bims-imseme 2025-06-01 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2025–06–01
sixteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Dual phosphorylation of glycogen synthase kinase 3β differentially integrates metabolic programs to determine T cell immunity across vertebrates.
HEB Restrains Effector Gene Expression during Early CD8+ Memory Precursor T Cell Differentiation.
Nck1 Regulates Glucose Metabolism in Primary Human T Cells.
Advancing T-cell immunotherapy for cellular senescence and disease: Mechanisms, challenges, and clinical prospects.
Aging and immunity: the age-old tango.
The metabolism-immunity axis in Immune thrombocytopenia: from energy regulation to targeted therapy.
Dual roles of IRE1α inhibition in reversing mitochondrial ROS-induced CD8+ T-cell senescence and exerting direct antitumor effects in multiple myeloma.
Mitochondrial calcium signaling regulates branched-chain amino acid catabolism in fibrolamellar carcinoma.
Dysfunctional Senescent Herpes Simplex Virus-Specific CD57+CD8+ T Cells Are Associated with Symptomatic Recurrent Ocular Herpes in Humans.
Campari2 genomic interrogation of homeostatic calcium activity identifies TIM1 as a negative regulator of T cell function.
Lipid metabolic reprogramming in immune regulation and chronic inflammatory diseases.
Comprehensive analysis of immune checkpoint molecules profiles phenotype and function of exhausted T cells in enzootic bovine leukosis.
A New Method of Canine CD4+ T Lymphocyte Differentiation Towards the Th17 Phenotype with Analysis of Properties and Mitochondrial Activity.
Unravelling T cell exhaustion through co-inhibitory receptors and its transformative role in cancer immunotherapy.
Lactate-mediated metabolic reprogramming of tumor-associated macrophages: implications for tumor progression and therapeutic potential.
The potential role of mitochondria in age-related health benefits conferred by moderate hypoxia.

Cell Mol Life Sci. 2025 May 28. 82(1): 218

Dual phosphorylation of glycogen synthase kinase 3β differentially integrates metabolic programs to determine T cell immunity across vertebrates.

Wei Liang, Ming Geng, Wenzhuo Rao, Kang Li, Yating Zhu, Yuying Zheng, Xiumei Wei, Jialong Yang.

  The integration of metabolic programs with T cell signaling establishes a molecular foundation for immune metabolism. As a key metabolic regulator, GSK3β's activity is dynamically modulated by phosphorylation at Ser9 and Tyr216. However, the contribution of these phosphorylation sites on metabolism-driven T cell response remains unclear. Using tilapia and mouse models, we investigated the regulation of GSK3β on T cell metabolism and its evolutionary variation. In tilapia, T cell activation induces GSK3β signaling, linking to both glycolysis and oxidative phosphorylation (OXPHOS). Tyr216 phosphorylation preferentially promotes glycolysis, facilitating T cell activation, proliferation, and antibacterial immunity; while inhibition of Ser9 phosphorylation specifically enhances OXPHOS to sustain T cell responses. Differently, Tyr216 phosphorylation supports both glycolysis and OXPHOS in mouse, ensuring CD4+ T and CD8+ T cell activation, proliferation, and cytokine production. Although Ser9 phosphorylation controls OXPHOS, its inhibition impairs rather than enhances OXPHOS and CD4+ T cell responses in mouse. We thus revealed a previously unknown mechanism underlying T cell metabolism and proposed that, through evolution, GSK3β has restructured the regulatory strategy, enabling bidirectional control of T cell metabolism and immunity in mammals and enhancing the flexibility of the adaptive immune system.

Keywords:  Evolution; Fish; GSK3β; Immunometabolism; T cells

DOI:  https://doi.org/10.1007/s00018-025-05746-1
Mol Cell Biol. 2025 May 26. 1-18

HEB Restrains Effector Gene Expression during Early CD8+ Memory Precursor T Cell Differentiation.

Joanne Pui-Ting Leung, Siamak Haddadi, Michael J Geuenich, Alara Tuncer, Vivien Musiime, Chao Wang, Juan-Carlos Zúñiga-Pflücker, Kieran R Campbell, Michele K Anderson.

  Memory T cells are essential for maintaining long-term adaptive immunity. Memory cell precursors and short-lived effector cells emerge from undifferentiated naïve T cells directly downstream of TCR signaling but little is known about how this lineage choice is regulated at the molecular level. The transcription factor HEB is known to be an important regulator of thymic T cell development, but how it functions in peripheral T cell differentiation is poorly understood. We assessed the role of HEB in the differentiation of memory-like T cell precursors by inducing TCR signaling in CD8 T cells in the context of memory-polarizing cytokines or inflammatory conditions and found that CD8 T cells from HEB-deficient mice underwent accelerated differentiation as compared to WT cells. Transcriptomic analysis revealed aberrant upregulation of immune response genes and decreased expression of genes promoting stemness from the earliest stages of post-TCR signal activation and persisting throughout the course of differentiation. In addition, acute viral infection of HEB cKO mice resulted in enhanced memory precursor cell formation and increased effector functionality. Therefore, we have identified HEB as a central participant in the gene regulatory networks that regulate early CD8 memory T cell differentiation and effector gene expression. This study showed that naïve CD8 T cells lacking HEB exhibit increased TCR signal strength and loss of signatures of stem-ness, revealing a role for HEB in promoting immune memory.

Keywords:  CD8 T cells; E proteins; T cell differentiation; gene regulation; memory precursor T cell

DOI:  https://doi.org/10.1080/10985549.2025.2505730
Immunology. 2025 May 27.

Nck1 Regulates Glucose Metabolism in Primary Human T Cells.

Araya Rattanasri, Pussadee Paensuwan, Wolfgang W W A Schamel, Sutatip Pongcharoen, Jatuporn Ngoenkam.

  Non-catalytic region of tyrosine kinase 1 (Nck1) is an adaptor protein found in many cell types and plays several functions. In T cells, Nck1 is functionally associated with a T cell receptor (TCR)-mediated actin rearrangement, insulin signalling, PI3K/Akt/mTOR pathway, and lipid production. However, the role of Nck1 in regulating glucose metabolism in T cells is still largely unknown. In the present study, the role of Nck1 in glucose metabolism in primary human T cells was investigated. Plasmid encoding Nck1-specific short hairpin RNA (shRNA) was delivered to primary T cells to mediate Nck1 silencing. Plasmids encoding Nck1-specific short hairpin RNA (shRNA) were delivered to primary human T cells to mediate Nck1 silencing. Nck1-knockdown (N1KD) cells were analysed for processes related to glucose metabolism and function. Despite an increased expression of glucose transporter 1 (GLUT1) in N1KD cells, these cells exhibited impaired glucose uptake and ATP production, indicating dysfunction of GLUT1 or altered intracellular glucose metabolism. Nck1 depletion disrupted metabolic signalling characterised by reduced TXNIP and phosphoribosomal protein S6 (pS6) levels, along with an increased phosphorylation of Akt and AMPK. The reduced extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) found in N1KD cells indicated impaired glycolysis and oxidative phosphorylation. Functionally, these metabolic alterations were associated with impaired T cell activation, reduced proliferation, and increased apoptosis. Collectively, Nck1 critically regulated glucose metabolism in T cells, linking metabolic reprogramming to immune function and cell survival.

Keywords:  Nck1; T cell; T cell activation; T cell signalling; glucose metabolism

DOI:  https://doi.org/10.1111/imm.13950
Ageing Res Rev. 2025 May 22. pii: S1568-1637(25)00129-1. [Epub ahead of print]109 102783

Advancing T-cell immunotherapy for cellular senescence and disease: Mechanisms, challenges, and clinical prospects.

Jizhun Wu, Lu Zhang, Zihan Zhao, Yuping Liu, Zhengxing Li, Xiaohang Feng, Lin Zhang, Xiang Yao, Jun Du, Liang Chen, Zhuolong Zhou.

  Cellular senescence is a complex biological process with a dual role in tissue homeostasis and aging-related pathologies. Accumulation of senescent cells promotes chronic inflammation, tissue dysfunction, age-related diseases, and tumor suppression. Recent advancements in immunotherapy have positioned T cell-based approaches as precision tools for the targeted clearance of senescent cells, offering a novel avenue for anti-aging interventions. This review explores the molecular mechanisms underlying cellular senescence, focusing on its immunogenic features and interactions with T cells, including T-cell activation, antigen recognition, modulation of tumor microenvironment (TME), and immune evasion strategies. Innovations such as chimeric antigen receptor (CAR)-T cells, immune checkpoint therapies, and SASP-neutralizing approaches are highlighted as breakthrough strategies for enhancing senescent cell eradication. The integration of multi-omics and artificial intelligence is further catalyzing the development of personalized therapies to amplify immune surveillance and tissue rejuvenation. Clinically, T cell-based interventions hold promise for mitigating age-related pathologies and extending healthspan, yet challenges remain in optimizing target specificity, countering immunosuppressive niches, and overcoming immune senescence in aging populations. This review synthesizes current advances and challenges, highlighting the potential of T cell immunotherapy as a cornerstone of anti-aging medicine and emphasizing the need for interdisciplinary innovation to translate preclinical findings into transformative therapies for aging and age-related diseases.

Keywords:  Aging and age-related diseases; CAR-T cells; Cellular senescence; Immune surveillance; Senotherapy; T-cell immunotherapy

DOI:  https://doi.org/10.1016/j.arr.2025.102783
Genes Dev. 2025 May 28.

Aging and immunity: the age-old tango.

Inés Fernández Maestre, Alexander S Harris, Corina Amor.

  The rising global demographic aging and the subsequent increase in the prevalence of age-related diseases highlight the need to understand aging biology. A key player in organismal aging is the immune system, which has broad systemic effects. On the one hand, immune aging involves the decline of hematopoietic stem cells and significant alterations in the functionality and composition of both innate and adaptive immunity. On the other hand, the aged immune system contributes to chronic inflammation and disrupted tissue homeostasis, thereby driving systemic aging processes. In this review, we examine the close interaction between aging and the immune system and discuss emerging therapeutic strategies aimed at modulating immune function to mitigate age-related pathologies.

Keywords:  aging; immunosenescence; senotherapeutics

DOI:  https://doi.org/10.1101/gad.352644.125
Pharmacol Res. 2025 May 27. pii: S1043-6618(25)00228-2. [Epub ahead of print]217 107803

The metabolism-immunity axis in Immune thrombocytopenia: from energy regulation to targeted therapy.

Xin Zhou, Ning-Ning Shan.

  Immunometabolism has received significant interest as a field exploring the dynamic interation between the immune system and metabolic processes. Immune cell activation, proliferation, and function are tightly regulated by metabolism, and metabolic products influence immune responses. These two aspects interact to maintain internal homeostasis. Disruption of immunometabolism plays a crucial role in the onset and progression of autoimmune diseases. Metabolic abnormalities may cause abnormal activation and differentiation of immune cells, leading to attacks on self-tissues. Immune thrombocytopenia (ITP) is an autoimmune disease characterized by platelet dysfunction and impaired production, which are closely related to metabolic dysfunction. Alterations in glycolysis, fatty acid oxidation, and amino acid metabolism affect platelet function and immune cell behavior, contributing to disease progression. This review discusses the role of immunometabolism in ITP, highlights recent advances in diagnosis and treatment, and explores potential therapeutic strategies.

Keywords:  Glycolysis; ITP; Immunometabolism; Metabolic Reprogramming

DOI:  https://doi.org/10.1016/j.phrs.2025.107803
J Immunother Cancer. 2025 May 26. pii: e011044. [Epub ahead of print]13(5):

Dual roles of IRE1α inhibition in reversing mitochondrial ROS-induced CD8+ T-cell senescence and exerting direct antitumor effects in multiple myeloma.

Yike Wan, Jingjing Wang, Mengping Chen, Junying Wang, Fajun Nan, Honghui Huang, Zhiqiang Liu, Jian Hou.

   BACKGROUND: Multiple myeloma (MM) is characterized by the proliferation of malignant plasma cells within the bone marrow (BM) microenvironment, which significantly contributes to immune suppression of CD8+ T cells. Our previous research identified that dysregulation of the IRE1α-XBP1s-SLC38A2 axis leads to decreased glutamine uptake and senescence of CD8+ T cells in MM. However, the underlying mechanisms of T-cell senescence remain unclear.
METHODS: Single-cell RNA sequencing was used to analyze mitochondrial function in CD8+ T cells in MM. The effects of XBP1s and SLC38A2 on mitochondrial reactive oxygen species (mtROS) were evaluated by flow cytometry under loss-of-function experiments. An IRE1α inhibitor (17#) was administered to explore its effects on T-cell senescence and MM cell growth. RNA sequencing was employed to disclose pathway alterations in T cells treated with 17#. The Vk*MYC mouse model was used to assess the impact of 17# on CD8+ T cell senescence and anti-myeloma effects.
RESULTS: BM-derived CD8+ T cells from patients with MM exhibited downregulated expressions of genes critical for glutamine transport (SLC38A2), mitochondrial respiratory chain, and ATP synthesis, while genes associated with ROS were upregulated. Suppression of XBP1s in CD8+ T cells resulted in decreased mtROS levels, whereas inhibition of SLC38A2 increased mtROS levels. Compound 17# significantly reduced senescence marker KLRG1 expression and increased perforin expression in nutrient-deprived BM CD8+ T cells from healthy donors and in BM CD8+ T cells from patients with MM, while promoting T-cell proliferation. Importantly, 17# did not impair the viability of peripheral blood mononuclear cells from healthy donors or alter the immune phenotypes of healthy CD8+ T cells. The NPR2-cGMP-PKG pathway was activated by IRE1α inhibition in restoring T-cell function. Furthermore, 17# exhibited direct inhibitory effects on MM cells. In Vk*MYC mouse model, 17# decreased mtROS levels in BM CD8+ T cells, reduced the proportion of senescent (KLRG1+CD57+CD28-) T cells, and resulted in a lower tumor burden.
CONCLUSION: Inhibiting IRE1α represents a promising strategy to reverse the senescence of CD8+ T cells by mitigating mtROS production. This dual mechanism not only rejuvenates T cells but also directly targets myeloma cells, offering a novel therapeutic approach for MM treatment.

Keywords:  Immunotherapy; Multiple Myeloma; T cell; Tumor microenvironment - TME

DOI:  https://doi.org/10.1136/jitc-2024-011044
Sci Adv. 2025 May 30. 11(22): eadu9512

Mitochondrial calcium signaling regulates branched-chain amino acid catabolism in fibrolamellar carcinoma.

Nicole M Marsh, Melissa J S MacEwen, Jane Chea, Heidi L Kenerson, Albert A Kwong, Timothy M Locke, Francisco Javier Miralles, Tanmay Sapre, Natasha Gozali, Madeleine L Hart, Theo K Bammler, James W MacDonald, Lucas B Sullivan, G Ekin Atilla-Gokcumen, Shao-En Ong, John D Scott, Raymond S Yeung, Yasemin Sancak.

Metabolic adaptations are essential for survival. The mitochondrial calcium uniporter plays a key role in coordinating metabolic homeostasis by regulating mitochondrial metabolic pathways and calcium signaling. However, a comprehensive analysis of uniporter-regulated mitochondrial pathways has remained unexplored. Here, we investigate consequences of uniporter loss and gain of function using uniporter knockout cells and fibrolamellar carcinoma (FLC), which we demonstrate to have elevated mitochondrial calcium levels. We find that branched-chain amino acid (BCAA) catabolism and the urea cycle are uniporter-regulated pathways. Reduced uniporter function boosts expression of BCAA catabolism genes and the urea cycle enzyme ornithine transcarbamylase. In contrast, high uniporter activity in FLC suppresses their expression. This suppression is mediated by the transcription factor KLF15, a master regulator of liver metabolism. Thus, the uniporter plays a central role in FLC-associated metabolic changes, including hyperammonemia. Our study identifies an important role for the uniporter in metabolic adaptation through transcriptional regulation of metabolism and elucidates its importance for BCAA and ammonia metabolism.

DOI: https://doi.org/10.1126/sciadv.adu9512
Viruses. 2025 Apr 24. pii: 606. [Epub ahead of print]17(5):

Dysfunctional Senescent Herpes Simplex Virus-Specific CD57+CD8+ T Cells Are Associated with Symptomatic Recurrent Ocular Herpes in Humans.

Aziz A Chentoufi, Arif A Khan, Ruchi Srivastava, Sweta Karan, Yassir Lekbach, Hawa Vahed, Lbachir BenMohamed.

  Herpes simplex virus (HSV)-specific CD8+ T cells protect mice from herpes infection and disease. However, the phenotype and function of HSV-specific CD8+ T cells that play a key role in the "natural" protection seen in HSV-1-seropositive healthy asymptomatic (ASYMP) patients (who have never had clinical herpes disease) remain to be determined. We previously reported that symptomatic (SYMP) patients (who have frequent bouts of recurrent ocular herpes disease) had more undifferentiated and dysfunctional HSV-specific CD8+ T cells. In contrast, healthy ASYMP individuals maintained a significantly higher proportion of differentiated polyfunctional CD8+ T cells. Here, we report that HSV-specific CD8+ T cells from 10 SYMP patients, but not HSV-specific CD8+ T cells from 10 ASYMP patients, have phenotypic and functional characteristics of cellular senescence, including: (i) high frequency of senescent (CD57+) and exhausted (PD-1+) CD8+ T cells; (ii) late terminally differentiated (KLRG1+), non-proliferating CD8+ T cells; (iii) HSV-specific CD8+ T cells which decreased in number over time and were not homeostatically maintained, as indicated by a reduction in the number of CD127+CD8+ T cells; (iv) loss of the co-stimulatory molecule CD28 on HSV-specific CD8+ T cells; and (v) decreased production of effector molecules (granzyme B and perforin) by HSV-specific CD8+ T cells. Our findings provide insights into the role of senescence in HSV-specific CD8+ T cells in susceptibility to recurrent herpes and have implications for T-cell-based immunotherapeutic strategies against recurrent herpes in humans.

Keywords:  CD57; CD8+ T cells; cornea; ocular herpes; senescent; trigeminal ganglia

DOI:  https://doi.org/10.3390/v17050606
Cell Calcium. 2025 May 17. pii: S0143-4160(25)00045-4. [Epub ahead of print]129 103036

Campari2 genomic interrogation of homeostatic calcium activity identifies TIM1 as a negative regulator of T cell function.

Sana Kouba, Xin Zhang, Raphael Néré, Cyril Castelbou, Nicolas Demaurex, Amado Carreras-Sureda.

  Calcium signals regulate crucial cellular functions yet many genes coding for Ca2+handling proteins remain unknown as their identification relies on low-throughput single-cell approaches. Here we describe a method to measure Ca2+ activity using CaMPARI2, flow cytometry and pooled genome interrogation. CAMPARI2 screen (CaMP-Screen) identified enhancers and inhibitors of homeostatic Ca2+ activity, highlighting a predominant role for store-operated Ca2+ entry (SOCE) and lipid signalling pathways. Genes reducing basal Ca2+ activity were linked to Prader Willy syndrome, T cell dysfunction, and deafness. Silencing of HAVCR1 gene, coding for T cell transmembrane immunoglobulin and mucin (TIM1), enhanced Ca2+ signals in T cells and promoted signaling under resting but not after TCR engagement. Our findings establish CaMP-Screen as an efficient detector of low-amplitude Ca2+ signals and identify new genes associated to pathologies that regulate Ca2+ homeostasis, reporting TIM1 as a negative regulator of Ca2+ signals driving T cell function.

Keywords:  CaMPARI2; Havcr1; SOCE; Screening; TIM1; lipid

DOI:  https://doi.org/10.1016/j.ceca.2025.103036
Endocr J. 2025 May 27.

Lipid metabolic reprogramming in immune regulation and chronic inflammatory diseases.

Ayaka Ito.

  Immune cells undergo substantial metabolic rewiring during differentiation and activation to satisfy the energy demands of an appropriate immune response. Lipids serve as energy sources and function as essential components of cellular membranes and signaling molecules. Recent studies have revealed that reprogramming of lipid metabolism, including lipid uptake, de novo synthesis of cholesterol and fatty acids, and fatty acid oxidation, leads to dynamic alterations in the quantity and quality of intracellular lipids. These metabolic changes play crucial roles in shaping immune cell functions, promoting anti-inflammatory responses, and facilitating the resolution of inflammation. Conversely, dysregulation of lipid metabolism can result in immune cell dysfunction, contributing to the onset and progression of chronic inflammatory diseases such as autoimmune diseases and metabolic syndrome. Notably, cholesterol and fatty acid metabolism influence immune responses by modulating membrane lipid composition and downstream inflammatory signaling. Given these insights, targeting lipid metabolism has emerged as a promising therapeutic approach for restoring immune homeostasis and treating chronic inflammatory diseases.

Keywords:  Autoimmunity; Chronic inflammation; Immune responses; Immunometabolism; Lipid metabolism

DOI:  https://doi.org/10.1507/endocrj.EJ25-0180
J Immunol. 2025 May 27. pii: vkaf050. [Epub ahead of print]

Comprehensive analysis of immune checkpoint molecules profiles phenotype and function of exhausted T cells in enzootic bovine leukosis.

Hayato Nakamura, Satoru Konnai, Tomohiro Okagawa, Naoya Maekawa, Wisa Tiyamanee, Mari Ikehata, Koume Matsubara, Kei Watari, Kana Kamitani, Maya Saito, Yukinari Kato, Yasuhiko Suzuki, Shiro Murata, Kazuhiko Ohashi.

  Bovine leukemia virus (BLV) causes enzootic bovine leukosis (EBL), a B-cell lymphoma in cattle. Previous studies have demonstrated that T cells of BLV-infected cattle show increased expression of immune checkpoint molecules, including programmed death-1 (PD-1), lymphocyte-activation gene-3 (LAG-3), cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), and T-cell immunoglobulin domain and mucin domain-3 (TIM-3), leading to T-cell exhaustion. However, the key immune checkpoint molecules driving T-cell exhaustion in BLV-induced tumorigenesis remained unclear. In this study, we identified the key immune checkpoint molecules by performing comprehensive flow cytometric analyses of T cells from EBL cattle, and elucidated the phenotype and function of exhausted T cells using a transcriptomic analysis by RNA sequencing and cell culture assays. The comprehensive expression analysis revealed that the proportion of CD4+ and CD8+ T cells co-expressing PD-1 and TIM-3 was significantly increased in the peripheral blood and tumor tissues of EBL cattle compared to healthy cattle. Transcriptomic analysis of PD-1+TIM-3+ T cells revealed the upregulation of genes related to terminal exhaustion and the downregulation of genes related to T-cell differentiation and response in this subset. Additionally, PD-1+TIM-3+ T cells exhibited higher expression of CTLA-4, LAG-3, and Eomes, and lower expression of T-bet, suggesting a terminally exhausted phenotype. Cell culture assays revealed a significant impairment in IFN-γ production in PD-1+TIM-3+ T cells upon stimulation, reflecting severe dysfunction. These findings indicate that PD-1+TIM-3+ T cells play a central role in T-cell exhaustion during BLV-induced tumorigenesis. This study provides valuable insights for future therapeutic strategies against BLV infection.

Keywords:  T cells; immunodeficiency diseases; large animals; tumor immunity; viral

DOI:  https://doi.org/10.1093/jimmun/vkaf050
Int J Mol Sci. 2025 May 21. pii: 4946. [Epub ahead of print]26(10):

A New Method of Canine CD4+ T Lymphocyte Differentiation Towards the Th17 Phenotype with Analysis of Properties and Mitochondrial Activity.

Iwona Monika Szopa, Kinga Majchrzak-Kuligowska, Rafał Pingwara, Marek Kulka, Monika Taşdemir, Małgorzata Gajewska.

  Th17 lymphocytes are a distinct subpopulation of T cells that are characterized by the production of interleukins IL-17, IL-21, IL-22, and IL-26, and high expression of RORγt. These cells play an important role in inflammation and autoimmune diseases. Recent studies using rodent and human models have also highlighted their promising properties as agents in cellular immunotherapy for cancer. However, much less is known about the properties of canine Th17 lymphocytes, despite the domestic dog being an important model used in comparative medicine. In this study, we developed methods of activation and differentiation of canine CD4+ T lymphocytes towards the Th17 phenotype. Additionally, we targeted the Wnt/β-catenin signaling pathway to modulate the efficiency of Th17 cells differentiation. CD4+ T cells were successfully activated with magnetic EpoxyBeads, and in combination with the appropriate programming medium, they acquired the Th17 phenotype. Furthermore, indomethacin, an inhibitor of the Wnt/β-catenin pathway, significantly increased the efficiency of differentiation, causing elevated production of IL-17 and changed T cell metabolism by promoting oxidative phosphorylation. The protocol elaborated in our study provides an efficient method of canine Th17 lymphocyte differentiation. Our findings also suggested that the modification of the Wnt/β-catenin signaling pathway could be a valuable strategy for optimizing canine Th17 cell differentiation and advancing cell-based immunotherapy.

Keywords:  T cell activation; T cell metabolism; Th17 lymphocytes; Wnt/β-catenin signaling pathway; domestic dog model; interleukin-17; magnetic EpoxyBeads; memory phenotype

DOI:  https://doi.org/10.3390/ijms26104946
Clin Transl Med. 2025 May;15(5): e70345

Unravelling T cell exhaustion through co-inhibitory receptors and its transformative role in cancer immunotherapy.

Simin Xiang, Sen Li, Junfen Xu.

  Persistent stimulation from cancer antigens leads to T lymphocytes (T cells) exhaustion, with up-regulated expression of co-inhibitory receptors, including programmed death-1 (PD-1), cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), lymphocyte-activation gene 3 (LAG-3), T cell immunoglobulin and mucin domain 3 (TIM-3) and T cell immunoreceptor with Ig and ITIM domains (TIGIT). These receptors collectively impair T cell function via distinct molecular pathways, contributing to immune evasion and cancer progression. This review highlights the therapeutic promise of immune checkpoint inhibitors (ICIs) in reversing T cell exhaustion while delving into the complex molecular processes and functional works of these important co-inhibitory receptors in tumourigenesis. Additionally, we examine the synergistic effects of combining ICIs with other therapeutic strategies, which can enhance anti-tumour efficacy. Finally, the clinical implications of bispecific antibodies are highlighted, representing a promising frontier in cancer immunotherapy, that could revolutionise treatment paradigms while improving patient outcomes. HIGHLIGHTS: This review discusses five major co-inhibitory receptors (PD-1, CTLA-4, LAG-3, TIM-3 and TIGIT) and their related mechanisms of T cell exhaustion in the tumour environment. We also discuss the clinical application of checkpoint inhibitors (ICIs) in cancer immunotherapy. The potential of bispecific antibodies (BsAbs) in cancer immunotherapy is highlighted.

Keywords:  T cell; co‐inhibitory receptors; exhaustion; immune checkpoint inhibitors; immunotherapy; tumour immunity

DOI:  https://doi.org/10.1002/ctm2.70345
Front Immunol. 2025 ;16 1573039

Lactate-mediated metabolic reprogramming of tumor-associated macrophages: implications for tumor progression and therapeutic potential.

Xiaohan Jin, Ni Zhang, Tinghao Yan, Jingyang Wei, Lingli Hao, Changgang Sun, Haibo Zhao, Shulong Jiang.

  The tumor microenvironment (TME) is characterized by distinct metabolic adaptations that not only drive tumor progression but also profoundly influence immune responses. Among these adaptations, lactate, a key metabolic byproduct of aerobic glycolysis, accumulates in the TME and plays a pivotal role in regulating cellular metabolism and immune cell function. Tumor-associated macrophages (TAMs), known for their remarkable functional plasticity, serve as critical regulators of the immune microenvironment and tumor progression. Lactate modulates TAM polarization by influencing the M1/M2 phenotypic balance through diverse signaling pathways, while simultaneously driving metabolic reprogramming. Furthermore, lactate-mediated histone and protein lactylation reshapes TAM gene expression, reinforcing their immunosuppressive properties. From a therapeutic perspective, targeting lactate metabolism has shown promise in reprogramming TAMs and enhancing anti-tumor immunity. Combining these metabolic interventions with immunotherapies may further augment treatment efficacy. This review underscores the crucial role of lactate in TAM regulation and tumor progression, highlighting its potential as a promising therapeutic target in cancer treatment.

Keywords:  cancer therapy; immune regulation; lactate metabolism; metabolic reprogramming; tumor microenvironment; tumor-associated macrophages

DOI:  https://doi.org/10.3389/fimmu.2025.1573039
Gerontology. 2025 May 26. 1-14

The potential role of mitochondria in age-related health benefits conferred by moderate hypoxia.

Johannes Burtscher, Kamilla Woznica Miskowiak, Katharina Hüfner, Hannelore Ehrenreich, Martin Kopp.

Background Mitochondrial integrity and efficiency deteriorate with age and are linked to cellular senescence. Mitochondria are highly responsive to reduced oxygen availability (hypoxia), which for example occurs when exposed to altitude. We hypothesize that mitochondria are involved in the observed health benefits at moderate altitude. Because the experimental evidence on mitochondrial changes at moderate altitude is limited, we also evaluate dose-response associations of oxygen transport and mitochondrial functions derived from measurements at normoxia and severe hypoxia. Summary We summarize the effects of environmental oxygen availability and changes in cellular oxygen demand/supply on mitochondrial functions and assess, how this may influence aging. Hypotheses are presented how mild hypoxia at moderate altitude (1000 - 2500 m) could improve mitochondrial function and possibly explain the reported lower levels of mortality from several age-related diseases. Key messages It is unknown, whether continuous or intermittent types of hypoxia exposure are more effective in improving mitochondrial functions and promoting healthy aging. The combination of tissue-specific oxygen demand (for example during physical exercise) with mild reductions of ambient oxygen availability may enable the reported health benefits associated with moderate altitude residence.

DOI: https://doi.org/10.1159/000546478