ImmunityPub Date : 2026-05-06DOI: 10.1016/j.immuni.2026.04.005
Jennifer Fransson, Chiara Sorini, Francisca Castillo, Yuhao Chi, Ning He, Martin Suarez-Alvarez, Maria Alejandra Ulloa, Rodrigo A Morales Castro, Ali Okhovat, Hailey Sounart, Chiara Zagami, Rebeca F Cardoso, Srustidhar Das, Stefania Giacomello, Anna Mechling, Charlotte R H Hedin, Philip Smith, Eduardo J Villablanca
{"title":"Spatiotemporal analysis reveals distinct inflammatory programs underlying chronic colitis.","authors":"Jennifer Fransson, Chiara Sorini, Francisca Castillo, Yuhao Chi, Ning He, Martin Suarez-Alvarez, Maria Alejandra Ulloa, Rodrigo A Morales Castro, Ali Okhovat, Hailey Sounart, Chiara Zagami, Rebeca F Cardoso, Srustidhar Das, Stefania Giacomello, Anna Mechling, Charlotte R H Hedin, Philip Smith, Eduardo J Villablanca","doi":"10.1016/j.immuni.2026.04.005","DOIUrl":"https://doi.org/10.1016/j.immuni.2026.04.005","url":null,"abstract":"<p><p>Inflammatory bowel disease (IBD) is a complex disorder that is often resistant to immunomodulatory treatments. Here, to understand how immune, epithelial, and stromal compartments are rewired during disease initiation and progression, we leveraged T cell transfer and Il10<sup>-/-</sup> spontaneous colitis models, including anti-IL-12p40 intervention, and integrated time-course transcriptomic analyses at bulk, single-cell, and spatial resolution. These well-established models exhibited conserved features of chronic inflammation, including neutrophil infiltration, and impaired tissue regeneration. Comparison of murine transcriptional programs and human IBD datasets revealed neutrophil-associated inflammation and cytokine signaling as the most conserved pathways across species. We identified spatial heterogeneity in inflammatory modules and described three gene programs with differential spatial and temporal distributions, including one corresponding to tertiary lymphoid structures. When used together, these models recapitulate complementary aspects of human disease at both cellular and transcriptional levels. This high-resolution spatiotemporal atlas will guide future translational research aimed at optimizing therapeutic strategies for IBD.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":" ","pages":""},"PeriodicalIF":26.3,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147837259","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ImmunityPub Date : 2026-04-30DOI: 10.1016/j.immuni.2026.03.027
Marcia A Munoz, Iona S Schuster, James Cremasco, Etienne N Masle-Farquhar, Oliver P Skinner, Zoe J Vandeleur, Maté Biro, Daryan Kempe, William D Renton, Sam Mehr, Charlotte Abell-King, Szun Szun Tay, Ryan C Chai, Samar Ojaimi, John J Zaunders, Geetha Rao, Ariel Castro-Martinez, Lisette van de Corput, Andrew N McCorkindale, Leonard D Goldstein, Xiaohong Li, Flore Wouters, Daniel L Kastner, Ignatius Chua, Nicole L Fewings, Fiona C McKay, Catharina M Mulders-Manders, Robert A Brink, Stuart G Tangye, Ivona Aksentijevich, Cindy S Ma, Jeroen van der Hilst, Joost Frenkel, Mariapia A Degli-Esposti, Michael J Rogers
{"title":"NK cell dysfunction and interferon gamma production underlie autoinflammation in mevalonate kinase deficiency.","authors":"Marcia A Munoz, Iona S Schuster, James Cremasco, Etienne N Masle-Farquhar, Oliver P Skinner, Zoe J Vandeleur, Maté Biro, Daryan Kempe, William D Renton, Sam Mehr, Charlotte Abell-King, Szun Szun Tay, Ryan C Chai, Samar Ojaimi, John J Zaunders, Geetha Rao, Ariel Castro-Martinez, Lisette van de Corput, Andrew N McCorkindale, Leonard D Goldstein, Xiaohong Li, Flore Wouters, Daniel L Kastner, Ignatius Chua, Nicole L Fewings, Fiona C McKay, Catharina M Mulders-Manders, Robert A Brink, Stuart G Tangye, Ivona Aksentijevich, Cindy S Ma, Jeroen van der Hilst, Joost Frenkel, Mariapia A Degli-Esposti, Michael J Rogers","doi":"10.1016/j.immuni.2026.03.027","DOIUrl":"https://doi.org/10.1016/j.immuni.2026.03.027","url":null,"abstract":"<p><p>Prenylopathies such as mevalonate kinase deficiency (MKD) are an emerging family of monogenic autoinflammatory diseases with an underlying defect in isoprenoid lipid synthesis and protein prenylation. The mechanisms linking defective protein prenylation to systemic inflammation remain unclear. We revealed that mice and humans with MKD had significant decreases in the frequency of mature natural killer (NK) cells, impaired trafficking of cytolytic granules, reduced cytotoxic activity, and increased production of the cytokine interferon γ (IFN-γ). Mice with MKD failed to clear murine cytomegalovirus (MCMV) infections and had elevated serum IFN-γ and inflammatory pathology, likely the result of decreased and dysregulated cytotoxic cells. Finally, we describe the beneficial effect of cytokine signaling blockade with a Janus kinase (JAK) inhibitor in an infant with severe MKD. Together, these findings reveal a fundamental role for dysregulated cytotoxic cells and IFN-γ production in MKD and likely other prenylopathies. Importantly, this work provides a rationale for the use of JAK inhibitors in the treatment of MKD.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":" ","pages":""},"PeriodicalIF":26.3,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147814559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ImmunityPub Date : 2026-04-29DOI: 10.1016/j.immuni.2026.04.004
Michael Scaglione, Montana Knight, Krittin Trihemasava, Kelly Rome, Anne-Sophie Archambault, Juhee Oh, Erin Tanaka, Elise Hall, Tran Ngoc Van Le, Caleb L Lines, Brian Goldspiel, Hossein Fazelinia, Clemence Queriault, Lucien Turner, Tanay Parnaik, Jimmy Xu, Morgan Brown, Oishi Bardhan, Jessie Axsom, Frederick C Bennett, Lynn A Spruce, Caroline Bartman, Clementina Mesaros, Ramon I Klein Geltink, Crystal S Conn, Will Bailis
{"title":"Metabolic and transcriptional plasticity supports CD8<sup>+</sup> T cell resilience and anti-tumor immunity under nutrient stress.","authors":"Michael Scaglione, Montana Knight, Krittin Trihemasava, Kelly Rome, Anne-Sophie Archambault, Juhee Oh, Erin Tanaka, Elise Hall, Tran Ngoc Van Le, Caleb L Lines, Brian Goldspiel, Hossein Fazelinia, Clemence Queriault, Lucien Turner, Tanay Parnaik, Jimmy Xu, Morgan Brown, Oishi Bardhan, Jessie Axsom, Frederick C Bennett, Lynn A Spruce, Caroline Bartman, Clementina Mesaros, Ramon I Klein Geltink, Crystal S Conn, Will Bailis","doi":"10.1016/j.immuni.2026.04.004","DOIUrl":"https://doi.org/10.1016/j.immuni.2026.04.004","url":null,"abstract":"<p><p>CD8<sup>+</sup> T cells need to function in complex environments with varied nutrient availability, including the tumor microenvironment and inflamed tissues. The mechanisms that allow CD8<sup>+</sup> T cells to maintain immune function in these perturbed settings are poorly understood. Here, we show that CD8<sup>+</sup> T cells adapt to nutrient stresses over time, reconfiguring gene-regulatory and metabolic networks to license functional recovery. Under acute stress, T cells reoriented translational programming, which limited nutrient demand and prioritized stress-sensitive metabolic and transcriptional responses. Within these responses, the transcription factors activating transcription factor 4 (ATF4) and CCAAT/enhancer-binding protein gamma (CEBPG) jointly established an adaptive metabolic program, promoting amino acid synthesis and uptake while maintaining mitochondrial metabolism. Despite diminished energetic capacity under environmental stress, this program sustained central carbon metabolism. This subsequently mitigated cellular dysfunction and potentiated anti-tumor immunity. Altogether, we demonstrate that biosynthetic plasticity via translational and metabolic reprioritization confers T cell resilience in unfavorable environments, offering potential strategies to enhance immunotherapies.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":" ","pages":""},"PeriodicalIF":26.3,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147814572","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ImmunityPub Date : 2026-04-29DOI: 10.1016/j.immuni.2026.04.003
Alina Ulezko Antonova, Patrick Fernandes Rodrigues, Chelsea Mannie, Giorgia Ferrari, Horacio Carvajal, Mattia Bugatti, William Vermi, Tong Wu, Marina Cella, Pirooz Eghtesady, Marco Colonna
{"title":"Age- and tissue-dependent diversity of human plasmacytoid dendritic cells uncovers a cycling subset dominant in early life and cancer.","authors":"Alina Ulezko Antonova, Patrick Fernandes Rodrigues, Chelsea Mannie, Giorgia Ferrari, Horacio Carvajal, Mattia Bugatti, William Vermi, Tong Wu, Marina Cella, Pirooz Eghtesady, Marco Colonna","doi":"10.1016/j.immuni.2026.04.003","DOIUrl":"10.1016/j.immuni.2026.04.003","url":null,"abstract":"<p><p>Plasmacytoid dendritic cells (pDCs) are innate sentinels that produce type I interferons (IFN-I) during infection. Here, we asked how developmental stage and tissue context shape human pDC transcriptional states. Single-cell RNA sequencing of pDCs from blood, thymus, lymph nodes, and tonsils across fetal, infant, and pediatric stages revealed tissue-enriched programs, including IFN-I-imprinted pDCs in the thymus, NF-κB-imprinted pDCs in tonsils, and resting pDCs in blood and lymph nodes. Across tissues, we identified a pDC subset characterized by prostaglandin D2 production and dopamine responsiveness, indicating a potential neuromodulatory axis. Cycling pDCs were abundant in fetal and infant lymphoid tissues and declined with age, while remaining enriched in bone marrow (BM) throughout life. Blastic pDC neoplasm was associated with enrichment of cycling, mutation-bearing pDCs in the BM, suggesting that this niche serves as a reservoir for malignant pDCs. Thus, early in life, pDCs are generated within various lymphoid tissues. This tissue-specific hematopoiesis may result in distinct cellular and functional outputs.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":" ","pages":""},"PeriodicalIF":26.3,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147814600","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Krüppel-like factor 2 programs early exhausted T cell states and restrains antiviral immunity.","authors":"Shengjun Geng, Zifeng Li, Wenhao Li, Huiqing Liang, Fan Xu, Leilei Zhang, Wei Zhang, Shengyong Tao, Yanhan Wang, Yurui Zhou, Shijie Luo, Xing Lei, Hailang Li, Wei-Feng Huang, Meixia Che, Wen-Hsien Liu, Jialiang Huang, Tianying Zhang, Kejia Wang, Nengming Xiao, Kairui Mao, Yajun Jiang, Hongling Huang","doi":"10.1016/j.immuni.2026.03.029","DOIUrl":"https://doi.org/10.1016/j.immuni.2026.03.029","url":null,"abstract":"<p><p>A key challenge in improving T cell-mediated immunotherapies is defining the factors that regulate functional versus exhausted T cell fates. Through multi-round in vivo CRISPR screens in chronic lymphocytic choriomeningitis virus Clone 13 (LCMV Cl13) infection and transcription factor (TF) benchmarking, we identified Krüppel-like factor 2 (KLF2) as a top TF driving CX3CR1<sup>+</sup> effector-like exhausted cell (Tex<sup>eff-like</sup>) differentiation. Overexpression of KLF2 converted CX3CR1⁻ cells into Tex<sup>eff-like</sup> cells by direct engagement of key loci. Conversely, loss of KLF2 increased inhibitory receptor expression and redirected cells toward terminal exhaustion. However, early after infection, KLF2 deficiency yielded increased CD8<sup>+</sup> T cell accumulation and improved viral control. This effect was, in part, mediated by TOX and improved T cell localization with dendritic cells. Additional deletion of PD-1 further enhanced viral control but induced severe immunopathology. Collectively, these findings identify KLF2 as a central regulator of the Tex<sup>eff-like</sup> program and underscore exhaustion features as checkpoints balancing antiviral immunity and immunopathology.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":" ","pages":""},"PeriodicalIF":26.3,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147770237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"An SPP1-SOCS1 pathway constrains interferon responses in tumor-associated macrophages and shapes an immunosuppressive tumor microenvironment","authors":"Liangzhan Sun, Xiaojing Chu, Tingting Kong, Xirui Chen, Jianing Ru, Qianqian Gao, Wei Zhou, Xiliang Wang, Sijin Cheng, Linnan Zhu, Zemin Zhang","doi":"10.1016/j.immuni.2026.04.001","DOIUrl":"https://doi.org/10.1016/j.immuni.2026.04.001","url":null,"abstract":"Tumor-associated macrophages (TAMs) can suppress antitumor immunity and reduce responses to immune checkpoint blockade (ICB). Here, we asked how TAM programs contribute to ICB non-response. Integration of public single-cell RNA sequencing (scRNA-seq) datasets across 12 cancer types identified SPP1<sup>+</sup> TAMs as a tumor-enriched macrophage subset with immunosuppressive features. TAMs from ICB non-responders across multiple tumor types exhibited higher SPP1 expression. In murine models, macrophage Spp1 deletion suppressed tumor growth and prolonged survival and was associated with a remodeled tumor microenvironment featuring reduced T regulatory cell (Treg) frequencies, increased interferon (IFN)-γ<sup>+</sup> CD4<sup>+</sup> and GZMB<sup>+</sup> CD8<sup>+</sup> T cells, and augmented interferon-stimulated gene (ISG) expression across immune and malignant compartments. Mechanistically, intracellular SPP1 interacted with TRIM21 to limit SOCS1 ubiquitination, stabilizing SOCS1-mediated negative feedback and dampening IFN-γ-STAT1-ISG signaling in TAMs. Consistently, SPP1 targeting enhanced the efficacy of anti-PD-L1 therapy <em>in vivo</em>. Thus, remodeling the TME via targeting the TAM SPP1-IFN-γ axis presents a therapeutic avenue for enhancing responses to ICB.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"13 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147751506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ImmunityPub Date : 2026-04-27DOI: 10.1016/j.immuni.2026.04.002
Daniel B Graham, Ramnik J Xavier
{"title":"Mechanisms of inflammatory bowel diseases: Insights from human genetics and chemical biology.","authors":"Daniel B Graham, Ramnik J Xavier","doi":"10.1016/j.immuni.2026.04.002","DOIUrl":"10.1016/j.immuni.2026.04.002","url":null,"abstract":"<p><p>Human genetics has proven remarkably productive in linking genetic variants to a wide variety of diseases. Discovery initiatives from medical and population genetics have been especially prolific in generating new leads that point to underlying mechanisms of immune-mediated inflammatory diseases. While synthesizing leads from genetics into a functional understanding of disease pathophysiology is gaining momentum, challenges and opportunities abound. Here, we review advancements from combined efforts in functional genomics and chemical biology to construct and dissect mechanisms of mucosal immunity based on the genetics of inflammatory bowel disease (IBD). Taken together, a framework is emerging for interpreting disease mechanisms and conceiving new therapeutic hypotheses.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":" ","pages":""},"PeriodicalIF":26.3,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13132028/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147770232","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Modular double-stranded DNA recognition defines specificity of the exonuclease TREX1 in cGAS-STING control","authors":"Jiali Zhu, Lei Wang, Changjie Lin, Shuchen Bian, Xiaohan Luan, Yingying Sui, Luhang Piao, Wen Zhou","doi":"10.1016/j.immuni.2026.03.025","DOIUrl":"https://doi.org/10.1016/j.immuni.2026.03.025","url":null,"abstract":"TREX1, but not other DEDDh exonucleases, restrains cyclic GMP-AMP synthase- stimulator of interferon genes (cGAS-STING) activation by cytosolic DNA. Here, we examined the mechanisms underlying this specificity. Biochemical comparison of TREX1 and TREX2 mapped TREX1’s ability to degrade dsDNA and suppress cGAS signaling to a single amino acid, R128. Metazoan TREX proteins containing an R128-equivalent functioned as double-stranded DNA (dsDNA) nucleases, often alongside cGAS-like receptors, defining an evolutionarily conserved family. Structurally, TREX1-R128 contacted the non-substrate strand to enable efficient dsDNA binding and cleavage. Examination of conserved structural features of the R128-containing TREX family further identified a substrate-sensing loop that inserted into the active-site cleft and stabilized the substrate strand. In human TREX1, a distinct auxiliary DNA-binding surface (B-site) strengthened DNA engagement and cGAS restraint independent of DNase activity, suggesting a competitive function. Autoimmune-associated TREX1 mutations mapped to TREX1-dsDNA interfaces, and mutations disrupting these interactions increased cGAS-STING signaling and antitumor immunity in murine models. Thus, a modular dsDNA-recognition architecture defines TREX1 specificity and regulation of the cGAS-STING pathway.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"6 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147751523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ImmunityPub Date : 2026-04-24DOI: 10.1016/j.immuni.2026.03.028
Bowie Yik-Ling Cheng, Raquel M Centeio, David Kung-Chun Chiu, Casey L Kiyohara, Ella Herzog, Rony Dahan, Wendy E Thomas, Taia T Wang
{"title":"Pharmacologic glycoengineering of Fcγ receptor IIIa enhances force-resistant IgG-FcγR interactions and anti-tumor antibody efficacy.","authors":"Bowie Yik-Ling Cheng, Raquel M Centeio, David Kung-Chun Chiu, Casey L Kiyohara, Ella Herzog, Rony Dahan, Wendy E Thomas, Taia T Wang","doi":"10.1016/j.immuni.2026.03.028","DOIUrl":"10.1016/j.immuni.2026.03.028","url":null,"abstract":"<p><p>Therapeutic monoclonal antibodies (mAbs) are central to cancer treatment but often show incomplete efficacy. We show that transient pharmacologic inhibition of complex N-glycans in host cells (\"glycoengineering\") enhances the in vivo activity of multiple depleting mAbs, including mAbs already engineered for heightened potency. In preclinical models, glycoengineering improved α-CD20-mediated tumor clearance and survival through FcγRIIIa- and natural killer (NK) cell-dependent pathways. In B16-F10 melanoma, glycoengineering similarly enhanced anti-CD25 depletion of intratumoral regulatory T cells (Tregs). Notably, glycoengineering produced minimal changes in equilibrium binding affinity but markedly increased the mechanical durability of IgG-FcγRIIIa interactions under physiological shear stress. These results establish antibody effector function as a mechano-immunological process in which IgG-FcγR interactions can be tuned for resilience to physiological forces, thereby moving beyond the current affinity-centric paradigm in mAb engineering. Integrating mechanobiology into therapeutic development may enable mAbs optimized for the dynamic forces of human physiology, which provides a route to enhance next-generation immunotherapies.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":" ","pages":""},"PeriodicalIF":26.3,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147770185","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Palmitic acid reprograms neutrophils to compromise vascular integrity and promote breast cancer lung metastasis.","authors":"Peng Qian, Yuxin Li, Yifeng Han, Chun Xu, Peng Zou, Fuming Yang, Xiaozhen Kang, Mengdi Wu, Jie Dong, Zhengyun Zou, Jiwu Wei","doi":"10.1016/j.immuni.2026.03.026","DOIUrl":"https://doi.org/10.1016/j.immuni.2026.03.026","url":null,"abstract":"<p><p>Pre-metastatic niche formation in the lung creates a permissive microenvironment for breast cancer metastasis, characterized by metabolic reprogramming of resident cells, recruitment of suppressive neutrophils, and vascular remodeling. However, the role of lipids in regulating neutrophil-endothelial interactions, particularly in facilitating tumor cell extravasation, remains largely undefined. Here, we showed that triple-negative breast cancer established a palmitic acid-enriched lung microenvironment that drove tumor cell extravasation and colonization. Pulmonary endothelial cells were a major source of palmitic acid, which activated neutrophils to produce lipocalin-2 (LCN2) via the Toll-like receptor 4 (TLR4)-NF-κB pathway. Neutrophil-derived LCN2 disrupted endothelial tight junctions, compromised vascular integrity, and facilitated tumor cell extravasation. Targeting endothelial fatty acid synthesis using glucagon-like peptide-1 receptor agonists preserved vascular integrity and suppressed lung metastasis. These findings uncover a lipid-driven mechanism underlying metastatic organotropism and highlight metabolic intervention as a potential therapeutic strategy against breast cancer lung metastasis.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":" ","pages":""},"PeriodicalIF":26.3,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147770197","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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