Frontiers in Immunology最新文献

{"title":"Longitudinal peripheral immune dynamics during anti-programmed cell death 1 neoadjuvant therapy in esophageal squamous cell carcinoma.","authors":"Linpeng Li, Lingwen Meng, Xinru Chen, Jiahui Li, Pengfei Li, Bo Dong, Chengjing Huang, Wei Zhou, Nuan Li, Guodong Sun, Jiawei Li, Guojie Tan, Li Jiang, Dan Tian","doi":"10.3389/fimmu.2026.1917487","DOIUrl":"https://doi.org/10.3389/fimmu.2026.1917487","url":null,"abstract":"<p><strong>Introduction: </strong>Anti-programmed cell death 1 (PD-1)-based neoadjuvant therapy is increasingly used for esophageal squamous cell carcinoma (ESCC), but paired peripheral immune dynamics and their exploratory relationship to response remain incompletely characterized.</p><p><strong>Methods: </strong>We performed a retrospective longitudinal flow-cytometry study of 39 patients with ESCC treated with anti-PD-1-based neoadjuvant therapy, including 20 patients with paired pre-treatment and post-treatment/preoperative peripheral immune profiles. The primary paired analysis tested 75 marker-defined immune features using Wilcoxon signed-rank tests with Benjamini-Hochberg false discovery rate (FDR) correction. Exploratory extensions included response-associated changes in candidate immune features, clinical burden context, baseline-dependence, and public tissue-context bioinformatics. Public tissue data were used only as descriptive tissue context.</p><p><strong>Results: </strong>Four features reached FDR q<0.05 in the primary paired screen: PD-1⁺ CD8 T cells, PD-1⁺ Vδ1 γδ T cells, PD-1⁺ Vδ2 γδ T cells, and CD19⁺ B cells. PD-1-defined features were interpreted as assay-defined detectable PD-1 staining readouts because therapeutic anti-PD-1 receptor occupancy or epitope masking may affect post-treatment staining. CD19⁺ B cells remained the non-PD-1 q<0.05 anchor in the PD-1-excluded paired sensitivity screen. In the pathology-evaluable paired cohort (n=17), no response-stratified candidate reached q<0.05; the change in NKG2D⁺ natural killer (NK) cells was the strongest nominal exploratory and hypothesis-generating signal.</p><p><strong>Discussion: </strong>These data support treatment-associated marker-defined peripheral immune dynamics and generate response-linked hypotheses requiring prospective validation.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"17 ","pages":"1917487"},"PeriodicalIF":7.0,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13696451/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149265823","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":"Functional single-cell omics in gynecological cancers immunotherapy: from heterogeneity dissection to clinical translation.","authors":"Dong-Mei Li, Kai-Ge Pei, Bo-Wen Yang, Ming-Rong Qie, Jin-Feng Xu, Lan Zhong, Liang Song","doi":"10.3389/fimmu.2026.1981010","DOIUrl":"https://doi.org/10.3389/fimmu.2026.1981010","url":null,"abstract":"<p><p>Ovarian, endometrial, and cervical cancers represent major threats to women's health worldwide. The profound heterogeneity of their immune microenvironments has rendered immune checkpoint blockade (ICB) therapies, particularly PD-1/PD-L1 inhibitors, far less effective than anticipated in gynecological malignancies. Conventional research approaches, constrained by coarse analytical resolution, are insufficient to unravel the underlying mechanisms of this therapeutic shortfall. Functional single-cell omics technologies, including single-cell RNA sequencing, single-cell chromatin accessibility profiling, spatial transcriptomics, and multi-omics integration, have provided a new framework for systematically studying the tumor immune microenvironment across three progressive dimensions: cellular identity, functional state, and spatial localization. This review systematically synthesizes the applications of this technological toolkit in the three major gynecological cancers. It reveals distinct bottlenecks across the three dimensions. In ovarian cancer, the core obstacle lies in the spatial dimension, where cancer-associated fibroblast-mediated physical barriers and pro-angiogenic macrophage subsets together construct a \"spatial exclusion\" microenvironment. In cervical cancer, the principal bottleneck resides in the functional dimension, where HPV status and histological subtype drive a \"functional disability\" phenotype, in which T cells infiltrate but fail to achieve effective activation, with therapy resistance-associated immune evasion clones further exacerbating functional impairment. In endometrial cancer, however, the immune fate is governed by the identity dimension, where molecular subtypes dictate the baseline nature of immune infiltration, and autophagy-related cellular subpopulations may offer new insights into intratumoral heterogeneity. Although single-cell omics has identified immunologically actionable targets with translational potential, including TREM2⁺ macrophages and the LAG-3/TIM-3 dual-target axis, clinical translation remains constrained by technical and biological bottlenecks, including stringent requirements for tissue sample quality, high assay costs, lack of standardized analytical pipelines, and the discordance between transcriptomic profiles and protein-level functionality.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"17 ","pages":"1981010"},"PeriodicalIF":7.0,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13697309/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149265860","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":"Microbial-derived metabolites in cancer: evidence boundaries, immune mechanisms and translational pathways.","authors":"Xuefeng Shi, Shunjun Wang, Wenhao Ouyang","doi":"10.3389/fimmu.2026.1947330","DOIUrl":"https://doi.org/10.3389/fimmu.2026.1947330","url":null,"abstract":"<p><p>Microbial metabolites can suppress or promote tumor development and modify treatment response, but the direction of an effect depends on its chemical identity, anatomical source, concentration and host target. This narrative review critically examines short-chain fatty acids, tryptophan derivatives, secondary bile acids, colibactin, cyclic dinucleotides and microbial activities that alter anticancer drugs. We distinguish individual metabolites from postbiotic preparations, microbial components and enzymes, and separate microbial production from host-microbial co-metabolism. Mechanistic examples include butyrate-dependent chromatin regulation, macrophage aryl hydrocarbon receptor signaling, microbial agonists of STING, colibactin-induced DNA cross-links and bacterial conversion of gemcitabine or irinotecan metabolites. For each, we consider the experimental model, evidence for causality, physiological exposure and limits of human translation. Particular attention is given to apparently conflicting short-chain-fatty-acid findings across checkpoint inhibitors, the conditional effects of dietary fiber, and discordance between experimental drug inactivation and human pancreatic tumor profiling. Human studies support selected biomarker associations and early intervention feasibility, including fecal microbiota transplantation and engineered bacterial delivery, but do not establish a general metabolite-based treatment strategy. We therefore propose a seven-step research framework linking patient sampling, direct quantification and source attribution, causal and functional testing, external biomarker validation, intervention selection, pharmacodynamic monitoring and prospectively defined clinical endpoints. Its contribution is to make the evidence required for each translational decision explicit while distinguishing clinically useful prediction from a causally justified intervention.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"17 ","pages":"1947330"},"PeriodicalIF":7.0,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13698034/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149265792","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":"Lactate dynamics at the <i>Pseudomonas aeruginosa</i>-host interface: bacterial metabolism, host defense, and emerging links to histone lactylation.","authors":"Yi Jian, Zhijie Wu, Yuqiang Liang, Jin Cao, Mei Li, Fashuang Yang, Ke Wang","doi":"10.3389/fimmu.2026.1979311","DOIUrl":"https://doi.org/10.3389/fimmu.2026.1979311","url":null,"abstract":"<p><p>At the <i>Pseudomonas aeruginosa</i>-host interface, lactate is both a host immunometabolic product and a preferred bacterial carbon source. Its local concentration reflects host production, bacterial utilization, transport, and clearance rather than inflammation alone. <i>P. aeruginosa</i> uses D- and L-lactate through stereospecific, conditionally regulated systems. It preferentially consumes lactate in human burn-wound exudate, and this capacity contributes to early intracellular survival in macrophages. Lactate-associated acidity also increases bacterial vesicle release and quinolone signaling, weakening antimicrobial-peptide activity independently of chromatin modification. On the host side, bacterial L-lactate utilization and virulence-factor-associated suppression of epithelial glycolysis lower epithelial lactate and histone H3 lysine 18 lactylation (H3K18la). These changes are linked to disrupted RNA regulation and impaired ciliary clearance. In macrophages, the quorum-sensing signal 2-aminoacetophenone (2-AA) reprograms bioenergetics, autophagy, and lipid metabolism, promoting tolerance and intracellular persistence. A separate hypothesis connecting 2-AA to increased macrophage lactate and H3K18la is supported only by a supplement abstract and requires full-length validation. Histone lactylation is therefore an emerging extension of this biology. This narrative review follows two linked strands: bacterial lactate utilization and lactate-associated changes in host defense. It distinguishes established metabolic effects from proposed lactylation-dependent mechanisms and considers potential therapeutic directions and their trade-offs. These include targeting bacterial lactate utilization, airway acidity, host transport or modification enzymes, and 2-AA-associated tolerance. Any benefit must be assessed against the possibility of supplying bacterial nutrients or worsening host injury.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"17 ","pages":"1979311"},"PeriodicalIF":7.0,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13697012/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149265833","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":"CAR-T-cell therapy for autoimmune neurologic diseases.","authors":"Yunhan Zhao, Yunyu Ding, Congfeng Tang, Zhengrong Wei, Yuqing Fan, Xianhui Hu, Jilong Yi","doi":"10.3389/fimmu.2026.1942249","DOIUrl":"https://doi.org/10.3389/fimmu.2026.1942249","url":null,"abstract":"<p><p>Autoimmune neurologic diseases include multiple sclerosis, neuromyelitis optica spectrum disorder, myelin oligodendrocyte glycoprotein antibody-associated disease, autoimmune encephalitis, myasthenia gravis, stiff-person syndrome, chronic inflammatory demyelinating polyradiculoneuropathy, and related syndromes. The contributions of B cells, plasma cells, and autoantibodies differ substantially across these disorders; however, the B-cell lineage represents a therapeutically actionable target in many of them. Chimeric antigen receptor T-cell therapy, originally developed for hematologic malignancies, offers a potential strategy for deep and potentially durable depletion of pathogenic B-lineage cells and subsequent immune reconstitution. In recent years, CD19, BCMA, dual-target, mRNA CAR-T-cell, and chimeric autoantibody receptor T-cell approaches have generated preliminary clinical or translational evidence, primarily in systemic autoimmune diseases. Clinical evidence in neurologic disorders remains limited and spans myasthenia gravis, NMOSD, MOGAD, multiple sclerosis, autoimmune encephalitis, stiff-person syndrome, and CIDP. This review summarizes the biologic rationale, disease-specific evidence, target selection, safety concerns, and trial-design considerations for CAR-T-cell therapy in autoimmune neurologic diseases. Current evidence supports further investigation of CAR-T cells in selected patients with highly refractory, antibody- or B-cell-driven neuroimmune disorders, but does not establish superiority over existing therapies. However, the field remains dominated by case reports and small early-phase studies, with randomized evidence currently confined to one phase 2b trial in myasthenia gravis. Establishing the risk-benefit profile will require stringent patient selection, disease-specific neurologic monitoring, controlled prospective studies, and long-term follow-up.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"17 ","pages":"1942249"},"PeriodicalIF":7.0,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13700213/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149266070","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":"Progress in research on gut microbiota regulation of tumorigenesis, progression, and therapeutic response via inflammatory cytokines.","authors":"Yan Liu, Dan Zang, Jun Chen","doi":"10.3389/fimmu.2026.1922678","DOIUrl":"https://doi.org/10.3389/fimmu.2026.1922678","url":null,"abstract":"<p><p>The gut microbiota has emerged as an important regulator of tumour biology through dynamic interactions with host immune and inflammatory networks. A growing number of preclinical studies and observational clinical studies suggest that dysbiosis-associated changes in microbial composition and metabolite profiles can remodel inflammatory signalling pathways and are associated with tumour initiation, progression, metastasis, and therapeutic response. Microbial components and metabolites can activate pattern-recognition receptor-related pathways, including nuclear factor kappa B (NF-κB), in cell and animal models. These changes may promote a tumour-supportive chronic inflammatory milieu or, under specific ecological conditions, help shape an immune-activated microenvironment. Current evidence also suggests that the gut microbiota and inflammatory cytokines may influence treatment response. Preclinical models and some patient cohort studies indicate that dysregulated inflammatory responses are associated with reduced chemotherapy tolerance and a higher risk of immune-related adverse events (irAEs), whereas certain beneficial microbial signals are associated with enhanced CD8⁺ T-cell activation and improved efficacy of immune checkpoint inhibitors (ICIs). However, these associations vary across cancer types and study populations, and their causality and clinical generalizability still require further validation. In this Review, we summarize current evidence on how the gut microbiota and inflammatory cytokines jointly regulate tumour development and therapeutic outcomes. We also discuss therapeutic strategies that target microbial composition and inflammatory signalling, with emphasis on their translational potential in precision oncology.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"17 ","pages":"1922678"},"PeriodicalIF":7.0,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13697595/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149265789","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":"Glutamine metabolic reprogramming in acute and chronic kidney diseases: mechanistic insights and therapeutic implications.","authors":"Ruotong Xu, Jin Zhao, Minna Liu, Yifan Qiao, Xiaoxuan Ning, Shiren Sun","doi":"10.3389/fimmu.2026.1939528","DOIUrl":"https://doi.org/10.3389/fimmu.2026.1939528","url":null,"abstract":"<p><p>Acute kidney injury (AKI) and chronic kidney disease (CKD) are common clinical disorders that have high incidence and mortality. Their pathogenesis and the mechanisms underlying AKI-to-CKD progression remain unclear. Metabolic reprogramming has emerged as a core mechanism driving the onset and progression of kidney diseases. Glutamine (Gln) metabolism, a central component of renal energy metabolism, not only maintains acid-base balance and cellular homeostasis but also actively participates in pathophysiological processes including ischemic injury, oxidative stress, inflammatory regulation and fibrosis. Multi-omics studies have revealed stage-specific alterations in Gln metabolism-associated signatures during kidney injury. In AKI, altered Gln levels and redox-related metabolites may suggest disturbances in metabolic pathways, whereas in CKD, elevated glutaminase 1 (GLS1) expression and glutaminolysis-associated metabolic reprogramming are associated with fibrosis. Gln, as an immunonutrient, also serves as a critical energy substrate to sustain the proliferation, activation, and effector functions of immune cells. Gln metabolism may reshape the immune microenvironment within the injured kidney, thereby modulating disease progression. Targeting the Gln metabolic axis may offer new therapeutic insights for AKI and CKD. However, the changes in Gln metabolism and its consequent immunometabolic effects during the AKI-to-CKD transition remain poorly understood. This narrative review aims to provide a comprehensive overview of the dynamic changes in Gln metabolism during acute and chronic kidney diseases, its stage-specific mechanisms, and its potential as a therapeutic target. We also seek to provide a theoretical basis for developing novel biomarkers and targeted therapies based on Gln metabolic reprogramming.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"17 ","pages":"1939528"},"PeriodicalIF":7.0,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13700215/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149265821","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":"Dried blood spot IP-10 as a biomarker of tuberculosis severity and treatment responses: results from a phase IIb trial of adjunctive acetylsalicylic acid and ibuprofen.","authors":"Iselin Høgbakk Edlund, Noelia Alonso-Rodriguez, Chiara Sopegno, Judith Farrés, Nino Gogichadze, Lilibeth Arias, Kaori L Fonseca, Kennedy Otwombe, Ziyaad Waja, Tumelo Moloantoa, Natasha Pillay, Thabiso Seiphetlo, Neil Martinson, Cristina Vilaplana, Anne Ma Dyrhol-Riise","doi":"10.3389/fimmu.2026.1924239","DOIUrl":"https://doi.org/10.3389/fimmu.2026.1924239","url":null,"abstract":"<p><strong>Background: </strong>Host-directed therapies may improve tuberculosis (TB) outcomes by modulating immune responses and attenuating hyperinflammation, yet accessible biomarkers remain limited. We hypothesized that interferon-γ-inducible protein 10 (IP-10/CXCL10) measured in dried blood spot (DBS), a low-threshold and field-adapted sampling method, has potential as a biomarker for treatment response in pulmonary TB. Accordingly, we assessed IP-10 levels in patients receiving adjunctive acetylsalicylic acid (ASA) or ibuprofen (IBU) alongside TB standard therapy.</p><p><strong>Methods: </strong>IP-10 levels were quantified longitudinally in DBS from 120 pulmonary TB patients enrolled in the SMA-TB clinical trial (NCT04575519) at two sites in South Africa. Samples collected at baseline, week 2, week 8, and week 24 were analyzed by the enzyme-linked immunosorbent assay (ELISA). Associations with disease severity and treatment response were assessed, and the predictive value of IP-10 for microbiological, clinical, and radiological outcomes was evaluated.</p><p><strong>Results: </strong>IP-10 levels correlated with TB disease severity, with higher concentrations observed in patients with elevated clinical and radiological scores and positive sputum acid-fast-bacilli staining. This association was reflected in treatment response, as patients with good clinical outcomes exhibited an earlier decline in IP-10 (week 8, p=0.0005), whereas those with poor outcomes showed a delayed decline (week 24, p<0.0001). Overall, IP-10 levels decreased during treatment irrespective of intervention or HIV status, with no significant differences between treatment arms at week 24. Notably, IP-10 levels at week 2 predicted rapid sputum culture conversion in the IBU arm, as well as in HIV-negative patients in the ASA arm (AUC: ASA 0.79; IBU 0.76).</p><p><strong>Conclusion: </strong>IP-10 levels measured in DBS are associated with disease severity and treatment response and may serve as a biomarker for therapy monitoring and early prediction of microbiological outcomes in TB, irrespective of adjunctive host-directed therapies. These findings require validation in larger patient cohorts before the method can be implemented in clinical practice.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"17 ","pages":"1924239"},"PeriodicalIF":7.0,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13696322/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149265802","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":"Ulvan, carrageenan, and fucoidan: comparative immunomodulatory mechanisms and future directions in major algal sulfated polysaccharides.","authors":"Shuang Zhao, Zhangyi Xia, Jinlin Liu, Meijing Zhang, Maozi Lin, Guangmao Ding, Longchen Tang, Fang Su, Jingyi Sun, Chao Zhao","doi":"10.3389/fimmu.2026.1949951","DOIUrl":"https://doi.org/10.3389/fimmu.2026.1949951","url":null,"abstract":"<p><p>Sulfated polysaccharides derived from marine algae have attracted considerable interest in innate immunity research due to their structural diversity and pronounced immunomodulatory activities. Ulvan, carrageenan, and fucoidan, derived from green, red, and brown algae, respectively, represent three paradigmatic classes of algal sulfated polysaccharides. This review establishes a four-tier analytical framework, namely \"structural features, receptor recognition, signaling pathways, and immune outcomes\", to systematically compare their mechanistic differences in innate immune modulation. This framework provides, for the first time, a unified causal chain from molecular structure to immune effector phenotypes. Ulvan is characterized by coordinated TLR4/cGAS-STING dual pathways: it drives pro-inflammatory responses via the TLR4-MyD88-NF-κB axis while inducing type I interferon production through the cGAS-STING-TBK1-IRF3 cascade. TBK1, as a shared downstream node of both the TLR4-TRIF and cGAS-STING pathways, may mediate signal integration and amplification, thereby conferring a distinctive advantage to ulvan in antiviral immunity. Carrageenan exhibits dual TLR4/NLRP3 activities, with κ/ι/λ subtypes displaying a functional spectrum from localized pro-inflammation to systemic immunostimulation, determined by their sulfate content and gelation properties. A critical distinction must be made between high-molecular-weight native carrageenan (>100 kDa), which is minimally absorbed in the intestine and considered safe, and low-molecular-weight degraded carrageenan (<50 kDa), which carries inflammatory and toxic risks. Fucoidan achieves immunomodulatory pleiotropy through dual TLR4/CLR recognition and concurrent engagement of multiple signaling cascades, encompassing NF-κB-driven pro-inflammation, bidirectional NLRP3 inflammasome regulation, and complement C3 activation. The antiviral effect of fucoidan via the STING pathway, potentially dependent on ROS-mediated DNA damage or endoplasmic reticulum stress, mechanistically differs from ulvan's cGAS-STING activation. The structural basis driving this pathway selectivity resides in an inverse gradient relationship between sulfate and uronic acid contents across the three polysaccharides: sulfate content ranks as fucoidan > carrageenan > ulvan, while uronic acid content follows the opposite order. This inverse gradient serves as the first unified structural principle explaining differential receptor preferences and pathway selection among these three distinct classes of algal polysaccharides. Based on this framework, we propose differentiated polysaccharide design strategies tailored to three therapeutic objectives (pro-inflammation, antiviral defense, and immune balance), offering a roadmap for structure-guided immunomodulation using algal sulfated polysaccharides.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"17 ","pages":"1949951"},"PeriodicalIF":7.0,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13700379/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149265920","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":"T-cell metabolic reprogramming in systemic lupus erythematosus: linking intracellular metabolism to effector differentiation and senescent-like/exhausted-like states.","authors":"Yi Zou, Zhichu Ren, Yuki Kudo, Michihito Kono","doi":"10.3389/fimmu.2026.1961063","DOIUrl":"https://doi.org/10.3389/fimmu.2026.1961063","url":null,"abstract":"<p><p>Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by immune dysregulation and multiorgan inflammation. T-cell metabolic reprogramming has recently emerged as an active area of investigation in the pathogenesis of SLE. This metabolic reprogramming, which involves glycolysis, mitochondrial oxidative phosphorylation, glutamine metabolism, and lipid metabolism, is associated not only with functional alterations in SLE T cells but also with changes in their differentiation and proliferation, potentially contributing to disease pathogenesis and progression. Moreover, metabolic alterations, including mitochondrial dysfunction and reactive oxygen species accumulation, in the context of persistent T-cell activation may contribute to phenotypic transitions toward senescent-like or exhausted-like states. These two partially overlapping but biologically distinct cellular phenotypes may represent divergent cellular responses to chronic inflammatory stimulation. Rather than representing mutually exclusive states or a simple loss of function, both may contribute to the perpetuation of chronic inflammation, immune imbalance and disease activity. This review summarizes recent advances in T-cell metabolic reprogramming in SLE and its potential relationship to senescent-like and exhausted-like T-cell states.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"17 ","pages":"1961063"},"PeriodicalIF":7.0,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13696886/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149265935","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}