Frontiers in Immunology最新文献

{"title":"Successful cryopreservation of marine invertebrates immune cells enables long-term studies of common octopus, <i>Octopus vulgaris</i> Cuvier 1797, hemocyte immune functions.","authors":"María M Costa, Estefania Paredes, Mercedes Peleteiro, Lucía Sánchez-Ruiloba, Francisco Gambón, Sonia Dios, Camino Gestal","doi":"10.3389/fimmu.2025.1543587","DOIUrl":"10.3389/fimmu.2025.1543587","url":null,"abstract":"<p><p>The common octopus, <i>Octopus vulgaris</i> Cuvier 1797, as all cephalopods, presents highly evolved characteristics compared to other classes of molluscs and the whole invertebrate phyla. However, to date, there is not much information about its immune system, and studying the defense mechanisms is a key step in understanding their response to external aggressions, having the tools to anticipate animal health problems and ensure their welfare. The lack of cell cultures in molluscs is a major problem when carrying out <i>in vitro</i> assays that help to deepen our knowledge of this species' main immune cells. Cryopreservation becomes an alternative to maintaining viable and functional cells after freezing/thawing processes. Having access to good high-quality cells for long periods allows cover a wider repertoire of studies, time courses, and the avoidance of logistical issues such as loss of viability and/or functionality, time constraints, or sample transport challenges. Additionally, high-quality cell suspensions are essential for successful applications, such as single-cell sequencing, where viability and functionality are the key to optimal identification. The optimal medium, cryoprotective agent, and freezing/thawing protocol for octopus hemocytes have been selected. We show here the first functional results from cryopreserved hemocytes. Cells cryopreserved in MAS medium supplemented with EG maintained viability above 80% after 15 weeks post cryopreservation storage at -80°C, and their functional ability to phagocytize bacteria similar to fresh cells. Moreover, thawed acclimated cells exhibited a gene expression pattern comparable to fresh cells, as opposed to directly thawed cells. The acclimation process after thawing was essential to recover the functional activity of the cells and to return to levels of gene expression involved in oxidative stress similar to fresh cells.The results presented here will facilitate functional studies of octopus immune cells and provide tools for cell preservation in other molluscs species.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1543587"},"PeriodicalIF":5.7,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11968374/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143795431","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":"Chemokines as therapeutic targets for multiple sclerosis: a spatial and chronological perspective.","authors":"Nagisa Nakata Arimitsu, Alicja Witkowska, Ayaka Ohashi, Chie Miyabe, Yoshishige Miyabe","doi":"10.3389/fimmu.2025.1547256","DOIUrl":"10.3389/fimmu.2025.1547256","url":null,"abstract":"<p><p>Multiple sclerosis (MS) is a chronic autoinflammatory disease of unknown origin, involving characterized by immune cell infiltration into the target tissue, central nervous system (CNS), resulting in local and/or systemic inflammation. The symptoms vary from gait disturbance, visual impairment and learning and memory impairment and are being managed with corticosteroid and/or immunosuppressive agents. However, several patients do not respond to these treatments, which can also elevate the risk of severe infections. Therefore, there remains an ongoing need to identify new therapeutic targets. MS exhibits distinctive pathology, clinical course, and treatment responses, suggesting the importance of targeting disease site-specific immune cells to mitigate immune system-induced inflammation, rather than employing broad immunosuppression. Chemokines and chemokine receptors play a crucial role in the pathogenesis of MS by recruiting immune cells to the CNS, leading to inflammation and demyelination. Therapies targeting chemokines have shown promising results in preclinical studies and clinical trials, but more research is needed to fully understand their mechanisms and optimize their efficacy.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1547256"},"PeriodicalIF":5.7,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11968728/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143795260","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":"The distinct roles of IL-37 and IL-38 in non-small cell lung carcinoma and their clinical implications.","authors":"Jiwei Zhang, Steven G Wise, Shunqing Zuo, Shisan Bao, Xufeng Zhang","doi":"10.3389/fimmu.2025.1564357","DOIUrl":"10.3389/fimmu.2025.1564357","url":null,"abstract":"<p><p>Lung cancer, a significant global health challenge, is primarily classified into non-small cell lung cancer (NSCLC) and small cell lung cancer. Despite advancements in targeted therapies and immunotherapies, NSCLC outcomes remain poor, with low five-year survival rates. Given the lung's constant exposure to the environment and the presence of mucosal-associated lymphoid tissues, immunity plays a crucial role in NSCLC development. Immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 have shown promise. However, adverse immune events limit their efficacy. This review highlights the contrasting roles of IL-37 and IL-38 in NSCLC pathogenesis. IL-37, an anti-inflammatory cytokine, suppresses tumour growth. It achieves this by modulating macrophage polarization and dendritic cell maturation. Correlations between intra-tumoral IL-37 expression and improved survival suggest a protective role in NSCLC. This may be mediated through VEGF inhibition and immune regulation. Conversely, IL-38, while anti-inflammatory in certain contexts, exhibits a pro-tumorigenic role in NSCLC. IL-38 enhances tumour progression by increasing pro-inflammatory cytokine secretion and facilitating immune evasion, potentially through NF-κB signalling. Notably, IL-38 negatively regulates IL-37, further promoting tumorigenesis. Emerging data suggest that IL-37 has therapeutic potential in inhibiting NSCLC metastasis and supporting immune modulation. In contrast, IL-38 presents a potential target for mitigating pro-inflammatory microenvironment effects. The distinct roles of these cytokines emphasize the complex immune dynamics in NSCLC. Further exploration of their molecular mechanisms and therapeutic implications is warranted. Targeting IL-37 and IL-38 may offer novel strategies for enhancing NSCLC treatment outcomes.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1564357"},"PeriodicalIF":5.7,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11968353/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143794705","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":"HIF-α signaling regulates the macrophage inflammatory response during <i>Leishmania major</i> infection.","authors":"Lucy G Fry, Charity L Washam, Hayden Roys, Anne K Bowlin, Gopinath Venugopal, Jordan T Bird, Stephanie D Byrum, Tiffany Weinkopff","doi":"10.3389/fimmu.2025.1487311","DOIUrl":"10.3389/fimmu.2025.1487311","url":null,"abstract":"<p><p>Cutaneous leishmaniasis (CL) contributes significantly to the global burden of neglected tropical diseases, with 12 million people currently infected with <i>Leishmania</i> parasites. CL encompasses a range of disease manifestations, from self-healing skin lesions to permanent disfigurations. Currently there is no vaccine available, and many patients are refractory to treatment, emphasizing the need for new therapeutic targets. Previous work demonstrated macrophage HIF-α-mediated lymphangiogenesis is necessary to achieve efficient wound resolution during murine <i>L. major</i> infection. Here, we investigate the role of macrophage HIF-α signaling independent of lymphangiogenesis. We sought to determine the relative contributions of the parasite and the host-mediated inflammation in the lesional microenvironment to myeloid HIF-α signaling. Because HIF-α activation can be detected in infected and bystander macrophages in leishmanial lesions, we hypothesize it is the host's inflammatory response and microenvironment, rather than the parasite, that triggers HIF-α activation. To address this, macrophages from mice with intact HIF-α signaling (LysM^CreARNT^f/+) or mice with deleted HIF-α signaling (LysM^CreARNT^f/f) were subjected to RNASequencing after <i>L. major</i> infection and under pro-inflammatory stimulus. We report that <i>L. major</i> infection alone is enough to induce some minor HIF-α-dependent transcriptomic changes, while infection with <i>L. major</i> in combination with pro-inflammatory stimuli induces numerous transcriptomic changes that are both dependent and independent of HIF-α signaling. Additionally, by coupling transcriptomic analysis with several pathway analyses, we found HIF-α suppresses pathways involved in protein translation during <i>L. major</i> infection in a pro-inflammatory environment. Together these findings show <i>L. major</i> induces a HIF-α-dependent transcriptomic program, but HIF-α only suppresses protein translation in a pro-inflammatory environment. Thus, this work indicates the host inflammatory response, rather than the parasite, largely contributes to myeloid HIF-α signaling during <i>Leishmania</i> infection.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1487311"},"PeriodicalIF":5.7,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11969800/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143795395","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":"Organoid models of ovarian cancer: resolving immune mechanisms of metabolic reprogramming and drug resistance.","authors":"Lanyue Zhang, Jiangnan Zhao, Chunyu Su, Jianxi Wu, Lai Jiang, Hao Chi, Qin Wang","doi":"10.3389/fimmu.2025.1573686","DOIUrl":"10.3389/fimmu.2025.1573686","url":null,"abstract":"<p><p>Metabolic reprogramming is a hallmark of ovarian cancer, enabling tumor progression, immune evasion and drug resistance. The tumor microenvironment (TME) further shapes metabolic adaptations, enabling cancer cells to withstand hypoxia and nutrient deprivation. While organoid models provide a physiologically relevant platform for studying these processes, they still lack immune and vascular components, limiting their ability to fully recapitulate tumor metabolism and drug responses. In this study, we investigated the key metabolic mechanisms involved in ovarian cancer progression, focusing on glycolysis, lipid metabolism and amino acid metabolism. We integrated metabolomic analyses and drug sensitivity assays to explore metabolic-TME interactions using patient-derived, adult stem cell-derived and iPSC-derived organ tissues. Among these, we found that glycolysis, lipid metabolism and amino acid metabolism play a central role in tumor progression and chemotherapy resistance. We identified methylglyoxal (MGO)-mediated BRCA2 dysfunction as a driver of immune escape, a role for sphingolipid signaling in tumor proliferation and a role for kynurenine metabolism in CD8+ T cell suppression. In addition, PI3K/AKT/mTOR and Wnt/β-catenin pathways promote chemoresistance through metabolic adaptation. By elucidating the link between metabolic reprogramming and immune evasion, this study identifies key metabolic vulnerabilities and potential drug targets in ovarian cancer. Our findings support the development of metabolically targeted therapies and increase the utility of organoid-based precision medicine models.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1573686"},"PeriodicalIF":5.7,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11968360/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143795428","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":"Corrigendum: Enhancing AAV-microdystrophin gene therapy after repeat dosing by blocking phagocytosis.","authors":"Rita Spathis, Deeva Robles Kuriplach, Sabrina Narvesen, Matthew Eybs, Karen Huang, Steven Torres, Madison King, Elizabeth Bagley, Pia Elustondo, Michael W Lawlor, Kanneboyina Nagaraju, Melissa Morales","doi":"10.3389/fimmu.2025.1593193","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1593193","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.3389/fimmu.2025.1527840.].</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1593193"},"PeriodicalIF":5.7,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11969264/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143795270","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":"Enhanced and long-lasting SARS-CoV-2 immune memory in individuals with common cold coronavirus cross-reactive T cell immunity.","authors":"David M Florian, Michael Bauer, Amelie Popovitsch, Ingrid Fae, David N Springer, Marianne Graninger, Marianna Traugott, Lukas Weseslindtner, Stephan W Aberle, Gottfried Fischer, Michael Kundi, Karin Stiasny, Alexander Zoufaly, Samuel J Landry, Judith H Aberle","doi":"10.3389/fimmu.2025.1501704","DOIUrl":"10.3389/fimmu.2025.1501704","url":null,"abstract":"<p><p>With the continuous emergence of novel SARS-CoV-2 variants, long-lasting and broadly reactive cellular and humoral immunity is critical for durable protection from COVID-19. We investigated SARS-CoV-2-specific T cell immunity in relation to antibodies, infection outcome and disease severity and assessed its durability in a longitudinal cohort over a three-year time course. We identified pre-existing T cells reactive to the seasonal coronavirus (CoV) OC43 that cross-react with the conserved SARS-CoV-2 spike S_813-829 peptide. These cross-reactive T cells increased in frequency following SARS-CoV-2 infection or vaccination and correlated with enhanced spike-specific T cell responses and significantly reduced viral loads. Furthermore, our data revealed that CoV-cross-reactive T cells were maintained as part of the long-lasting memory response, contributing to increased T cell frequencies against omicron variants. These findings suggest a functional role of CoV-cross-reactive T cells that extends beyond the initial SARS-CoV-2 exposure, contributing to enhanced immunity against highly mutated SARS-CoV-2 variants.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1501704"},"PeriodicalIF":5.7,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11968687/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143795278","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":"Impact of atopic dermatitis on renal dysfunction: insights from patient data and animal models.","authors":"Arisa Ikeda, Ge Peng, Wanchen Zhao, Alafate Abudouwanli, Shigaku Ikeda, François Niyonsaba, Yusuke Suzuki","doi":"10.3389/fimmu.2025.1558596","DOIUrl":"10.3389/fimmu.2025.1558596","url":null,"abstract":"<p><strong>Introduction: </strong>Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by pruritus, immune dysregulation, and compromised skin barrier function. Although there are some reports that indicate a link between AD and chronic kidney disease (CKD), the prevalence and underlying mechanism of the association between AD and CKD are still unclear. We aimed to clarify the mechanism underlying the association between AD and CKD using an AD-like mouse model.</p><p><strong>Methods: </strong>Human serum and urine samples from adults in the U.S. were analyzed using data from the National Health and Nutrition Examination Survey (NHANES). An AD-like mouse model was established by repeatedly applying 2,4-dinitrochlorobenzene to the backs and ears of the mice. Kidney inflammation and podocyte function were evaluated via PAS and H&E staining, immunofluorescence staining, and electron microscopy.</p><p><strong>Results: </strong>We found that compared to healthy subjects in the NHANES cohort study, patients with AD had altered kidney function. AD-like model mice exhibited albuminuria and renal dysfunction one to three months after the induction of AD. In addition, there were remarkable decreases in triglyceride and very-low-density lipoprotein levels and increases in low-density lipoprotein and non-high-density lipoprotein levels in AD-like model mice. After histological staining of the kidneys of AD-like model mice, macrophage and neutrophil infiltration was detected, and the foot process effacement of podocytes was observed via electron microscopy. In addition, the gene expression of slit diaphragm- and podocyte-related proteins such as nephrin, podocin, and synaptopodin decreased, whereas the gene expression of inflammatory mediators such as S100A8 and S100A9 increased.</p><p><strong>Discussion: </strong>Following improvements in skin inflammation, alleviation of albuminuria, renal dysfunction and dyslipidemia were observed. These findings suggest that AD-related cutaneous inflammation is associated with albuminuria and podocyte dysfunction.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1558596"},"PeriodicalIF":5.7,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11968387/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143795409","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":"Circadian rhythm related genes identified through tumorigenesis and immune infiltration-guided strategies as predictors of prognosis, immunotherapy response, and candidate drugs in skin cutaneous malignant melanoma.","authors":"Chengling Liu, Xingchen Liu, Pengjuan Cao, Haiming Xin, Xin Li, Sailing Zhu","doi":"10.3389/fimmu.2025.1513750","DOIUrl":"10.3389/fimmu.2025.1513750","url":null,"abstract":"<p><strong>Background: </strong>Skin cutaneous malignant melanoma (SKCM) is among the most aggressive forms of skin cancer, notorious for its rapid progression and poor prognosis under late diagnosis. This study investigates the role of circadian rhythm-related genes (CRGs) in SKCM addressing a gap in understanding how CRGs affect tumor progression and patient outcomes.</p><p><strong>Methods: </strong>An analysis of CRGs expression was conducted on SKCM samples derived from The Cancer Genome Atlas datasets(TCGA). Moreover, a correlation between various subtypes and their clinical features was identified. The study employed various bioinformatics methods, including differential expression analysis, consensus clustering, and survival analysis, to investigate the role of CRGs. The functional consequences of various CRG expression patterns were further investigated using immune infiltration analysis and gene set variation analysis (GSVA). A scoring system based on CRGs was developed to predict overall survival (OS) and treatment responses in SKCM patients. The predictive accuracy of this score system was then tested, and a nomogram was used to improve its clinical usefulness.</p><p><strong>Results: </strong>Key findings from this study include significant genetic alterations in circadian rhythm-related genes (CRGs) in skin cutaneous melanoma (SKCM), such as mutations and CNVs. Two molecular subtypes with distinct clinical outcomes and immune profiles were identified. A prognostic model based on six CRGs (<i>CMTM</i>, <i>TNPO1</i>, <i>CTBS</i>, <i>UTRN</i>, <i>HK2</i>, and <i>LIF</i>) was developed and validated with TCGA and GEO datasets, showing high predictive accuracy for overall survival (OS). A high CRGs score correlated with poor OS, immune checkpoint expression, and reduced sensitivity to several chemotherapeutics, including AKT inhibitor VIII and Camptothecin.</p><p><strong>Conclusions: </strong>This work provides valuable insights into the circadian regulation of SKCM and underscores the potential of CRGs as biomarkers for prognosis and targets for therapeutic interventions. The novel molecular subtypes and CRGs prognostic scoring model introduced in this study offer significant contributions to the understanding and management of SKCM.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1513750"},"PeriodicalIF":5.7,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11968383/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143795264","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":"Metabolic reprogramming shapes the immune microenvironment in pancreatic adenocarcinoma: prognostic implications and therapeutic targets.","authors":"Weihua Song, Yabin Yu, Siqi Wang, Zhengyi Cui, Qiusi Zhu, Wangrui Liu, Shiyin Wei, Jiachang Chi","doi":"10.3389/fimmu.2025.1555287","DOIUrl":"10.3389/fimmu.2025.1555287","url":null,"abstract":"<p><strong>Introduction: </strong>Pancreatic adenocarcinoma (PAAD) is characterized by a profoundly immunosuppressive tumor microenvironment (TME) that limits the efficacy of immunotherapy. Emerging evidence suggests that tumor-specific metabolic reprogramming may drive disease progression and shape the immune landscape in PAAD.</p><p><strong>Methods: </strong>We integrated multi-omics data from TCGA, GEO, and ICGC to identify key metabolism-related genes (MRGs) that influence immune cell infiltration, tumor progression, and patient survival. Based on nine pivotal MRGs (including ANLN, PKMYT1, and HMGA1), we developed and validated a novel metabolic-prognostic index (MPI). Functional enrichment analyses were conducted to elucidate the metabolic pathways associated with different MPI risk groups. <i>In vitro</i> experiments and drug sensitivity analyses were performed to confirm the oncogenic role of selected MRGs and to explore their therapeutic implications.</p><p><strong>Results: </strong>The MPI effectively stratified patients into high- and low-risk groups. High-MPI scores correlated with poor overall survival, elevated tumor mutation burden (TMB), and an immunosuppressive TME, evidenced by reduced CD8⁺ T-cell infiltration and increased expression of immune checkpoints (PD-L1, TGF-β). Functional enrichment revealed glycolysis and folate biosynthesis as dominant pathways in high-MPI groups, whereas fatty acid metabolism prevailed in low-MPI groups. Experimental validation underscored the role of ANLN in promoting epithelial-mesenchymal transition (EMT) and immune evasion via NF-κB signaling. ANLN knockdown significantly reduced glycolytic activity, tumor cell migration, and immune evasion. Drug sensitivity analyses indicated resistance to gemcitabine but sensitivity to afatinib in high-MPI patients. Although TIDE analysis predicted immune checkpoint inhibitor (ICI) resistance in high-MPI tumors, a subset of patients showed favorable responses to anti-PD-L1 therapy.</p><p><strong>Discussion: </strong>These findings provide a comprehensive framework for understanding how metabolic reprogramming shapes PAAD's immunosuppressive TME and affects treatment outcomes. By accurately stratifying patients, the MPI serves as a promising tool to guide therapeutic decisions, including targeted therapy selection and immunotherapy prediction, ultimately offering potential for more personalized management of PAAD.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1555287"},"PeriodicalIF":5.7,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11968369/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143795413","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}