Cellular &Molecular Immunology最新文献

{"title":"CD39 as a metabolic rheostat of immunoregulation.","authors":"Vincenzo Barnaba, Silvano Sozzani","doi":"10.1038/s41423-025-01302-w","DOIUrl":"https://doi.org/10.1038/s41423-025-01302-w","url":null,"abstract":"","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":" ","pages":""},"PeriodicalIF":21.8,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144483359","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":"Dermal adipogenesis protects against neutrophilic skin inflammation during psoriasis pathogenesis.","authors":"Tian Xia, Wenlu Zhang, Rundong Wu, Xiaowei Zhang, Rongshuang Xia, Xiao Hu, Shuai Wu, Yanhang Liao, Jiacheng Li, Youxi Liu, Yiman Liu, Zhuolin Guo, Chi Zhang, Wenjie Liu, Ming Chen, Jiajing Lu, Yuling Shi, Ling-Juan Zhang","doi":"10.1038/s41423-025-01296-5","DOIUrl":"https://doi.org/10.1038/s41423-025-01296-5","url":null,"abstract":"<p><p>The immune response of the skin to danger signals involves rapid recruitment of neutrophils, but their excessive accumulation leads to inflammatory skin diseases, such as psoriasis; however, the mechanisms governing their initiation and resolution are poorly understood. Here, we revealed a dynamic immunoregulatory role of dermal white adipose tissue (dWAT) in the progression and resolution of neutrophilic skin inflammation in an imiquimod-induced psoriasis mouse model. During inflammation onset, dWAT repopulates PDGFRA⁺ preadipocytes (pAds), which secrete CXCL1 and SAA3, attracting and activating CXCR2⁺ neutrophils. These neutrophils further activate pAds through the IL-1R-NFκB-C/EBPδ pathway, establishing a self-sustaining inflammatory loop. Paradoxically, prolonged IL-1β signaling triggers PPARγ-dependent adipogenesis, transitioning pAds into anti-inflammatory early adipocytes that resolve neutrophilic inflammation via lipid mediators. Inhibition of adipogenesis, via pharmacological or genetic inhibition of PPARγ, disrupts the formation of early adipocytes, prevents neutrophil regression, and exacerbates inflammation. Analysis of human psoriatic cells revealed a C/EBPδ⁺ dermal fibroblast (dFB) subpopulation enriched with preadipocytes, the IL-1 pathway, and inflammatory gene signatures. Furthermore, transcriptomic analyses revealed a negative correlation between the neutrophil-related inflammatory response and the dermal lipogenesis response in generalized pustular psoriasis. Together, our findings reveal the dual role of dWAT: PDGFRA+ pAds initiate inflammation via CXCL1/IL-1β crosstalk with neutrophils, whereas PPARγ-driven adipogenesis resolves this process through lipid mediators. This work establishes dWAT as a critical immunomodulatory hub and proposes adipogenic reprogramming of proinflammatory fibroblasts or topical delivery of early adipocyte lipids as innovative therapies for neutrophil-driven skin diseases, such as psoriasis and ulcers.</p>","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":" ","pages":""},"PeriodicalIF":21.8,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144474082","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":"Topical delivery of a human single-domain antibody targeting IL-33 to inhibit mucosal inflammation.","authors":"Keke Huang, Yuqing Wu, Yu Kong, Qingyuan Xu, Mingwei Lv, Yirou Zhang, Yiteng Lu, Quanxiao Li, Cheng Li, Wenping Song, Xiaoyi Zhu, Zhenlin Yang, Changchang Xin, Xujiao Zhou, Tianlei Ying, Yanling Wu, Jiaxu Hong","doi":"10.1038/s41423-025-01305-7","DOIUrl":"https://doi.org/10.1038/s41423-025-01305-7","url":null,"abstract":"<p><p>Addressing mucosal inflammatory disorders in the ocular surface or respiratory system remains a formidable challenge owing to the limited penetration of biological therapeutics across epithelial barriers. In this study, we explored the potential of human single-domain antibodies (UdAbs) as topical therapeutics for the targeted modulation of interleukin-33 (IL-33) in two mucosal-associated inflammatory disorders. The anti-IL-33 UdAb A12 demonstrated potent inhibition of the IL-33-mediated signaling pathway, despite not potently blocking the IL-33 receptor interaction. Compared with the anti-IL-33 control IgG itepekimab, the topical delivery of A12 resulted in significantly elevated corneal concentrations in vivo, which resulted in negligible ocular penetration. Moreover, A12 considerably ameliorated dry eye disease severity by exerting anti-inflammatory effects. Furthermore, in another murine model of allergic asthma, inhaled A12 substantially reduced overall lung inflammation. Our findings revealed the capacity of UdAbs to penetrate mucosal barriers following noninvasive localized delivery, highlighting their potential as an innovative therapeutic strategy for modulating mucosal inflammation.</p>","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":" ","pages":""},"PeriodicalIF":21.8,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144274288","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":"Immune microenvironment in hepatocellular carcinoma: from pathogenesis to immunotherapy.","authors":"Deniz Seyhan, Manon Allaire, Yaojie Fu, Filomena Conti, Xin Wei Wang, Bin Gao, Fouad Lafdil","doi":"10.1038/s41423-025-01308-4","DOIUrl":"https://doi.org/10.1038/s41423-025-01308-4","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) is an increasingly prevalent and deadly disease that is initiated by different etiological factors, such as alcohol-associated liver disease (ALD), metabolic dysfunction-associated steatohepatitis (MASH), viral hepatitis, and other hepatotoxic and hepatocarcinogenic agents. The tumor microenvironment (TME) of HCC is characterized by several different fibroblastic and immune cell types, all of which affect the initiation, progression and metastasis of this malignant cancer. This complex immune TME can be divided into an innate component that includes macrophages, neutrophils, dendritic cells, myeloid-derived suppressor cells, mucosal-associated invariant T cells, natural killer cells, natural killer T cells, and innate lymphoid cells, as well as an adaptive component that includes CD4⁺ T cells, CD8⁺ T cells, regulatory T cells, and B cells. In this review, we discuss the latest findings shedding light on the direct or indirect roles of these immune cells (and fibroblastic-like cells such as hepatic stellate cells) in the pathogenesis of HCC. Henceforth, further characterization of this heterogeneous TME is highly important for studying the progression of HCC and developing novel immunotherapeutic treatment options. In line with this, we also review novel groundbreaking experimental techniques and animal models aimed at specifically elucidating this complex TME and discuss emerging immune-based therapeutic strategies intended to treat HCC and predict the efficacy of these immunotherapies.</p>","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":" ","pages":""},"PeriodicalIF":21.8,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144274287","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":"Immunopathogenic mechanisms and immunoregulatory therapies in MASLD.","authors":"Yong He, Yingfen Chen, Shengying Qian, Schalk van Der Merwe, Debanjan Dhar, David A Brenner, Frank Tacke","doi":"10.1038/s41423-025-01307-5","DOIUrl":"https://doi.org/10.1038/s41423-025-01307-5","url":null,"abstract":"<p><p>Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as nonalcoholic fatty liver disease (NAFLD), is the most prevalent chronic liver disease worldwide, with an estimated global prevalence of approximately 30%; however, effective pharmacotherapies are still limited due to its complex pathogenesis and etiology. Therefore, a more thorough understanding of disease pathogenesis is urgently needed. An increasing number of studies suggest that MASLD and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), are driven by chronic overnutrition, multiple genetic susceptibility factors, and pathogenic consequences, including hepatocyte damage and liver inflammation. Hepatic inflammation is the key event fueling the conversion from simple steatosis to steatohepatitis and fibrosis. Current therapies for MASH, including the recently approved thyroid hormone receptor-beta agonist resmetirom or the available incretin mimetics, mainly target metabolic injury to the liver but not inflammation directly. In this review, we provide an in-depth discussion of current data related to the immunological mechanisms of MASLD and summarize the effects of current and experimental therapies on immunoregulation in MASLD.</p>","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":" ","pages":""},"PeriodicalIF":21.8,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144265385","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":"Transitioning from native to synthetic receptors: broadening T-cell engineering and beyond.","authors":"Li Yu, Yue Liu, Xin Lin","doi":"10.1038/s41423-025-01304-8","DOIUrl":"https://doi.org/10.1038/s41423-025-01304-8","url":null,"abstract":"<p><p>T-cell immunotherapy has progressed rapidly, evolving from native T-cell receptor biology to the development of innovative synthetic receptors that extend therapeutic applications beyond cancer. This review explores engineering strategies, ranging from natural TCRs to synthetic receptors, that increase T-cell activation and therapeutic potential. We begin by highlighting the foundational role of native receptors in the T-cell response, emphasizing how these structural and functional insights inform the design of next-generation synthetic receptors. Comparisons between CAR and TCR-like synthetic receptors underscore their respective advantages in specificity, efficacy, and safety, as well as potential areas for further improvement. In addition, gene editing technologies such as CRISPR-Cas9 enable precise modifications to the T-cell genome, enhancing receptor performance and minimizing immunogenic risks. In addition to tumors, these engineered T cells can be directed against viral infections, autoimmune disorders, and other diseases. We also explore advanced strategies that engage multiple immune cell types to achieve synergistic, durable responses. By demonstrating how native and synthetic receptors collectively drive innovation, this review aims to inspire new research directions and ultimately expand the scope of T-cell engineering for universal therapeutic applications.</p>","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":" ","pages":""},"PeriodicalIF":21.8,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144246716","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":"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":"<p><p>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 Ly6C^hiCCR2⁺ 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.</p>","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}

{"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":"<p><p>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.</p>","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}

{"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":"<p><p>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.</p>","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}

{"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":"<p><p>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.</p>","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}