Cellular &Molecular Immunology最新文献

CCR2⁺ monocytes promote memory CD8⁺ T-cell differentiation via membrane-bound TGF-β. CCR2+单核细胞通过膜结合TGF-β促进记忆性CD8+ t细胞分化。

IF 21.8 1区医学

Cellular &Molecular Immunology Pub Date : 2025-06-03 DOI: 10.1038/s41423-025-01299-2

Lina Sun, Cangang Zhang, Anjun Jiao, Yanhong Su, Tianzhe Zhang, Qianhao Wang, Yao Ge, Chen Yang, Ning Yuan, Lianjun Zhang, Chenming Sun, Liang Chen, Lilin Ye, Baojun Zhang

{"title":"CCR2+ monocytes promote memory CD8+ T-cell differentiation via membrane-bound TGF-β.","authors":"Lina Sun, Cangang Zhang, Anjun Jiao, Yanhong Su, Tianzhe Zhang, Qianhao Wang, Yao Ge, Chen Yang, Ning Yuan, Lianjun Zhang, Chenming Sun, Liang Chen, Lilin Ye, Baojun Zhang","doi":"10.1038/s41423-025-01299-2","DOIUrl":"https://doi.org/10.1038/s41423-025-01299-2","url":null,"abstract":"Upon antigen recognition, CD8+ T cells undergo robust expansion and differentiation to give rise to effector and memory CD8+ T cells. The spatial determinants of the fate of effector and memory CD8+ T cells during acute infection are poorly understood. By integrating single-cell RNA sequencing (scRNA-seq) and spatially resolved transcriptomics, we revealed that naïve CD8+ T cells adopted a divergent trajectory in which they rapidly differentiated into memory precursor (MP) cells and IFN-responsive cells, with the latter representing the entry point of the effector T-cell lineage. In the spleen, monocytes largely colocalized with CD8+ MP cells following antigen stimulation. Specifically, compared with dendritic cells (DCs), the Ly6ChiCCR2+ subset of monocytes promotes memory CD8+ T-cell differentiation. Mechanistically, monocytes express high levels of membrane-bound transforming growth factor-β (TGF-β), which is activated by thrombospondin-1 (TSP-1) to drive the memory CD8+ T-cell program through Smad signaling. Overall, our study reveals a novel spatial mechanism for CD8+ T-cell fate decisions, shedding light on the importance of monocytes in fostering memory CD8+ T-cell development in a cell‒cell contact- and TGF-β-dependent manner.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":" ","pages":""},"PeriodicalIF":21.8,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144215090","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

Liver macrophages: development, dynamics, and functions. 肝巨噬细胞：发育、动态和功能。

IF 21.8 1区医学

Cellular &Molecular Immunology Pub Date : 2025-06-03 DOI: 10.1038/s41423-025-01298-3

Ysbrand Nusse, Paul Kubes

{"title":"Liver macrophages: development, dynamics, and functions.","authors":"Ysbrand Nusse, Paul Kubes","doi":"10.1038/s41423-025-01298-3","DOIUrl":"https://doi.org/10.1038/s41423-025-01298-3","url":null,"abstract":"The liver is a sizeable visceral organ whose primary functions involve nutrient metabolism, clearance of toxins, and energy storage. Besides these critical functions, the liver is also a major immunological site. It is populated by several specialized resident immune cells, including B cells, T Cells, dendritic cells, and several populations of macrophages. It is also the site for the production and release of acute-phase proteins during inflammation. One reason for garrisoning these immune sentinels and effectors in the liver is its relative location in the circulatory system. The liver is the first significant organ downstream of the intestine, where blood originating from the intestine enters the liver through the portal vein. This organization facilitates the liver's uptake and processing of nutrient-rich blood directly from the intestinal source. However, the intestine is also home to trillions of microbes, many of which are commensals but also represent potential pathogens. As such, the portal blood supply represents an avenue for systemic infection. To sterilize the portal blood, the liver immune system filters pathogens, which is primarily accomplished by liver macrophages. Here, we will discuss the major populations of macrophages resident in the liver, their location, functions, development, and role in maintaining the liver in the face of injury and infection.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":" ","pages":""},"PeriodicalIF":21.8,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144215091","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

γδ⁺ T-cell-derived IL-17A stimulates airway epithelial/stromal cells to secrete G-CSF, promoting lung-specific pathogenic Siglec-F⁺ neutrophil development in PPE-induced emphysema. γδ+ t细胞源性IL-17A刺激气道上皮/间质细胞分泌G-CSF，促进肺特异性致病性siglece - f +中性粒细胞在肺气肿中的发育。

IF 21.8 1区医学

Cellular &Molecular Immunology Pub Date : 2025-06-03 DOI: 10.1038/s41423-025-01301-x

JungHyub Hong, Myeong-Ho Kang, Jinjoo Lee, Min-Suk Cha, Yoe-Sik Bae, Hye Young Kim, Yong Taik Lim, Yong-Soo Bae

{"title":"γδ+ T-cell-derived IL-17A stimulates airway epithelial/stromal cells to secrete G-CSF, promoting lung-specific pathogenic Siglec-F+ neutrophil development in PPE-induced emphysema.","authors":"JungHyub Hong, Myeong-Ho Kang, Jinjoo Lee, Min-Suk Cha, Yoe-Sik Bae, Hye Young Kim, Yong Taik Lim, Yong-Soo Bae","doi":"10.1038/s41423-025-01301-x","DOIUrl":"https://doi.org/10.1038/s41423-025-01301-x","url":null,"abstract":"Neutrophils play a pivotal role in the progression of IL-17-mediated airway inflammation, but the mechanisms underlying their pathological differentiation remain poorly understood. In this study, we identified a distinct population of lung-specific pathogenic Siglec-F+ neutrophils in a porcine pancreatic elastase (PPE)-induced mouse model of emphysema. Compared with conventional neutrophils, these Siglec-F+ neutrophils exhibited increased phagocytic activity, increased extracellular trap formation, increased production of proinflammatory cytokines, and reduced IL-10 levels. During the early phase of acute inflammation following PPE instillation, IL-17A levels in the lungs increase, which is driven primarily by γδ+ T cells. IL-17A stimulated lung epithelial/stromal cells to secrete granulocyte colony-stimulating factor (G-CSF), which promoted the differentiation of Siglec-F+ neutrophils via the JAK2/STAT3 pathway and the PI3K-independent mTOR and p38 MAPK signaling pathways. Neutralizing G-CSF or inhibiting JAK2/STAT3, mTOR or p38 MAPK signaling significantly suppressed Siglec-F+ neutrophil development, resulting in the alleviation of emphysematous symptoms. Our findings underscore the crucial role of Siglec-F+ neutrophils in the pathogenesis of PPE-induced emphysema and suggest that targeting the IL-17A/G-CSF axis or G-CSF receptor downstream signaling pathways may represent a promising therapeutic strategy for treating emphysema.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":" ","pages":""},"PeriodicalIF":21.8,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144215092","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 21.8 1区医学

Cellular &Molecular Immunology Pub Date : 2025-06-01 Epub 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":" ","pages":"645-660"},"PeriodicalIF":21.8,"publicationDate":"2025-06-01","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

Activation and maturation of antigen-specific B cells in nonectopic lung infiltrates are independent of germinal center reactions in the draining lymph node. 非异位肺浸润中抗原特异性B细胞的激活和成熟与引流淋巴结的生发中心反应无关。

IF 21.8 1区医学

Cellular &Molecular Immunology Pub Date : 2025-06-01 Epub Date: 2025-04-11 DOI: 10.1038/s41423-025-01285-8

Sarah-Sophie Schacht, Josefine Graffunder, Pawel Durek, Jonas Wehrenberg, Annette Siracusa, Charlotte Biese, Mir-Farzin Mashreghi, Kevin Thurley, Laura Bauer, Andreas Hutloff

{"title":"Activation and maturation of antigen-specific B cells in nonectopic lung infiltrates are independent of germinal center reactions in the draining lymph node.","authors":"Sarah-Sophie Schacht, Josefine Graffunder, Pawel Durek, Jonas Wehrenberg, Annette Siracusa, Charlotte Biese, Mir-Farzin Mashreghi, Kevin Thurley, Laura Bauer, Andreas Hutloff","doi":"10.1038/s41423-025-01285-8","DOIUrl":"10.1038/s41423-025-01285-8","url":null,"abstract":"Pulmonary T and B cells are important for protection of this mucosal barrier site. While viral infections lead to the development of ectopic lymphoid structures highly similar to those in germinal centers in secondary lymphoid organs, little is known about how T/B cooperation occurs in the unstructured, diffuse tissue infiltrates characteristic of autoimmune diseases and nonviral infections. Using a mouse model of interstitial lung inflammation, we found that naive B cells are directly activated in lung tissue. Despite the absence of any germinal center-like structures, the interaction of B cells with peripheral T helper cells results in efficient somatic hypermutation and class switching. As antigen-presenting cells, macrophages are critical for this process. Unique B-cell repertoires indicated that the lung response was autonomous from the lung-draining lymph node. Only lung GC-like B cells were switched to IgA and had a broader repertoire, making them ideal candidates for producing broadly neutralizing immunoglobulins against respiratory pathogens.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":" ","pages":"612-627"},"PeriodicalIF":21.8,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12125278/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143969444","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 21.8 1区医学

Cellular &Molecular Immunology Pub Date : 2025-06-01 Epub 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":" ","pages":"661-673"},"PeriodicalIF":21.8,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12125261/pdf/","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":"OA","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 21.8 1区医学

Cellular &Molecular Immunology Pub Date : 2025-06-01 Epub 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":" ","pages":"563-596"},"PeriodicalIF":21.8,"publicationDate":"2025-06-01","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

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 21.8 1区医学

Cellular &Molecular Immunology Pub Date : 2025-06-01 Epub 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":" ","pages":"674-689"},"PeriodicalIF":21.8,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12125281/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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 21.8 1区医学

Cellular &Molecular Immunology Pub Date : 2025-06-01 Epub 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":" ","pages":"628-644"},"PeriodicalIF":21.8,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12125383/pdf/","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":"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 21.8 1区医学

Cellular &Molecular Immunology Pub Date : 2025-06-01 DOI: 10.1038/s41423-025-01274-x

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

引用次数: 0