Cellular &Molecular Immunology最新文献_第7页

NETosis exacerbates skin inflammation in obese psoriasis patients NETosis加重肥胖牛皮癣患者的皮肤炎症。

IF 19.8 1区医学

Cellular &Molecular Immunology Pub Date : 2025-05-20 DOI: 10.1038/s41423-025-01287-6

Bruno Marcel Silva de Melo, José Carlos Alves-Filho, Bernhard Ryffel

引用次数: 0

Targeting Lp-PLA2 inhibits profibrotic monocyte-derived macrophages in silicosis through restoring cardiolipin-mediated mitophagy 靶向Lp-PLA2通过恢复心磷脂介导的线粒体自噬抑制矽肺中纤维化单核细胞来源的巨噬细胞。

IF 19.8 1区医学

Cellular &Molecular Immunology Pub Date : 2025-05-19 DOI: 10.1038/s41423-025-01288-5

Shifeng Li, Hong Xu, Shupeng Liu, Jinkun Hou, Yueyin Han, Chen Li, Yupeng Li, Gaigai Zheng, Zhongqiu Wei, Fang Yang, Shuwei Gao, Shiyao Wang, Jing Geng, Huaping Dai, Chen Wang

{"title":"Targeting Lp-PLA2 inhibits profibrotic monocyte-derived macrophages in silicosis through restoring cardiolipin-mediated mitophagy","authors":"Shifeng Li, Hong Xu, Shupeng Liu, Jinkun Hou, Yueyin Han, Chen Li, Yupeng Li, Gaigai Zheng, Zhongqiu Wei, Fang Yang, Shuwei Gao, Shiyao Wang, Jing Geng, Huaping Dai, Chen Wang","doi":"10.1038/s41423-025-01288-5","DOIUrl":"10.1038/s41423-025-01288-5","url":null,"abstract":"Monocyte-derived macrophages (MoMacs) are the most important effector cells that cause pulmonary fibrosis. However, the characteristics of MoMac differentiation in silicosis and the mechanisms by which MoMacs affect the progression of pulmonary fibrosis remain unclear. Integration of single-cell and spatial transcriptomic analyses revealed that the silicosis niche was occupied by a subset of MoMacs, identified as Spp1hiMacs, which remain in an immature transitional state of differentiation during silicosis. This study investigated the mechanistic foundations of mitochondrial damage induced by the lipoprotein-associated phospholipase A2 (Lp-PLA2, encoded by Pla2g7)–acyl-CoA:lysocardiolipin acyltransferase-1 (ALCAT1)–cardiolipin (CL) signaling pathway, which interferes with Spp1hiMac differentiation. We demonstrated that in SiO2-induced MoMacs, Lp-PLA2 induces abnormal CL acylation through the activation of ALCAT1, resulting in impaired mitochondrial localization of PINK1 and LC3B and mitochondrial autophagy defects. Simultaneously, lysosomal dysfunction causes the release of the lysosomal protein cathepsin B into the cytoplasm, which involves M1 and M2 macrophage polarization and the activation of proinflammatory and profibrotic pathways. Furthermore, we assessed the efficacy of the Lp-PLA2 inhibitor darapladib in ameliorating silica-induced pulmonary fibrosis in a murine model. Our findings enhance our understanding of silicosis pathogenesis and offer promising opportunities for developing targeted therapies to mitigate fibrotic progression and maintain lung function in affected individuals.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 7","pages":"776-790"},"PeriodicalIF":19.8,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12206922/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144101429","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}

引用次数: 0

Synergistic effects of LCN2 and TWEAK on the progression of psoriasis LCN2和TWEAK对银屑病进展的协同作用。

IF 19.8 1区医学

Cellular &Molecular Immunology Pub Date : 2025-05-15 DOI: 10.1038/s41423-025-01292-9

Kaixuan Ren, Xueting Peng, Xudong Duan, Rongfang Feng, Christopher Cook, Mei Lu, Min Li, Hanjiang Gu, Xiaoyu Wang, Guorong Deng, Huiqun Ma, Yale Liu, Yumin Xia

{"title":"Synergistic effects of LCN2 and TWEAK on the progression of psoriasis","authors":"Kaixuan Ren, Xueting Peng, Xudong Duan, Rongfang Feng, Christopher Cook, Mei Lu, Min Li, Hanjiang Gu, Xiaoyu Wang, Guorong Deng, Huiqun Ma, Yale Liu, Yumin Xia","doi":"10.1038/s41423-025-01292-9","DOIUrl":"10.1038/s41423-025-01292-9","url":null,"abstract":"Lipocalin 2 (LCN2) and the TWEAK/Fn14 signaling pathways are pivotal in psoriasis, influencing epidermal development, inflammatory cell chemotaxis, and inflammatory factor release. Despite their significant roles, the intricate relationship between LCN2 and TWEAK/Fn14 pathways remains unclear. Our study revealed the correlation between the expression of TWEAK, LCN2, and Fn14 in psoriatic lesions. We found that TWEAK is expressed by keratinocytes and macrophages, while LCN2 is expressed by keratinocytes and neutrophils. Surface plasmon resonance experiments demonstrated binding between LCN2 and Fn14, which was further validated by co-immunoprecipitation and cellular co-localization via immunofluorescence. In vitro, LCN2 promoted macrophage differentiation and TWEAK secretion, enhanced TWEAK and Fn14 expression in keratinocytes, and activated the MAPK signaling pathway. TWEAK upregulated LCN2 expression in neutrophils but not in keratinocytes. Bulk RNA-seq analysis revealed a synergistic effect of LCN2 and TWEAK in promoting inflammatory cytokine expression in keratinocytes, with enhanced MAPK pathway activation in the presence of M5 cytokines. Lcn2 knockout reduced Fn14 expression in skin lesions and serum TWEAK levels of imiquimod-induced murine psoriasis model, while Fn14 knockout attenuated the epidermal hyperplasia-promoting effects of TWEAK and LCN2. Overexpression of Fn14 in keratinocytes led to higher TWEAK expression upon LCN2 stimulation, suggesting a self-reinforcing loop among TWEAK, LCN2, and Fn14. We propose that LCN2 synergizes with TWEAK through Fn14 to drive psoriasis pathogenesis. LCN2 and TWEAK synergistically interact with Fn14, leading to epidermal proliferation and inflammation in psoriasis through the MAPK signaling pathway; however, these effects can be reversed by LCN2 knockout.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 7","pages":"760-775"},"PeriodicalIF":19.8,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12206918/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144076321","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}

引用次数: 0

Malonate promotes CD8+ T cell memory formation via protein malonylation 丙二酸盐通过蛋白丙二酸化促进CD8+ T细胞记忆形成。

IF 19.8 1区医学

Cellular &Molecular Immunology Pub Date : 2025-05-14 DOI: 10.1038/s41423-025-01294-7

Qianqian Duan, Jiajia Wang, Liang Sun, Zihan Chen, Wenhui Li, Xiaowei Liu, Aijun Zhang, Yong Liu, Lianjun Zhang

{"title":"Malonate promotes CD8+ T cell memory formation via protein malonylation","authors":"Qianqian Duan, Jiajia Wang, Liang Sun, Zihan Chen, Wenhui Li, Xiaowei Liu, Aijun Zhang, Yong Liu, Lianjun Zhang","doi":"10.1038/s41423-025-01294-7","DOIUrl":"10.1038/s41423-025-01294-7","url":null,"abstract":"Protein malonylation represents a recently identified posttranslational modification whose role in CD8+ T cell differentiation and functionality remains incompletely understood. In this study, we demonstrate that enhancing protein malonylation through sodium malonate (SM) treatment promotes CD8+ T cell memory formation in response to bacterial infection, subsequently potentiating recall responses. Comparative metabolomic analysis between SM-treated and control CD8+ T cells revealed significant metabolic alterations associated with protein malonylation. We present the first comprehensive proteomic analysis of lysine malonylation in murine CD8+ T cells, identifying 77 malonylation sites across 64 proteins involved in diverse cellular processes, particularly metabolic pathways. Malonylation of STAT6 was confirmed via the use of a specific chemical probe. Notably, we established that malonylation at the lysine 374 site of STAT6 results in increased TCF1 expression, due to alleviated transcriptional repression of TCF1 by STAT6. Collectively, our findings provide compelling evidence that protein malonylation plays a significant role in regulating CD8+ T cell memory formation.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 6","pages":"674-689"},"PeriodicalIF":19.8,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144076320","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}

引用次数: 0

Sexual dimorphism of lung immune-regulatory units imprint biased pulmonary fibrosis 肺免疫调节单位的性别二态性印记偏倚性肺纤维化。

IF 19.8 1区医学

Cellular &Molecular Immunology Pub Date : 2025-05-14 DOI: 10.1038/s41423-025-01293-8

Peng Xiang, Liwen Wang, Xu Feng, Qi Guo, Genqing Xie, Langqing Sheng, Linyun Chen, Jianhui Teng, Jinlin Yang, Xuecheng Wu, Xi Peng, Renbin Lu, Xianghang Luo, Jie Wen, Hai-Yan Zhou

{"title":"Sexual dimorphism of lung immune-regulatory units imprint biased pulmonary fibrosis","authors":"Peng Xiang, Liwen Wang, Xu Feng, Qi Guo, Genqing Xie, Langqing Sheng, Linyun Chen, Jianhui Teng, Jinlin Yang, Xuecheng Wu, Xi Peng, Renbin Lu, Xianghang Luo, Jie Wen, Hai-Yan Zhou","doi":"10.1038/s41423-025-01293-8","DOIUrl":"10.1038/s41423-025-01293-8","url":null,"abstract":"Pulmonary fibrosis (PF) is sexually dimorphic, with a relatively high prevalence and severity in males; however, the mechanism remains unclear. Our study revealed pronounced sexual dimorphism of immune cell genes in the lung, among which grancalcin (GCA) showed profound sex differences. GCA was produced by lung-infiltrating bone marrow macrophages triggered by heightened inflammation in the lung. However, a unique HTR2C+ alveolar macrophage population enriched in female lungs metabolically reprogramed bone marrow-derived macrophages and constrained local GCA amplification. As a novel chemokine, GCA bound to protein tyrosine phosphatase receptor type T (PTPRT) in Th17 cells and facilitated pathogenic lung infiltration by activating the ROCK1-MLC pathway, thus aggravating lung fibrosis. Notably, both GCA and Th17 cells abundantly accumulated in lung biopsies from male PF patients but not in those from female patients. GCA-neutralizing antibodies in combination with pirfenidone, a prescribed medication for treating fibrosis, provided superior effectiveness and survival rates against PF compared with treatment with pirfenidone alone. Overall, our findings reveal that sex-biased lung fibrosis is shaped by lung immune-regulatory units, which could be targeted to limit lung fibrosis.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 7","pages":"743-759"},"PeriodicalIF":19.8,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143983072","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}

引用次数: 0

Harnessing nutrient scarcity for enhanced CAR-T-cell potency and safety in solid tumors 利用营养稀缺增强car - t细胞在实体肿瘤中的效力和安全性。

IF 19.8 1区医学

Cellular &Molecular Immunology Pub Date : 2025-05-08 DOI: 10.1038/s41423-025-01290-x

Enzo Manchon, Nell Hirt, Benjamin Versier, Aravindhan Soundiramourty, Ludmila Juricek, Celeste Lebbe, Maxime Battistella, Yves Christen, Jacques Mallet, Dominique Charron, Nabila Jabrane-Ferrat, Che Serguera, Reem Al-Daccak

{"title":"Harnessing nutrient scarcity for enhanced CAR-T-cell potency and safety in solid tumors","authors":"Enzo Manchon, Nell Hirt, Benjamin Versier, Aravindhan Soundiramourty, Ludmila Juricek, Celeste Lebbe, Maxime Battistella, Yves Christen, Jacques Mallet, Dominique Charron, Nabila Jabrane-Ferrat, Che Serguera, Reem Al-Daccak","doi":"10.1038/s41423-025-01290-x","DOIUrl":"10.1038/s41423-025-01290-x","url":null,"abstract":"Despite significant advancements, the effectiveness of chimeric antigen receptor (CAR)-T-cell-based therapies in solid tumors remains limited. Key challenges include on-target effects, off-tumor toxicity and reduced CAR-T-cell function within the tumor microenvironment, which is often characterized by metabolic stress triggered by factors such as amino acid scarcity. Activating transcription factor-4 (ATF4) and its upstream regulator GCN2 play crucial roles in the metabolic reprogramming and functionality of CD4+ and CD8+ T cells. ATF4 can be activated by various cellular stress signals, including amino acid deprivation. While ATF4 activation may be associated with T-cell dysfunction, its role in stress adaptation presents an opportunity for therapeutic intervention—particularly in the tumor microenvironment, where T-cell exhaustion is a major challenge. In this study, we developed a strategy to harness the GCN2‒ATF4 axis in CAR-T cells. We employed an amino acid-dependent inducible promoter, which triggers ATF4-dependent gene expression to regulate CAR expression in T cells under conditions of amino acid scarcity within the tumor microenvironment. In vitro and murine xenograft models demonstrate the potential of this system to effectively restrict CAR expression to the tumor site. This targeted strategy not only enhances safety by minimizing off-tumor activity but also CAR-T-cell fitness by reducing exhaustion. By validating this pathophysiologically regulatable CAR expression system for solid tumors, our findings address key limitations of current CAR-T-cell therapies and pave the way for innovative strategies targeting solid malignancies.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 6","pages":"645-660"},"PeriodicalIF":19.8,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12125372/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143955224","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}

引用次数: 0

FXR protects against neonatal sepsis by enhancing the immunosuppressive function of MDSCs FXR通过增强MDSCs的免疫抑制功能来预防新生儿脓毒症。

IF 19.8 1区医学

Cellular &Molecular Immunology Pub Date : 2025-05-08 DOI: 10.1038/s41423-025-01289-4

Juan He, Yuxin Zhang, Yuchao Jing, Rui Dong, Tongyang Li, Xiaoqing Zheng, Pan Zhou, Kun Shi, Wei Zhong, Qiang Liu, Jie Zhou

{"title":"FXR protects against neonatal sepsis by enhancing the immunosuppressive function of MDSCs","authors":"Juan He, Yuxin Zhang, Yuchao Jing, Rui Dong, Tongyang Li, Xiaoqing Zheng, Pan Zhou, Kun Shi, Wei Zhong, Qiang Liu, Jie Zhou","doi":"10.1038/s41423-025-01289-4","DOIUrl":"10.1038/s41423-025-01289-4","url":null,"abstract":"Myeloid-derived suppressor cells (MDSCs) play a protective role against neonatal inflammation during the early postnatal period. However, the mechanisms regulating neonatal MDSC function remain to be fully elucidated. In this study, we report that the bile acid receptor farnesoid X receptor (FXR) acts as a positive regulator of neonatal MDSC function. The FDA-approved FXR agonist obeticholic acid (OCA) protects against neonatal sepsis in an FXR-dependent manner. Genetic deficiency of FXR impairs the immunosuppressive and antibacterial functions of MDSCs, thereby exacerbating the severity of neonatal sepsis. Adoptive transfer of MDSCs alleviates sepsis in both Fxr−/− and Fxrfl/flMrp8-Cre+ pups. Mechanistic studies revealed that Hif1α, a well-established regulator of MDSCs, is a direct transcriptional target of FXR. In patients with neonatal sepsis, downregulation of FXR and HIF-1α in MDSCs was observed, which was inversely correlated with clinical parameters. These observations demonstrate the importance of FXR in neonatal MDSC function and its therapeutic potential in neonatal sepsis.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 6","pages":"661-673"},"PeriodicalIF":19.8,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143966387","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}

引用次数: 0

Updated insights into the molecular networks for NLRP3 inflammasome activation NLRP3炎性小体激活分子网络的最新见解。

IF 19.8 1区医学

Cellular &Molecular Immunology Pub Date : 2025-04-30 DOI: 10.1038/s41423-025-01284-9

Seungwha Paik, Jin Kyung Kim, Hyo Jung Shin, Eun-Jin Park, In Soo Kim, Eun-Kyeong Jo

{"title":"Updated insights into the molecular networks for NLRP3 inflammasome activation","authors":"Seungwha Paik, Jin Kyung Kim, Hyo Jung Shin, Eun-Jin Park, In Soo Kim, Eun-Kyeong Jo","doi":"10.1038/s41423-025-01284-9","DOIUrl":"10.1038/s41423-025-01284-9","url":null,"abstract":"Over the past decade, significant advances have been made in our understanding of how NACHT-, leucine-rich-repeat-, and pyrin domain-containing protein 3 (NLRP3) inflammasomes are activated. These findings provide detailed insights into the transcriptional and posttranslational regulatory processes, the structural–functional relationship of the activation processes, and the spatiotemporal dynamics of NLRP3 activation. Notably, the multifaceted mechanisms underlying the licensing of NLRP3 inflammasome activation constitute a focal point of intense research. Extensive research has revealed the interactions of NLRP3 and its inflammasome components with partner molecules in terms of positive and negative regulation. In this Review, we provide the current understanding of the complex molecular networks that play pivotal roles in regulating NLRP3 inflammasome priming, licensing and assembly. In addition, we highlight the intricate and interconnected mechanisms involved in the activation of the NLRP3 inflammasome and the associated regulatory pathways. Furthermore, we discuss recent advances in the development of therapeutic strategies targeting the NLRP3 inflammasome to identify potential therapeutics for NLRP3-associated inflammatory diseases. As research continues to uncover the intricacies of the molecular networks governing NLRP3 activation, novel approaches for therapeutic interventions against NLRP3-related pathologies are emerging.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 6","pages":"563-596"},"PeriodicalIF":19.8,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12125403/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143975742","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}

引用次数: 0

Author Correction: Cancer-associated fibroblasts express CD1d and activate invariant natural killer T cells under cellular stress 作者更正：癌症相关成纤维细胞表达CD1d并在细胞应激下激活不变的自然杀伤T细胞。

IF 19.8 1区医学

Cellular &Molecular Immunology Pub Date : 2025-04-28 DOI: 10.1038/s41423-025-01274-x

Shengduo Pei, Jonas Sjölund, Yueyun Pan, Kristian Pietras, Mikael C. I. Karlsson

引用次数: 0

The NET-DNA-CCDC25 inhibitor di-Pal-MTO suppresses tumor progression and promotes the innate immune response NET-DNA-CCDC25抑制剂di-Pal-MTO抑制肿瘤进展并促进先天免疫反应。

IF 19.8 1区医学

Cellular &Molecular Immunology Pub Date : 2025-04-14 DOI: 10.1038/s41423-025-01286-7

Shun Wang, Xinyan Liang, Heliang Li, Junying Zou, Linxi Xu, Yetong Zhang, Jianghua Lin, Jiayi Zeng, Xiaoming Zhong, Xu Liu, Zhou Liu, Yue Zheng, Man Nie, Linbin Yang

{"title":"The NET-DNA-CCDC25 inhibitor di-Pal-MTO suppresses tumor progression and promotes the innate immune response","authors":"Shun Wang, Xinyan Liang, Heliang Li, Junying Zou, Linxi Xu, Yetong Zhang, Jianghua Lin, Jiayi Zeng, Xiaoming Zhong, Xu Liu, Zhou Liu, Yue Zheng, Man Nie, Linbin Yang","doi":"10.1038/s41423-025-01286-7","DOIUrl":"10.1038/s41423-025-01286-7","url":null,"abstract":"The DNA component of neutrophil extracellular traps (NET-DNA) is associated with cancer metastasis and chemotherapy resistance. However, recent studies have suggested that NET-DNA contributes to the activation of dendritic cells (DCs) and promotes the innate immune response to anticancer immunity. Therefore, exploring therapeutic approaches to inhibit NET-mediated tumor progression while maintaining antitumor immunity is essential. Our groups recently identified CCDC25 as a specific NET-DNA sensor on the cytoplasmic membrane of cancer cells that promotes cancer metastasis. In this study, we performed small-molecule compound screening and revealed that mitoxantrone (MTO) could block the interaction between NET-DNA and CCDC25. Molecular docking results indicated that MTO competed with NET-DNA by binding with the amino acid residues Tyr24 (Y24), Glu25 (E25), and Asp28 (D28) of the crystal structure of CCDC25. More importantly, we conjugated MTO with palmitoleic acids such as di-Pal-MTO to increase its residence time on the cytoplasmic membrane, which increased its inhibitory efficiency and decreased its cytotoxicity. In addition, di-Pal-MTO markedly inhibited the RAC1-CDC42 cascade to alleviate the NET-induced cytoskeleton arrangement and chemotactic migration of cancer cells. In multiple mouse models, di-Pal-MTO can suppress breast cancer metastasis and have synergistic effects with chemotherapeutics. Moreover, di-Pal-MTO promotes NET-DNA-dependent DC activation, leading to the subsequent expression of various chemokines that facilitate the infiltration of CD8+ T cells. Overall, we successfully identified a small molecule inhibitor, di-Pal-MTO, with dual effects on tumor repression and the antitumor immune response, which provides a novel therapeutic strategy against breast cancer.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 6","pages":"628-644"},"PeriodicalIF":19.8,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143974828","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}

引用次数: 0