represents a fundamental barrier to effective cancer immunotherapy. Although immune checkpoint blockades and adoptive cell transfer have achieved clinical success, therapeutic resistance remains prevalent across cancer types. Thymopentin (TP5), a synthetic immunomodulatory pentapeptide (Arg-Lys-Asp-Val-Tyr), has demonstrated immunostimulatory properties, yet its anticancer potential remains unexplored. The aim of this study was to investigate TP5's antitumor efficacy and underlying immunological mechanisms. Methods: We evaluated TP5's therapeutic effects in multiple murine tumor models, including B16-F10 melanoma, MC38 colorectal carcinoma, Hepa 1-6, and LM3 hepatocellular carcinoma. Immune cell populations and functional states were characterized using flow cytometry, ELISAs, and immunofluorescence analyses. The potential of TP5 as an adjuvant for T cell-based therapies was also systematically assessed. Results: The TP5 treatment markedly suppressed tumor growth across caner models through strictly T cell-dependent mechanisms. Critically, TP5 promoted thymic rejuvenation under immunocompromised conditions, restoring the thymus-tumor immunological balance and revitalizing peripheral T cell immunity. TP5 functionally reprogrammed T cell states, preserving effector function while ameliorating exhaustion. Furthermore, TP5 demonstrated synergistic efficacy when combined with adoptive T cell therapies, enhancing both proliferation and effector functions. Conclusions: TP5 represents a promising immunomodulator that addresses fundamental limitations of current T cell therapies by simultaneously enhancing T cell function and reversing thymic involution under immunocompromised conditions. Our findings provide compelling evidence for TP5's clinical translation in cancer treatment.
    Keywords:  T cell exhaustion; cancer; cancer immunotherapy; thymopentin
    DOI:  https://doi.org/10.3390/biomedicines13102494
  15. Int Immunopharmacol. 2025 Oct 26. pii: S1567-5769(25)01723-0. [Epub ahead of print]167 115735
    Analysis of immune cell remodeling and functional alterations induced by aging and obesity in mice.
    Hyun Bo Sim, Yu-Jeong Choi, Seul-Ki Mun, Sonny C Ramos, Dae-Han Park, Ju-Bin Lee, Seung-Hyun Jeong, Jong-Jin Kim.
      As human life expectancy increases, aging and obesity have become major contributors to immune dysfunction. Aging impairs homeostatic regulation and increases disease susceptibility, while a Western-style diet and sedentary lifestyle accelerate obesity, particularly in older individuals. Together, they promote chronic inflammation and immunosenescence. To investigate immune alterations associated with aging and obesity, we used young (2-month-old) and aged (14-month-old) C57BL/6 mice feed either a normal diet (10 % fat) or high-fat diet (HFD; 60 % fat) for 13 weeks. HFD increased body mass index (BMI), total cholesterol, and liver enzymes (ALT, AST). Hematological analysis revealed age- and obesity-associated changes in white blood cell composition. High-dimensional immune profiling of splenic cells using flow cytometry and CyTOF showed that aging and HFD led to reduced T cells, NK cells, and monocytes, while B cells, neutrophils, and eosinophils increased. Notably, aging was associated with expansion of aging-associated B cells (ABCs) and PD-1+ T cells, while obesity promoted MHCIIlow macrophages. Inflammatory cytokine production (IL-6, TNF-α) was elevated in splenocytes following LPS stimulation. Feature importance analysis identified ALT, total cholesterol, BMI, IL-6, neutrophils, eosinophils, and MHCIIlow macrophages as key markers distinguishing aging and obesity. In conclusion, aging and obesity jointly remodel the immune landscape, promoting chronic inflammation and T cell exhaustion. Our findings offer insight into age- and obesity-related immune decline and suggest potential biomarkers for monitoring immune health in metabolic aging.
    Keywords:  Biomarker prediction; High-dimensional data; Immune aging; Immune cells; Obesity
    DOI:  https://doi.org/10.1016/j.intimp.2025.115735
  16. Sci Immunol. 2025 Oct 31. 10(112): eadw1992
    Stem-like tissue-resident memory T cells control functional heterogeneity and reactivation of T cell memory in the intestine.
    Kevin Man, Vinicius A Duarte da Silva, Nikita Potemkin, Sarah S Gabriel, Teisha Mason, Tarek Elmzzahi, Marcela De Lima Moreira, Chun-Hsi Su, Laura Mackay, Marc D Beyer, Jan Schröder, Georg Gasteiger, Axel Kallies.
      Tissue-resident memory T (TRM) cells provide localized immunity against intracellular pathogens and cancer. Upon antigen reencounter, TRM cells differentiate into effector cells while also giving rise to another generation of memory cells. Here, we show that intestinal TRM cells that express the transcriptional regulators TCF1 or ID3 exhibit stem-like memory properties and are endowed with a superior capacity to regenerate effector and memory T cells after pathogen reencounter. Ablation of TCF1 using a TRM cell-specific mouse model resulted in impaired formation of intestinal TRM cells, altered their transcriptional heterogeneity, and increased their differentiation into tissue-confined and recirculating CX3CR1+ effector cells during recall. TGF-β and retinoic acid were required for formation and survival of TCF1- and ID3-expressing TRM cells and restrained their differentiation into CX3CR1+ effector cells during reinfection. Thus, stem-like cells control the quality and recall capacity of TRM cells, thereby contributing to anamnestic memory responses.
    DOI:  https://doi.org/10.1126/sciimmunol.adw1992
  17. J Neuroinflammation. 2025 Oct 28. 22(1): 246
    STAT3 S727 phosphorylation drives pathogenic Th17 differentiation and neuroinflammation in autoimmune disease.
    Douglas S Prado, Achyudhan R Kutuva, Richard T Cattley, Andreza Buzolin Sonego, Parth Sutariya, Elena Im, Shuxian Wu, Mijoon Lee, Rachel L Cumberland, Isha Mehta, Greg M Delgoffe, William C Boggess, James R Faeder, Mark J Shlomchik, William F Hawse.
      
    DOI:  https://doi.org/10.1186/s12974-025-03591-4
  18. Nat Commun. 2025 Oct 27. 16(1): 9458
    Stage-specific roles of clonally expanded CD8+ T cells in regulating amyloid pathology in Alzheimer's disease models.
    Masaki Ohyagi, Minako Ito, Mana Iizuka-Koga, Setsuko Mise-Omata, Akihiko Yoshimura.
      Clonally expanded CD8+ T cells may contribute to Alzheimer's disease (AD) pathology through interactions with brain-resident cells. However, the functional impact of AD-specific T cell receptor (TCR) clonotypes remains unclear. Here, we demonstrate that CD8+ T cells undergo clonal expansion in early-stage AD mouse models, AppNL-G-F and 5xFAD, and that their depletion reduces amyloid plaque accumulation. Expanded TCR-expressing CD8+ T cells preferentially infiltrate the brain, exacerbating plaque deposition. Moreover, brain-infiltrating CD8+ T cells impair microglial transition into disease-associated states, suppressing amyloid clearance via CCL5-CCR5 signaling. Pharmacological blockade of CCL5 attenuates amyloid deposition, whereas CCL5 administration aggravates pathology. Notably, T cell depletion at later disease stages exacerbates amyloid pathology, suggesting a temporal shift in their function. Early-stage CD8+ T cells exhibit cytotoxic and effector profiles, whereas late-stage cells acquire tissue-resident and exhausted phenotypes. This temporal switch-from pathogenic to protective roles-highlights the stage-specific contribution of CD8+ T cells to AD and their potential as therapeutic targets.
    DOI:  https://doi.org/10.1038/s41467-025-64503-x
  19. Sci Transl Med. 2025 Oct 29. 17(822): eadk0627
    Targeting PTPN2 enhances human CAR T cell efficacy and the development of long-term memory in mouse xenograft models.
    Xin Du, Pei K Goh, Chenkai Ma, Eamon Coughlan, Spencer Greatorex, Laura H Porter, Brendan Russ, Katherine D Cummins, Kevin Sek, Clare Y Slaney, Andrew M Scott, Jane Oliaro, Paul J Neeson, Gail P Risbridger, Renea A Taylor, Joseph A Trapani, Stephen J Turner, Phillip K Darcy, Florian Wiede, Tony Tiganis.
      Chimeric antigen receptor (CAR) T cells have been ineffective against solid tumors, where the hostile tumor microenvironment limits CAR T cell function and persistence. Protein tyrosine phosphatase N2 (PTPN2) attenuates T cell receptor and cytokine signaling to maintain T cell tolerance. Here, we used CRISPR-Cas9 gene editing or an inhibitor to target PTPN2 in human CAR T cells specific for the Lewis Y (LeY) neoantigen, which is expressed in most epithelial tumors. Targeting PTPN2 increased CAR and cytokine signaling, including interferon signaling, and enhanced the antigen-induced expansion, activation, and cytotoxicity of anti-LeY CAR T cells in vitro and in vivo. The deletion of PTPN2 in CAR T cells repressed the growth of human tumor and patient-derived xenografts in mice, when compared with unedited CAR T cells, and prolonged mouse survival. The administration of inhibitor also enhanced the ability of α-LeY CAR T cells to repress tumor growth. Cellular indexing of transcriptomes and epitopes by sequencing analysis of splenic PTPN2-deficient CD8+ CAR T cells in tumor-bearing mice revealed that PTPN2 deficiency favored the generation of CD45RA+ CAR T cells expressing markers of long-lived stem cell memory (SCM) CAR T cells. Flow cytometric analysis reaffirmed that the deletion or inhibition of PTPN2 promoted the intratumoral accumulation of SCM CD8+ CAR T cells and the overall persistence of CD8+ CAR T cells. These data support the use of gene editing or small-molecule inhibitors targeting PTPN2 in human CAR T cells to treat solid tumors.
    DOI:  https://doi.org/10.1126/scitranslmed.adk0627
  20. Nat Rev Chem. 2025 Oct 29.
    Small-molecule control of CAR T cells.
    Eric L Adams, Andrew C McGovern, Victor So, Sneha Srinivasan, Alexander Deiters, Jason Lohmueller.
      Chimeric antigen receptor (CAR) T cell therapy is a 'living drug' in which the T cells of patients are genetically engineered with an artificial receptor that directs them to attack diseased cells. CAR T cell therapies have had remarkable impact, curing subsets of patients with previously untreatable, late-stage cancers. However, limitations persist, including severe toxicities, limited survival of engineered cells, and therapeutic resistance. Genetically encoded small-molecule control systems have been developed to address these limitations. They can halt toxicities by eliminating CAR T cells or switching off their function. Furthermore, they can enhance therapy by directly targeting antigens or broadening cell killing ability through cytotoxic pro-drug activation. Small-molecule controllers include protease inhibitors, protein dimerizers, protein degraders, bi-specific adaptors and conditionally activated chemotherapeutics. Here, we outline small-molecule-based control approaches, categorizing them by function and detailing their molecular mechanisms. We emphasize systems in the clinic and highlight emerging applications and unmet areas.
    DOI:  https://doi.org/10.1038/s41570-025-00768-6
  21. Eur J Cancer. 2025 Oct 18. pii: S0959-8049(25)00943-8. [Epub ahead of print]231 116057
    Can NaCl predict or even enhance responses to immunotherapy in cancer?
    Jonas Saal, Michael Hölzel, Niklas Klümper.
      The advent of immune checkpoint blockers (ICB) has transformed cancer treatment, but reliable predictive biomarkers remain limited. Emerging evidence suggests that sodium chloride (NaCl) modulates immune responses and may synergize with ICB in solid tumors. NaCl enhances CD8+ T cell activation, boosting their metabolic reprogramming, effector function, and antitumor activity. It also promotes a pro-inflammatory shift in CD4+ T cells and inhibits regulatory T cell function, supporting a pro-immunogenic tumor microenvironment. Conversely, NaCl impacts myeloid cells by reducing the suppressive activity of myeloid-derived suppressor cells and altering macrophage polarization. Preclinical studies reveal that dietary NaCl may augment ICB efficacy and highlight its potential as a combinatorial therapeutic strategy. Retrospective clinical data and post-hoc analyses of phase 3 clinical trials indicate that elevated serum sodium levels are associated with improved survival and enhanced response to ICB in cancer patients. These findings suggest that serum sodium could serve as a simple and predictive biomarker for treatment outcomes. However, prolonged high-sodium diet may promote chronic inflammation and cardiovascular disease, raising concerns about long-term safety. Gaps in mechanistic understanding persist regarding the correlation between dietary sodium, serum sodium, and intratumoral NaCl levels. This review discusses current evidence supporting NaCl's immunomodulatory effects and its potential as both a biomarker and therapeutic adjunct in cancer immunotherapy. We advocate for randomized clinical trials to evaluate NaCl-based interventions, given the low associated risks and costs. Clarifying NaCl's role could pave the way for novel, cost-effective strategies to enhance ICB efficacy and improve outcomes for patients with cancer.
    Keywords:  Biomarkers; Immune-Checkpoint Inhibitors; Immunotherapy; Salt; Sodium; Sodium Chloride
    DOI:  https://doi.org/10.1016/j.ejca.2025.116057
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