Journal of Translational Medicine最新文献

{"title":"Single-cell transcriptomics reveals transcriptional reprogramming and microenvironmental remodeling in ectopic ACTH/CRH-secreting pheochromocytomas.","authors":"Wan Su, Shiwei Chen, Jinghua Liu, Penghu Lian, Xuebin Zhang, Yushi Zhang, Wencong Han, Qi Shen, Di Zhang, Xiang Zhou, Yu Xiao, Qing Ling, Ying Gao, Lin Lu, Zheng Zhang","doi":"10.1186/s12967-026-09066-1","DOIUrl":"10.1186/s12967-026-09066-1","url":null,"abstract":"<p><strong>Background: </strong>Ectopic ACTH- and/or CRH-secreting pheochromocytomas (ACTH⁺CRH⁺PCCs) are rare tumors that can mimic Cushing's syndrome and complicate the diagnosis and treatment clinically. However, the tumor-intrinsic and microenvironmental features of ACTH⁺CRH⁺ PCCs remains poorly understood.</p><p><strong>Methods: </strong>Fresh tumor specimens from three ACTH⁺CRH⁺ and three ACTH^- CRH^- PCCs were profiled by single-cell RNA sequencing. Developmental trajectories and transcriptional regulatory networks were analyzed to investigate tumor-intrinsic programs, while CellChat and NicheNet were used to characterize cell-cell communication and infer ligand-mediated microenvironmental remodeling. Findings were also validated using TCGA datasets and immunohistochemical staining.</p><p><strong>Results: </strong>ACTH⁺ CRH⁺ PCCs showed increased POMC and CRH expression and were enriched for a Schwann cell precursor (SCP)-like population positioned at an early pseudotime state. Regulatory network analysis further identified increased CEBPB activity in ACTH⁺ CRH⁺ tumor cells. Microenvironmental analysis revealed enrichment of SELE⁺ endothelial cells and CD8⁺ T cells in ACTH⁺ CRH⁺ PCCs. Cell-cell communication analysis showed more frequent interactions between ACTH⁺ CRH⁺ tumor cells and SELE⁺ endothelial cells, together with predicted ECM-associated interactions between SELE⁺ endothelial cells and T cells. In contrast, ACTH^- CRH^- PCCs exhibited stronger VEGFA-related angiogenic signaling, greater enrichment of stromal populations and MRC1⁺ M2-like macrophages, and more prominent LGALS9-CD45 signaling between macrophages and T cells.</p><p><strong>Conclusions: </strong>Our study provides single-cell insights into the tumor-intrinsic and microenvironmental heterogeneity between ACTH⁺CRH⁺ PCCs and ACTH^-CRH^- PCCs, revealing distinct tumor cell states and subtype-specific vascular and immune landscapes.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"24 1","pages":""},"PeriodicalIF":9.7,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13660345/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149165243","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":"Toward regionally equitable precision medicine: microbiota‑associated mechanisms and emerging personalized strategies in multiple sclerosis.","authors":"Ameera Saeed Alshinnawy, Elham AbdelBadiea Rashwan, Mahmoud Saad Swelam, Mohamed R Mohamed, Ahmed A Sayed","doi":"10.1186/s12967-026-08830-7","DOIUrl":"10.1186/s12967-026-08830-7","url":null,"abstract":"<p><p>Multiple sclerosis (MS) is a chronic immune-mediated disorder of the central nervous system in which dysregulated immune signalling and barrier dysfunction play central pathogenic roles. Increasing evidence implicates the gut microbiota as a key modulator of host immune homeostasis; however, current understanding is largely derived from Western cohorts and remains fragmented at the mechanistic level. This review synthesizes global evidence alongside emerging data from underrepresented regions, including Egypt, Iran, and India, to delineate molecular pathways linking MS-associated dysbiosis to immune dysregulation. Across studies, dysbiosis is consistently associated with impaired short-chain fatty acid-mediated immunoregulation, skewing toward proinflammatory Th1/Th17 responses, and disruption of intestinal and blood-brain barrier integrity, with region-dependent functional signatures involving oxidative stress and neurotransmitter and tryptophan metabolism. Several regional signatures reported here derive from a single pilot-scale cohort and should be regarded as hypothesis-generating pending independent validation, and current microbiota-targeted interventions remain investigational rather than established disease-modifying therapies for MS. We critically examine microbiota-derived signals, including short-chain fatty acids, lipopolysaccharide, and polysaccharide A, that modulate dendritic cell programming, regulatory T-cell differentiation, and neuroinflammatory cascades. We further evaluate microbiome-targeted therapeutic strategies and discuss how sex, regional context, and sequencing methodology influence functional interpretation and therapeutic responsiveness. Finally, we propose a roadmap for regionally equitable precision medicine, advocating for standardized multi-omics and culturally inclusive longitudinal designs to move beyond empiric interventions toward personalized, strain-defined biotherapeutics tailored to the unique microbial and environmental landscapes of MS patients worldwide.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"24 1","pages":""},"PeriodicalIF":9.7,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13653396/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149148751","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":"SPP1⁺ macrophage-derived WNT5A contributes to MMP11⁺ myCAF-mediated matrix remodeling and immunotherapy resistance in lung adenocarcinoma.","authors":"Menglei Wang, Pengcheng Zhang, Xuefeng Li, Lan Shao, Shijie Dai, Zhuo Chen","doi":"10.1186/s12967-026-09069-y","DOIUrl":"10.1186/s12967-026-09069-y","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Lung adenocarcinoma (LUAD) is the leading subtype of non-small cell lung cancer. However, the stromal-immune circuits that coordinate matrix remodeling and immunotherapy resistance in LUAD remain incompletely understood. This study aimed to characterize the stromal-immune interactions associated with LUAD progression and poor response to PD-1 blockade.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Bulk transcriptomic datasets, single-cell RNA sequencing, and spatial transcriptomic data were integrated with clinical immunotherapy cohorts. Weighted gene co‑expression network analysis, survival meta‑analysis, and tissue enrichment scoring identified high‑risk cell subpopulations. Cell‑cell communication, virtual gene knockout, and spatial deconvolution were used to predict ligand‑receptor interactions and colocalization. Multiplex immunohistochemistry of clinical specimens validated spatial relationships. In vitro, MMP11-overexpressing cancer-associated fibroblasts (CAFs) and SPP1-overexpressing macrophages (Macs) were generated, and a macrophage-CAF co‑culture system was constructed. Migration, contractility, extracellular matrix deposition, and YAP/INHBA pathway activation was measured. In vivo, a murine tumor model was established and evaluated using in vivo imaging, flow cytometry, atomic force microscopy assay, HE, masson staining, and multiplexed IHC staining.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;MMP11⁺ myofibroblastic CAF (MMP11⁺ myCAF) was identified as a high-risk CAF subset enriched in primary tumor and metastatic lesions, characterized by elevated expression of matrix-remodeling and contractile genes, including MMP11, ACTA2, and TAGLN. Increased abundance of MMP11⁺ myCAF was associated with advanced tumor stage, metastasis, poor overall survival, and reduced benefit from immune checkpoint blockade (ICB). Spatial transcriptomic deconvolution and multiplex immunohistochemistry revealed that MMP11⁺ myCAFs spatially co-localized with SPP1⁺ Mac, a pro-tumor myeloid population enriched in malignant and metastatic LUAD tissues. Ligand-receptor and downstream target analyses identified WNT5A as a key macrophage-derived mediator linking SPP1⁺ Mac to MMP11⁺ myCAF activation. Mechanistically, SPP1⁺ Mac exhibited activation of NFKB2/RELB-associated transcriptional programs, and SPP1 overexpression increased Nfkb2, Relb, and WNT5A protein levels in macrophages. WNT5A stimulation promoted YAP/INHBA-associated signaling in CAFs, enhancing CAF migration, contractility and extracellular matrix deposition. In animal models, activation of WNT5A signaling impaired the therapeutic efficacy of PD-1 blockade, reduced intratumoral CD8⁺ T-cell infiltration, and increased MMP11⁺ CAF-associated collagen deposition and tissue stiffness.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;SPP1⁺ Mac-derived WNT5A may contribute to MMP11⁺ myCAF-mediated matrix remodeling and immunotherapy resistance in LUAD, highlighting a potential therapeutic strategy to overcome ICB re","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"24 1","pages":""},"PeriodicalIF":9.7,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13692972/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149244672","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":"Treatment benefit does not establish senolysis or lifespan extension.","authors":"Wei Chen, Xiaohu Sun","doi":"10.1186/s12967-026-09014-z","DOIUrl":"10.1186/s12967-026-09014-z","url":null,"abstract":"","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"24 1","pages":""},"PeriodicalIF":9.7,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13640179/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149110722","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":"Gene expression profiles in benign prostate tissue reflect tumor proximity, grade, and molecular subtype.","authors":"Pernilla Wikström, Eva Freyhult, Julius Semenas, Marie Lundholm, Andreas Josefsson, Sofia Halin Bergström, Anders Bergh","doi":"10.1186/s12967-026-09035-8","DOIUrl":"10.1186/s12967-026-09035-8","url":null,"abstract":"<p><strong>Background: </strong>Normal tissue in a tumor-bearing organ shows morphological and molecular differences from normal tissue in a tumor-free organ. One explanation to this is that tumors actively instruct adjacent normal tissues to support growth and invasion. The aim of this study was to examine if changes in gene-expression patterns in tumor-adjacent histologically benign prostate tissue, termed tumor instructed normal tissue (TINT), were associated with tumor proximity, grade and molecular subtype and, furthermore, whether they could indicate the presence of high-grade cancer elsewhere in the prostate.</p><p><strong>Methods: </strong>Gene-expression analysis using Clariom D microarrays was performed on matched formalin-fixed paraffin-embedded samples including tumor tissue (n = 44), benign prostate tissue taken near (TINT-N, n = 44) or distant (TINT-D, n = 42) to the tumor in 44 men with unifocal cancer treated by prostatectomy. TINT changes related to cell proliferation and immune cell infiltration were examined using immunohistochemical markers. In addition, gene expression was compared between tumor-negative biopsies from men later diagnosed with high-grade cancer (Bx-later-tumor, n = 46), tumor-negative biopsies from men who remained cancer-free (Bx-control, n = 49), and cancer-containing biopsies (Bx-tumor, n = 28). Gene set enrichment analysis (GSEA) was performed to explore hallmark gene sets in tumor and TINT tissue in relation to tumor grade (high vs. low) and molecular subtype (Luminal B vs. Luminal A).</p><p><strong>Results: </strong>The transcriptome in TINT differed significantly from that in cancer-free biopsy control tissue and was related to tumor grade (high- vs. low), molecular subtype (Luminal B vs. Luminal A), and tumor proximity (TINT-N vs. TINT-D). Hallmarks related to cell proliferation and increased Ki67 staining as well as signs of increased metabolism were generally enriched in both tumor and TINT tissue of high grade and Luminal B tumors. In contrast, some immune responses were unique to TINT areas of high-grade and Luminal A tumors, respectively, and more obvious in TINT-N than in TINT-D. Analysis of Bx-later-tumor indicated enriched metabolism compared to Bx-control, without clear proliferative or immunological differences.</p><p><strong>Conclusions: </strong>TINT effects involving proliferation, metabolism and immune responses are related to distance, tumor grade and molecular subtype. TINT alterations hold potential as diagnostic and prognostic biomarkers and may provide a basis for further exploration of tumor-host interactions and potential targets for intervention.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"24 1","pages":""},"PeriodicalIF":9.7,"publicationDate":"2026-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13640278/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149111513","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":"Lineage-specific immune checkpoint dynamics define a context-dependent regulatory framework with translational relevance in human γδ T cells.","authors":"Anna Maria Corsale, Marta Di Simone, Juan Pablo Cerapio, Elena Lo Presti, Gabriele Pizzolato, Claudia Avellone, Costanza Dieli, Salvatore Marchiafava, Laura Di Paola, Francesco Dieli, Serena Meraviglia","doi":"10.1186/s12967-026-09004-1","DOIUrl":"https://doi.org/10.1186/s12967-026-09004-1","url":null,"abstract":"<p><strong>Background: </strong>Immune checkpoint receptors (ICRs) are widely used as markers of T-cell exhaustion, yet their interpretation remains context-dependent and is poorly described in γδ T cells. Here, we investigated the dynamics, functional impact, and differentiation-associated distribution of ICRs across human γδ and αβ T-cell subsets.</p><p><strong>Methods: </strong>Peripheral blood mononuclear cells from healthy donors were stimulated in vitro to assess ICR dynamics in γδ and αβ T-cell subsets by flow cytometry. Functional effects of PD-1 and TIM-3 blockade were evaluated through proliferation, cytokine production, and degranulation assays. In parallel, previously published single-cell RNA-sequencing datasets of tumor-infiltrating γδ and CD8 T cells were subjected to secondary bioinformatic analysis to characterize differentiation-associated ICR expression patterns and their modulation following immune checkpoint blockade (ICB) therapy.</p><p><strong>Results: </strong>ICR expression was regulated in a receptor-, lineage- and context-dependent manner. Polyclonal stimulation induced broad ICR upregulation, whereas phosphoantigen-driven Vδ2 T cell expansion resulted in a selective profile with sustained TIM-3 expression and transient modulation of PD-1 and TIGIT. Checkpoint distribution was structured across differentiation states, with TIGIT enriched in antigen-experienced subsets, LAG-3 and TIM-3 in naive compartments, and PD-1 broadly expressed. PD-1 blockade was associated with donor-dependent trends toward increased proliferation and cytokine production, particularly under IL-15 stimulation, whereas TIM-3 inhibition showed variable effects and combined blockade did not produce a consistent additive response. Single-cell transcriptomic analyses revealed that tumor-infiltrating γδ T cells displayed heterogeneous ICR expression across differentiation states, whereas CD8 T cells showed a more progressive pattern of checkpoint expression. Because classical exhaustion-associated transcriptional and epigenetic programs were not evaluated, these patterns neither establish nor exclude the presence of exhausted γδ T-cell subsets. ICB therapy was associated with persistence or upregulation of alternative checkpoints.</p><p><strong>Conclusions: </strong>These findings indicate that ICR expression in γδ T cells is dynamically shaped by activation, differentiation, and environmental context. However, ICR expression alone is insufficient to define or exclude a state of T-cell exhaustion.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"24 1","pages":""},"PeriodicalIF":9.7,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13629053/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149111508","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":"Muscle symptoms and a latent physiological symptom-dysregulation factor in ME/CFS: exploratory analyses by sex and age-defined menopausal-status proxy group.","authors":"Lotte Habermann-Horstmeier, Lukas M Horstmeier","doi":"10.1186/s12967-026-09018-9","DOIUrl":"10.1186/s12967-026-09018-9","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Muscle-related symptoms are among the most disabling manifestations of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), yet their position within the broader symptom architecture of the disease remains unclear. We hypothesized that muscle symptoms may represent a candidate integrative symptom within a broader shared symptom-dysregulation structure and their symptom associations differ according to sex and menopausal status.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Cross-sectional data from 736 individuals with physician-diagnosed ME/CFS enrolled in the APAV-ME/CFS registry were analysed. Muscle problems served as the primary outcome variable. Associations with 14 symptom domains were examined using multivariable logistic regression. Pearson and tetrachoric correlations, exploratory factor analysis, and structural equation modeling (SEM) were used to identify latent symptom structures. Exploratory analyses were stratified by sex, menopausal status, and disease duration.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;In the full multivariable model (non-robust estimates), breathing problems (OR 2.49 [95% Conf. Interval: 1.42-4.38], p = 0.001), flu-like symptoms (OR 1.97 [1.14-3.42], p = 0.015), and temperature-regulation disorders (OR 1.97 [1.10-3.51], p = 0.021) independently predicted muscle problems. A reduced physiological model (not-robust estimates) additionally identified cardiovascular symptoms (OR 1.87 [1.09-3.24], p = 0.024) as a significant predictor. Tetrachoric correlations demonstrated substantial latent associations between muscle problems and breathing difficulties (ρ = 0.52), cardiovascular symptoms (ρ = 0.49), temperature-regulation disorders (ρ = 0.49), visual disturbances (ρ = 0.39), and flu-like symptoms (ρ = 0.39). Factor analysis and SEM supported a single latent physiological dysregulation factor with good model fit (RMSEA = 0.046, CFI = 0.971, TLI = 0.952, SRMR = 0.026). The sex-stratified analyses revealed differences in the pattern of statistically significant symptom associations across the subgroups. However, the overall test of the symptom-by-sex interaction terms did not provide evidence for a statistically established difference in the symptom associations by sex. Thus, the subgroup-specific patterns should primarily be interpreted as descriptive and exploratory. At the individual symptom level, the association between breathing-related symptoms and muscle problems showed a statistically significant interaction with sex, suggesting that this association may differ between women and men. However, this finding should be interpreted cautiously given the non-significant overall interaction test and the wide confidence interval of the interaction estimate. In women, all five physiological symptoms independently predicted muscle problems, whereas in men only breathing problems and temperature-regulation disorders remained significant. Women classified as premenopausal and postmenopausal based on an age-","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"24 1","pages":""},"PeriodicalIF":9.7,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13621514/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149075057","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":"RAMP3 is associated with macrophage-driven immune exclusion and promotes resistance to PD-1 blockade in breast cancer: integrated in vivo and single-cell transcriptomic analyses.","authors":"Yan Zhang, Megumu Tanaka, Takayuki Sakurai, Akiko Kamiyoshi, Yuka Ichikawa-Shindo, Qianqian Guo, Ken Hoshiyama, Peixuan Li, Jiake Li, Jun Duan, Marina Hayashi, Kensuke Kai, Yunlu Zhao, Kun Dai, Takayuki Shindo","doi":"10.1186/s12967-026-09001-4","DOIUrl":"https://doi.org/10.1186/s12967-026-09001-4","url":null,"abstract":"<p><strong>Background: </strong>Receptor activity-modifying protein 3 (RAMP3) has been implicated in stromal regulation in cancer. However, its role in tumor microenvironment (TME) remodeling and immune checkpoint resistance remains unclear. In this study, we aimed to define the role of RAMP3 in shaping the immunosuppressive TME and evaluate its potential as a therapeutic target to enhance immunotherapy responses.</p><p><strong>Methods: </strong>We used syngeneic mouse models of breast cancer with genetic manipulation of RAMP3 to investigate tumor progression, immune remodeling, and response to immune checkpoint blockade in vivo. Tumor growth, metastasis, and survival were evaluated. Single-cell RNA sequencing was performed on murine tumor tissues, and a publicly available spatial transcriptomic dataset was analyzed to characterize immune cell states and spatial organization within the TME. Human breast cancer datasets from The Cancer Genome Atlas were analyzed to assess the clinical relevance of RAMP3-associated immune signatures.</p><p><strong>Results: </strong>Our results suggest that RAMP3 contributed to the establishment of an immunosuppressive TME. In mouse models, RAMP3 deletion suppressed primary tumor growth, reduced lung metastasis, and improved survival. These effects were associated with a shift from M2-like tumor-associated macrophages to antigen-presenting macrophage states, increased CD8⁺ T cell infiltration, and reduced T cell exhaustion. Mechanistically, RAMP3 deficiency was associated with reduced IL-4/STAT6 signaling in macrophages and decreased expression of immunosuppressive genes, including the chemokine CCL8. Pharmacological inhibition of CCL synthesis phenocopied the effects of RAMP3 deficiency, and RAMP3 deficiency enhanced the efficacy of PD-1 blockade. Spatial transcriptomic analysis demonstrated co-localization of RAMP3 and CCL8 within the TME. In the TCGA-BRCA cohort, a higher weighted RAMP3/CD163/CD8A risk score was associated with poorer overall survival and remained significantly associated with overall survival in complete-case multivariable Cox models adjusted for clinicopathological variables.</p><p><strong>Conclusions: </strong>RAMP3 was identified as a potential regulator of the immunosuppressive TME and its functional impact was demonstrated in vivo. Integration with human clinical datasets supports further investigation of RAMP3 as a potential therapeutic target for overcoming resistance to immune checkpoint therapy in breast cancer.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"24 1","pages":""},"PeriodicalIF":9.7,"publicationDate":"2026-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13718171/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149298258","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":"Persistent symptom burden in long-standing systemic lupus erythematosus: a subgroup-focused hypothesis for an SLE-ME/CFS research phenotype.","authors":"Lotte Habermann-Horstmeier","doi":"10.1186/s12967-026-08867-8","DOIUrl":"10.1186/s12967-026-08867-8","url":null,"abstract":"<p><strong>Background: </strong>Despite improved control of inflammatory disease activity in systemic lupus erythematosus (SLE), many patients experience persistent fatigue, impaired physical function, cognitive symptoms, sleep disturbance, and reduced exercise tolerance, including during remission. These symptoms are multifactorial and may not be adequately explained by conventional measures of inflammatory activity. Clinical and biological parallels with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) suggest that interacting immune, metabolic, vascular, and autonomic mechanisms may contribute to persistent symptom burden in a subgroup of patients with long-standing SLE.</p><p><strong>Objective: </strong>To develop a subgroup-focused, non-linear, and testable framework for persistent symptoms in SLE by integrating established SLE evidence with carefully distinguished mechanistic insights from ME/CFS research.</p><p><strong>Methods: </strong>This Commentary is based on a targeted, non-systematic literature synthesis of publications identified in PubMed and Web of Science. Evidence was categorized as direct SLE evidence, evidence from ME/CFS, or cross-condition mechanistic inference. Priority was given to human studies, systematic reviews, meta-analyses, and translational research addressing persistent symptoms, autonomic and endothelial dysfunction, mitochondrial and redox alterations, and neurocognitive manifestations.</p><p><strong>Results: </strong>We propose a hypothesized SLE-ME/CFS research phenotype characterized by persistent, functionally limiting symptoms despite low inflammatory disease activity or remission. The phenotype includes fatigue lasting at least six months together with post-exertional symptom exacerbation, unrefreshing sleep, cognitive symptoms, and/or orthostatic intolerance, following structured exclusion or assessment of alternative explanations and comorbidities. Direct SLE evidence supports the relevance of residual immune activation, oxidative stress, mitochondrial alterations, endothelial dysfunction, and dysautonomia. Findings from ME/CFS further suggest potentially convergent mechanisms involving impaired cellular energetics, autonomic dysfunction, altered cerebral perfusion, and neuroimmune dysregulation. However, these cross-condition inferences require direct validation in SLE.</p><p><strong>Conclusions: </strong>Persistent symptom burden in long-standing SLE may reflect a biologically distinct subgroup in which immune, autonomic, vascular, metabolic, and neurocognitive mechanisms interact dynamically. The proposed framework does not define a new diagnostic entity or fixed disease trajectory but provides a hypothesis-generating basis for prospective longitudinal studies. Multidimensional phenotyping may improve patient stratification, biomarker discovery, and supportive care for patients whose symptoms remain disproportionate to conventional measures of disease activity.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"24 1","pages":""},"PeriodicalIF":9.7,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13617818/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149075055","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":"Engineering human endogenous retrovirus-K for improving immunogenicity and broad cancer targeting.","authors":"Mikkel Dons Müller, Lasse Neukirch, Emeline Ragonnaud, Amaia Vergara Bermejo, Joana Daradoumis, Victoria Jaded, Emilie Sofie Engdal, Felix Faas, Maria Perez-Penco, Cristina Picon-Jara, Karen Nørgaard Nielsen, Lara Duvnjak, Ditte Rahbaek Boilesen, Sara Kusiński, Isabella Skandorff, Nanna Skeltved, Lene Linh Ngoc Trinh, Louise Turner, Kaare Villum Grunddal, Huda Salahudin Darusman, Silmi Mariya, Silke Schrödel, Kristoffer Staal Rohrberg, Frederik Otzen Bagger, Christian Thirion, Per Thor Straten, Anne-Marie Carola Andersson, Peter Johannes Holst","doi":"10.1186/s12967-026-09012-1","DOIUrl":"10.1186/s12967-026-09012-1","url":null,"abstract":"<p><strong>Background: </strong>HERV-K (HML-2) is the most studied transcriptionally active endogenous retrovirus in human cancers, yet immune tolerance and incomplete mechanistic understanding have impeded its clinical use as an immunotherapy target. We hypothesized that rational engineering of the HERV-K envelope putative immunosuppressive domain (ISD) could improve immunogenicity.</p><p><strong>Methods: </strong>We performed a mutational screen across the ISD region, evaluated NF-κB activation and then analyzed antigen expression in human monocyte-derived dendritic cells (moDCs) using flow cytometry, RNA-seq, and TEM. Human PBMCs were expanded with HERV-K-transduced moDCs to assess T cell priming and expansion ex vivo. Immunogenicity was tested in mice, HERV-K transgenic mice, and cynomolgus macaques using adenoviral and LNP-mRNA vectors. Antitumor efficacy was evaluated in a murine metastatic renal carcinoma HERV-K expressing tumor model.</p><p><strong>Results: </strong>Engineering the HERV-K envelope ISD to Q525A (ISDmut) enhanced NF-κB activation, antigen expression, and antigen presentation and cell death associated gene expression pathways in human dendritic cells while preserving virus-like particle assembly. HERV-K-ISDmut-transduced human dendritic cells expanded CD4⁺ and CD8⁺ T cells capable of recognizing HLA-matched, HERV-K expressing tumors, demonstrating that T cells from the human repertoire can be expanded ex vivo. In vivo, mRNA and adenoviral vectors encoding HERV-K-ISDmut elicited strong immune responses in mice, broke tolerance in HERV-K transgenic mice, and induced humoral responses in cynomolgus macaques. In mice, an adenovirus vectored HERV-K-ISDmut immunization further conferred increased survival in a murine renal carcinoma HERV-K expressing tumor model and benefitted from anti-PD-1 therapy.</p><p><strong>Conclusions: </strong>These results show that the rational redesign of the HERV-K ISD generates a potent immunogen capable of expanding human T cells and mediating mechanistically relevant anti-tumor immunity. We propose that HERV-K-ISDmut antigens represent a promising platform for cancer immunotherapy which should be explored in future clinical trials.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"24 1","pages":""},"PeriodicalIF":9.7,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13693031/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149245234","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}