{"title":"Neuro-immune-tumor axis in gliomas: a review of mechanisms, models, and translational opportunities.","authors":"Lu Xu, Shuangyu Chen, Yixin Fu, Tingting Zhou, Jianghao Yu, Jiayang Li, Wei Chen","doi":"10.3389/fimmu.2025.1682322","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1682322","url":null,"abstract":"<p><p>Neuroimmuno-oncology is an emerging interdisciplinary field that explores the complex interactions among the nervous system, the immune system, and tumor cells within the tumor microenvironment (TME). Recent studies have underscored the critical role of neurons in gliomas, where synaptic signaling and the release of neurotrophic factors contribute not only to tumor progression but also to mechanisms of immune evasion. Neurotransmitters such as glutamate and gamma-aminobutyric acid (GABA), along with neuron-derived factors including brain-derived neurotrophic factor (BDNF) and neuroligin-3 (NLGN3), have been shown to modulate immune cell function and promote the formation of an immunosuppressive TME. In particular, neuronal electrical activity mediated through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) signaling facilitates immune escape in glioma cells, leading to the development of an \"immune-excluded\" phenotype that compromises the efficacy of immunotherapy. Therapeutic strategies that combine AMPAR antagonists with immune checkpoint inhibitors-alongside neuromodulatory techniques such as repetitive transcranial magnetic stimulation (rTMS) or deep brain stimulation (DBS)-hold potential to reprogram the neuro-immune-tumor axis, remodel the immune landscape, and improve immunotherapy responses in central nervous system malignancies. Advancing our understanding of how neuronal activity regulates the glioma immune microenvironment may open new avenues for precision-targeted therapeutic approaches in neuro-oncology.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1682322"},"PeriodicalIF":5.9,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12540510/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145354525","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Frontiers in ImmunologyPub Date : 2025-10-08eCollection Date: 2025-01-01DOI: 10.3389/fimmu.2025.1675786
Isabella Micallef Nilsson, Thomas Poiret, Jinhye Ryu, Mohammadali Mohammadpour, Johan Henriksson, Anders Österborg, Jonas Mattsson, Anna Schurich, Isabelle Magalhaes
{"title":"Production of functional CD19 CAR T cells under hypoxic manufacturing conditions.","authors":"Isabella Micallef Nilsson, Thomas Poiret, Jinhye Ryu, Mohammadali Mohammadpour, Johan Henriksson, Anders Österborg, Jonas Mattsson, Anna Schurich, Isabelle Magalhaes","doi":"10.3389/fimmu.2025.1675786","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1675786","url":null,"abstract":"<p><strong>Introduction: </strong>Chronic lymphocytic leukemia (CLL) has proven difficult to treat with chimeric antigen receptor (CAR) T cell therapy. CLL cells can negatively alter T cell fitness and induce a pseudohypoxic state. We hypothesized that production of CAR T cells under restricted oxygen conditions resembling physiological oxygen levels that can be encountered in tissues (<i>i.e.</i> 2% O<sub>2</sub>) could promote outgrowth of hypoxia-tolerant CAR T cells.</p><p><strong>Methods: </strong>We performed <i>in vitro</i> phenotypic and functional assessments of CD19-directed CAR T cells produced in either 21% (<sup>Nor</sup>CAR) or 2% (<sup>Hyp</sup>CAR) O<sub>2</sub> derived from healthy donors (HDs) or patients with CLL.</p><p><strong>Results: </strong>Production of HD-derived CAR T cells in 2% O<sub>2</sub> promoted the enrichment of a naïve-like subset. <sup>Hyp</sup>CAR and <sup>Nor</sup>CAR cells were functionally distinct; CD4+ <sup>Hyp</sup>CAR cells produced more IL-2 and tumor necrosis factor than CD4+ <sup>Nor</sup>CAR cells. Production in 2% O<sub>2</sub> was not detrimental to viability or proliferation upon cognate antigen-stimulation and led to increased activation. After chronic stimulation in hypoxia, <sup>Hyp</sup>CAR-product remained enriched in naïve-like cells, and demonstrated cytotoxic and cytokine production capacity. In CAR T cells derived from patients with CLL, <sup>Nor</sup>CAR and <sup>Hyp</sup>CAR subsets were functionally and phenotypically comparable, but displayed different mitochondrial metabolism.</p><p><strong>Discussion: </strong>We demonstrated that production in 2% O<sub>2</sub> is not detrimental, confers subtle but lasting functional and phenotypic changes in CAR T cells warranting further research on the impact of hypoxic production on CAR T cell functionality in hypoxic tumor microenvironments.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1675786"},"PeriodicalIF":5.9,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12540424/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145354568","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Frontiers in ImmunologyPub Date : 2025-10-08eCollection Date: 2025-01-01DOI: 10.3389/fimmu.2025.1656776
Helena Moretti, Giorgia Cioccoloni, Esperanza Perucha
{"title":"Immunometabolism in cancer: a systemic perspective.","authors":"Helena Moretti, Giorgia Cioccoloni, Esperanza Perucha","doi":"10.3389/fimmu.2025.1656776","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1656776","url":null,"abstract":"<p><p>Cancer incidence is increasing, becoming a significant public health concern. Cancer arises from the uncontrolled division of cells that cannot be restrained by the anti-tumour response mounted by the immune system. Both tumour and immune cells require high levels of energy in the form of ATP and synthesis of macromolecules to support differentiation and proliferation. To support these metabolic demands, adaptations at the cell, tissue and systemic level are required. Here, we take a systemic perspective to summarise the energetic needs of the anti-tumour response and how metabolic overload and obesity affects these processes. We describe how immunotherapies that aim to reverse immune cell exhaustion have unexpected effects depending on the metabolic background of the patient and finally we propose the use of this knowledge to advance current cancer prevention and treatment strategies.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1656776"},"PeriodicalIF":5.9,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12540421/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145354603","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Frontiers in ImmunologyPub Date : 2025-10-08eCollection Date: 2025-01-01DOI: 10.3389/fimmu.2025.1655573
Bin Du, Leqi Li, Jingjing Li, Yiping Liu, Pu Wang
{"title":"Hydroxychloroquine's diverse targets: a new frontier in precision medicine.","authors":"Bin Du, Leqi Li, Jingjing Li, Yiping Liu, Pu Wang","doi":"10.3389/fimmu.2025.1655573","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1655573","url":null,"abstract":"","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1655573"},"PeriodicalIF":5.9,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12541592/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145354480","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Ribosome biogenesis-related gene signature predicts prognosis and immune landscape in glioma and identifies UTP20 as a therapeutic target.","authors":"Yadan Li, Xiaolong Tang, Wenhui Zhao, Xiuwen Si, Yanfang Cui, Yanbin Dong, Yongshuo Liu","doi":"10.3389/fimmu.2025.1680667","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1680667","url":null,"abstract":"<p><strong>Background: </strong>Glioma, the most prevalent primary brain tumor, exhibits dysregulated ribosome biogenesis closely linked to malignant behavior. However, the role of ribosome biogenesis in glioma and prognosis remains incompletely understood. This study aimed to construct a molecular signature based on ribosome biogenesis-related genes to predict patient survival and therapeutic response in glioma.</p><p><strong>Methods: </strong>Utilizing The Cancer Genome Atlas (TCGA) glioma cohort data, we constructed a ribosome biogenesis-related genes (RBRGs) signature using LASSO regression and multivariate Cox analyses, and subsequently validating its prognostic value in independent cohorts. We systematically evaluated the signature's associations with clinicopathological features, tumor immunity, genomic instability, tumor stemness, and therapeutic sensitivity. The oncogenic role of the key gene UTP20 was experimentally validated in U87 and U251 glioma cell lines through MTS, colony formation, and transwell assays.</p><p><strong>Results: </strong>We established a four-gene RBRGs signature (NOP10, UTP20, SHQ1, and PIH1D2). Elevated RBRGs score significantly correlated with shortened overall survival and adverse clinical characteristics, including advanced age, high WHO grade, IDH wild-type status, and absence of 1p/19q codeletion. A nomogram incorporating the RBRGs score demonstrated excellent predictive performance (C-index = 0.841). RBRGs-associated genes were enriched in immune regulatory pathways. The high-risk group exhibited increased infiltration of immunosuppressive cells (macrophages, myeloid-derived suppressor cells [MDSCs], and cancer-associated fibroblasts [CAFs]), upregulation of immunosuppressive checkpoints, and resistance to immunotherapy. Furthermore, the RBRGs signature correlated with genomic alterations, heterogeneity, tumor stemness, and therapeutic sensitivity. Crucially, UTP20 knockdown significantly suppressed glioma cell proliferation and invasion <i>in vitro</i>.</p><p><strong>Conclusion: </strong>The RBRGs signature was successfully developed and validated as an independent prognostic biomarker and predictor of therapeutic response in glioma, highlighting its extensive association with tumor heterogeneity. Furthermore, this study identified UTP20 as a key oncogenic driver that facilitates glioma progression.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1680667"},"PeriodicalIF":5.9,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12540490/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145354354","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Frontiers in ImmunologyPub Date : 2025-10-08eCollection Date: 2025-01-01DOI: 10.3389/fimmu.2025.1680791
Hicham Sid, Theresa von Heyl, Sabrina Schleibinger, Romina Klinger, Leah Heymelot Nabel, Hanna Vikkula, Rodrigo Guabiraba, Vanaique Guillory, Ryan Scicluna, Mohanned Naif Alhussien, Brigitte Böhm, Benjamin Schade, Daniel Elleder, Samantha Sives, Lonneke Vervelde, Sascha Trapp, Benjamin Schusser
{"title":"Genetic reinstatement of RIG-I in chickens reveals insights into avian immune evolution and influenza interaction.","authors":"Hicham Sid, Theresa von Heyl, Sabrina Schleibinger, Romina Klinger, Leah Heymelot Nabel, Hanna Vikkula, Rodrigo Guabiraba, Vanaique Guillory, Ryan Scicluna, Mohanned Naif Alhussien, Brigitte Böhm, Benjamin Schade, Daniel Elleder, Samantha Sives, Lonneke Vervelde, Sascha Trapp, Benjamin Schusser","doi":"10.3389/fimmu.2025.1680791","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1680791","url":null,"abstract":"<p><p>Retinoic acid-inducible gene I (<i>RIG-I</i>) activates mitochondrial antiviral signaling proteins, initiating the antiviral response. <i>RIG-I</i> and <i>RNF135</i>, a ubiquitin ligase regulator, are missing in domestic chickens but conserved in mallard ducks. The chickens' <i>RIG-I</i> loss was long believed to be linked to increased avian influenza susceptibility. We reinstated both genes in chickens and examined their susceptibility to infection with an H7N1 avian influenza virus. Uninfected <i>RIG-I</i>-expressing chickens exhibited shifts in T and B cells. At the same time, the H7N1 infection led to severe disease, persistent weight loss, and increased viral replication. The simultaneous expression of <i>RIG-I</i> and <i>RNF135</i> potentiated the <i>RIG-</i>I activity and was associated with exacerbated inflammatory response and increased mortality without influencing virus replication. Additional animal infection experiments with two other avian influenza viruses validated these findings. They confirmed that the harmful effects triggered by <i>RIG-I</i> or <i>RIG-I</i>-<i>RNF135</i>-expression require a minimum degree of viral virulence. Our data indicate that the loss of <i>RIG-I</i> in chickens has likely evolved to counteract deleterious inflammation caused by viral infection and highlight an outcome of restoring evolutionary lost genes in birds.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1680791"},"PeriodicalIF":5.9,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12540166/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145354513","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Frontiers in ImmunologyPub Date : 2025-10-08eCollection Date: 2025-01-01DOI: 10.3389/fimmu.2025.1630836
Qianqian Xu, Yue Yang, Cong Zhang, Min Tan, Jiayi Li, Wenge Li
{"title":"Identification and validation of biomarkers in gastric cancer-associated membranous nephropathy: Insights from comprehensive bioinformatics analysis and machine learning.","authors":"Qianqian Xu, Yue Yang, Cong Zhang, Min Tan, Jiayi Li, Wenge Li","doi":"10.3389/fimmu.2025.1630836","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1630836","url":null,"abstract":"<p><strong>Background: </strong>This study explores the genetic basis of membranous nephropathy (MN) in gastric adenocarcinoma (GC) through bioinformatics and machine learning analyses.</p><p><strong>Methods: </strong>Gene expression profiles from MN (GSE108109) and GC (GSE54129) datasets were obtained from the Gene Expression Omnibus. Common differentially expressed genes (DEGs) were identified using the limma R package. Biological functions were analyzed via Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways with the Cluster Profiler package. LASSO regression and Random Forest algorithms were used to identify hub genes associated with GC-related MN. The area under the curve (AUC) of ROC analysis validated these genes for their diagnostic potential. Gene Set Enrichment Analysis (GSEA) and immune cell infiltration analysis were conducted, with hub genes validated through immunohistochemistry on renal and gastric cancer tissues.</p><p><strong>Results: </strong>We identified 40 common DEGs between GC and MN datasets. Using protein-protein interaction networks, 20 significant hub genes were selected, primarily involved in inflammatory and immune response regulation. Key hub genes identified were <i>CCND1</i>, <i>CEBPD</i>, <i>COL10A1</i>, and <i>BMP2</i>, which demonstrated high accuracy in discriminating MN. Notably, <i>CCND1</i>, <i>CEBPD</i>, and <i>BMP2</i> were significantly overexpressed in glomerular and gastric cancer tissues.</p><p><strong>Conclusions: </strong>Our findings highlight the crucial roles of <i>CCND1</i>, <i>CEBPD</i>, and <i>BMP2</i> in the pathogenesis of GC-associated MN, providing insights for future research and potential therapeutic strategies.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1630836"},"PeriodicalIF":5.9,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12540328/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145354520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Oncolytic virus therapy in the elderly: immune frailty, challenges, and perspectives.","authors":"Jia-Wen Wang, Jia-Hui Liu, Yue-Lin Liu, Wen-Zheng Xu, Zi-Bo Zhang","doi":"10.3389/fimmu.2025.1686659","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1686659","url":null,"abstract":"<p><p>With global aging accelerating, cancer incidence among older adults is rapidly increasing. Individuals aged ≥65 years now represent 64% of new cancer cases and 71.3% of cancer-related deaths worldwide. This population exhibits a distinct immune imbalance-driven by tumor-induced immunosuppression, immunosenescence, and inflammaging-which contributes to poor tolerance of standard therapies and suboptimal outcomes with PD-1/PD-L1 inhibitors. As an emerging immunotherapeutic strategy, oncolytic viruses (OVs) selectively infect tumor cells, induce immunogenic cell death (ICD), and activate the cGAS-STING pathway. Although clinical data in elderly patients with esophageal, lung, or pancreatic cancer are scarce, promising outcomes have been reported in melanoma/sarcoma subgroups, including objective response rates of 26.4-32.9% and a median duration of response of 33.7 months, highlighting the potent antitumor potential of OVs. However, age-related immunological vulnerability-manifesting across different frailty stages as reflected by G8 scoring-may predispose elderly patients to immune overload, cytokine storm, and impaired tolerance, while this group remains underrepresented in OV trials. Systematic studies in this context are lacking. This review highlights the immunological characteristics of aging, emphasizes the importance of addressing immunological vulnerability across different age stages (G8 scoring), and outlines emerging challenges and future directions for OV-based therapies tailored to frail elderly populations.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1686659"},"PeriodicalIF":5.9,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12540392/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145354536","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Atherosclerotic cardiovascular disease and mortality in a cohort of patients with rheumatoid arthritis: a prospective study investigating microRNAs as predictors of atherosclerosis and mortality.","authors":"Dídac Llop, Silvia Paredes, Daiana Ibarretxe, Roser Rosales, Lluís Masana, Josep Ribalta, Joan Carles Vallvé","doi":"10.3389/fimmu.2025.1667553","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1667553","url":null,"abstract":"<p><p>Rheumatoid arthritis (RA) is a chronic autoimmune disorder associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD) that is not fully explained by traditional risk factors. This study investigated whether a novel microRNA (hsa-miR) panel could improve cardiovascular risk prediction and stratification in RA patients. In this 8-year prospective cohort study, 235 RA patients were enrolled, of whom 148 completed follow-up. We quantified six hsa-miRs (hsa-miR-24, -146, -Let7a, -425, -451, and -155-5p) using qPCR and evaluated their predictive value for two primary endpoints: ASCVD progression (new atherosclerotic plaques and/or non-fatal cardiovascular events) and all-cause mortality using partial least squares discriminant analysis (PLS-DA), linear mixed models, and multivariate regression. During follow-up, 58 patients (39%) experienced ASCVD progression, and 35 died (ASCVD accounting for 31% of deaths). PLS-DA models indicated that baseline hsa-miR levels predicted both ASCVD progression and mortality, explaining 43% and 42% of outcome variability, respectively. Longitudinal changes in five hsa-miRs (-24, -146, -let-7a, -425, and -155-5p) also predicted ASCVD progression. Age, hypertension, and disease duration modulated hsa-miR expression levels over time. This hsa-miR panel represents a promising tool for improving cardiovascular risk prediction in RA, potentially addressing critical gaps in current stratification approaches. Following validation, it could support implementation of personalized cardiovascular risk assessment in RA clinical practice.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1667553"},"PeriodicalIF":5.9,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12540091/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145354334","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Frontiers in ImmunologyPub Date : 2025-10-08eCollection Date: 2025-01-01DOI: 10.3389/fimmu.2025.1644289
Xuefeng Lei, Diandian Qian, Wenzheng Zhang, Bin'an Zhao, Yabin Li, Hua Hao, Jing Yuan, Le Zhao, Centao Liu
{"title":"Macrophage PTP1B regulates mitochondrial dynamics via the JAK2/STAT3-OPA1 axis and activates the cGAS/STING signaling pathway.","authors":"Xuefeng Lei, Diandian Qian, Wenzheng Zhang, Bin'an Zhao, Yabin Li, Hua Hao, Jing Yuan, Le Zhao, Centao Liu","doi":"10.3389/fimmu.2025.1644289","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1644289","url":null,"abstract":"<p><p>Tendinopathy is characterized by degenerative changes in tendon tissue, with its pathogenesis closely associated with macrophage-mediated chronic inflammation and mitochondrial dysfunction. Bioinformatics analysis of tendinopathic tissues revealed a significant upregulation of protein tyrosine phosphatase 1B (PTP1B) in macrophages, which accompanied with robust immune activation and marked Janus Kinase 2/Signal Transducer and Activator of Transcription 3 (JAK2/STAT3) signaling pathway inhibition. In tendinopathy mouse models, both pro-inflammatory cytokines and PTP1B were found to be highly expressed in tendon tissues. However, conditional deletion of <i>Ptpn1</i> (encoding PTP1B, Ptpn1<sup>-/-</sup>) in macrophages significantly alleviated tendon inflammation and fibrosis, indicating a strong association between PTP1B and tendinopathy. Mechanistically, in vivo experiments demonstrated that macrophage PTP1B suppressed STAT3 activation by inhibiting JAK2 phosphorylation, and inhibited the mitochondrial fusion protein Optic Atrophy1 (OPA1), resulting in mitochondrial fragmentation and mitochondrial DNA (mtDNA) release. This process activated the Cyclic GMP-AMP synthase/Stimulator of interferon genes (cGAS/STING) pathway, elevating the levels of inflammation and exacerbating tendon injury. In summary, macrophage PTP1B was shown to regulate mitochondrial dynamics via the JAK2/STAT3-OPA1 axis and trigger inflammation through activation of the cGAS/STING pathway, representing a key mechanism underlying the progression of tendinopathy. Targeting PTP1B or associated pathways may provide novel therapeutic strategies for tendinopathy.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1644289"},"PeriodicalIF":5.9,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12540072/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145354564","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}