Cellular &Molecular Immunology最新文献

{"title":"CD2 augmentation enhances CAR-T-cell efficacy via immunological synapse remodeling and T-cell exhaustion mitigation","authors":"Qi Zhu, Jiajia Li, Nan Liu, Lu Han, Zhiqiang Wu, Yao Wang, Xin Lin, Jianshu Wei, Weidong Han","doi":"10.1038/s41423-025-01314-6","DOIUrl":"10.1038/s41423-025-01314-6","url":null,"abstract":"CAR-T-cell therapy has made significant strides in treating hematological malignancies, yet its efficacy is often hampered by suboptimal T-cell functionality, marked by weak antitumor capabilities and a lack of durability. The immunological synapse, a key determinant of T-cell function, is influenced by the CD58-CD2 axis. The dynamic regulation of CD2 expression on T cells impacts the quality of CAR-mediated immunological synapses, affecting CAR-T-cell functional outcomes and differentiation. Our study demonstrated that CD2 expression levels are closely linked to the quality of immunological synapses formed by CAR-T cells and their antitumor potency. Exogenous CD2 supplementation enhances the ability of CAR-T cells to form high-quality synapses, reduces T-cell exhaustion, and increases sustained antitumor efficacy. Additionally, ectopic CD2 expression increases CAR-T-cell sensitivity to low-density antigens. Thus, replenishing CD2 in CAR-T cells is a promising strategy to increase the therapeutic efficacy of CAR-T-cell therapy.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 8","pages":"935-948"},"PeriodicalIF":19.8,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12311108/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144564634","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":"Metabolic reprogramming via FOXP3 engineering: A Novel strategy to enhance CAR-T cell efficacy in solid tumors","authors":"Dan Li, Siyuan Qiang, Bin Li","doi":"10.1038/s41423-025-01315-5","DOIUrl":"10.1038/s41423-025-01315-5","url":null,"abstract":"","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 8","pages":"809-810"},"PeriodicalIF":19.8,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144559351","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":"Human liver immunology: from in vitro models to new insights","authors":"Milad Rezvani","doi":"10.1038/s41423-025-01312-8","DOIUrl":"10.1038/s41423-025-01312-8","url":null,"abstract":"The liver hosts a variety of immune cells while creating a tolerogenic environment under homeostatic conditions. However, most chronic liver diseases shift toward inflammation over time. Understanding and intercepting the crosstalk between various immune cells and liver tissue is crucial, as it is often the rate-limiting factor in preclinical drug development. Owing to significant interspecies differences in liver immunology, human models, such as classical cocultures or organogenesis-inspired liver organoids with immune compartments, are becoming essential for advancing the field. Therefore, this review evaluates human-specific models of hepatic-immune crosstalk and assesses a range of models from basic 2D cultures to microphysiological systems (MPSs) and advanced multitissue organoids. It serves as a guide for experimentalists to identify suitable approaches. For example, traditional cocultures offer robustness, reductionist approaches, and modularity but have limited spatial fidelity and cell heterogeneity. In contrast, multitissue organoids inspired by mammalian ontogeny are created from pluripotent stem cells and integrate multiple tissue niche-constituting cells, which include Kupffer-like cells. In conclusion, this review discusses progress in human liver immunology modeling and highlights limitations and numerous untapped opportunities. These include the potential to model in vitro autoimmunity and more complex myeloid inflammatory responses, incorporating contributions from embryonic tissue and bone marrow. Additionally, future in vitro models may include hard-to-culture populations such as neutrophils.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 10","pages":"1226-1236"},"PeriodicalIF":19.8,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41423-025-01312-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144552479","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":"Inflammation and immunity in liver homeostasis and disease: a nexus of hepatocytes, nonparenchymal cells and immune cells","authors":"Enis Kostallari, Robert F. Schwabe, Adrien Guillot","doi":"10.1038/s41423-025-01313-7","DOIUrl":"10.1038/s41423-025-01313-7","url":null,"abstract":"The liver is a central hub in lipid, carbohydrate and protein metabolism and protects against gut-derived antigens and toxins. The etiology of liver diseases includes altered metabolism, viral infections, autoimmunity, toxins and genetic alterations. Liver-resident cells, including hepatocytes, biliary epithelial cells, endothelial cells, and hepatic stellate cells, are essential for liver function and homeostasis but may also drive the development of inflammation, fibrosis, cirrhosis and liver cancer via interactions with immune cells. This review highlights the often-underappreciated contributions of epithelial, endothelial and mesenchymal liver cells in regulating inflammation and immunity across various liver diseases, emphasizing their importance in disease onset, progression and regression. Immune cells and their mediators also play a role in stimulating liver regeneration and repair following injury. Recent findings on the bidirectional interactions between immune cells and resident liver cells provide deeper insights into the underlying pathophysiology and identify novel therapeutic targets for the treatment of liver disease.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 10","pages":"1205-1225"},"PeriodicalIF":19.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41423-025-01313-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144539159","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":"Multiscale dynamic immunomodulation by a nanoemulsified Trojan-TLR7/8 adjuvant for robust protection against heterologous pandemic and endemic viruses","authors":"Yeon Jeong Yoo, Suhyeon Kim, Asha Wickramasinghe, Jaemoo Kim, JuA Song, Young-Il Kim, Juryeon Gil, Young-Woock Noh, Min-Ho Lee, Sang-Seok Oh, Myeong-Mi Lee, Yebin Seong, Jong-Soo Lee, Young Ki Choi, Yong Taik Lim","doi":"10.1038/s41423-025-01306-6","DOIUrl":"10.1038/s41423-025-01306-6","url":null,"abstract":"The demand for safe vaccines that ensure long-term and broad protection against multiple viral variants has dramatically increased after the emergence of catastrophic infectious diseases such as COVID-19. To ensure long-term and broad protection against heterologous virus variants, antigen-specific polyfunctional T cells should be orchestrated with the activation of follicular helper T (TFH) cells and germinal center (GC) B cells. Herein, we suggest a novel engineered nanoadjuvant (SE(Trojan-TLR7/8a)) that enhances the migration of nonexhausted antigen-presenting cells (APCs) into lymph nodes and elicits the activation of TFH cells, the generation of GC B cells, and polyfunctional T cells via multiscale dynamic immunomodulation through squalene nanoemulsion (SE)-mediated macroscopic control of vaccine delivery and Trojan-TLR7/8a-enabled dynamic and sustained activation of APCs at the cellular level. SE(Trojan-TLR7/8a) can be lyophilized, reduce systemic toxicity, and outperform current commercial vaccine adjuvants (Alum or AS03) and mRNA vaccines. SE(Trojan-TLR7/8a) ensures cross-protection against diverse influenza and SARS-CoV-2 variants, providing 100% protection while maintaining a healthy state. SE(Trojan-TLR7/8a) also sustains a potent T-cell response in an aged ferret model of SFTSV infection. SE(Trojan-TLR7/8a) suggested herein provides a novel vaccine design principle for dynamic modulation at the multiscale level and demonstrates long-term and broad protective immunity against emerging pandemic and endemic infectious viruses.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 9","pages":"1045-1060"},"PeriodicalIF":19.8,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12398497/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144494921","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":"FXR inhibition functions as a checkpoint blockade of the pathogenic Tfh cell response in lupus","authors":"Xiangyang Wang, Linsen Ye, Shanshan Liu, Yuhao Zheng, Lisi Zhu, Wenqian Huang, Jiawei Song, Jingxuan Shao, Fan Wu, Chunmin Zhang, Xiaomin Li, Shan Zeng, Youjun Xiao, Xiangyu Chen, Shunjun Fu, Lilin Ye, Jie Zhou, Yingjiao Cao","doi":"10.1038/s41423-025-01309-3","DOIUrl":"10.1038/s41423-025-01309-3","url":null,"abstract":"T follicular helper (Tfh) cells specialize in facilitating germinal center B-cell activation and high-affinity antibody generation, which are crucial in humoral immune responses. However, aberrant control of Tfh cells also contributes to the generation of self-reactive autoantibodies and promotes autoimmune diseases such as systemic lupus erythematosus (SLE). The mechanisms that control proper Tfh expansion remain unclear. Here, we show that farnesoid X receptor (FXR) is relatively upregulated in Tfh cells. Genetic deletion of Fxr restrains Tfh expansion both at steady state and in pristane-induced lupus. As a consequence of these defects, mice lacking Fxr manifested GC dysfunction and decreased plasma cell and autoantibody production, which alleviated nephritis progression in pristane-induced lupus. Mechanistically, FXR intrinsically regulates cholesterol homeostasis in Tfh cells, which subsequently controls Tfh cell proliferation. Preclinical treatment of wild-type (WT) mice with the clinically approved drug ursodeoxycholic acid (UDCA) to reduce FXR signaling mitigated lupus disease progression by repressing Tfh expansion, the GC reaction and autoantibody production. These findings provide a rationale for exploring FXR as a potential therapeutic target for SLE.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 8","pages":"889-900"},"PeriodicalIF":19.8,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144494920","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":"NF-κB in inflammation and cancer","authors":"Hongmei Mao, Xiaocui Zhao, Shao-cong Sun","doi":"10.1038/s41423-025-01310-w","DOIUrl":"10.1038/s41423-025-01310-w","url":null,"abstract":"Nuclear factor-κB (NF-κB) is a family of transcription factors that transactivates genes associated with a wide range of biological processes, including immune responses, inflammation, cell growth and survival. Dysregulated NF-κB activation contributes to acute and chronic inflammatory disorders, mostly through the aberrant induction of genes encoding proinflammatory factors and metabolic disorders. Abnormal NF-κB activation also influences the development and stability of regulatory T cells, contributing to the pathogenesis of autoimmune disorders. Given the critical role of inflammation in promoting oncogenesis, the proinflammatory role of NF-κB is also linked to cancer development. In addition, aberrant NF-κB activation contributes to uncontrolled tumor cell proliferation, survival, metabolism, metastasis, tumor angiogenesis and therapy resistance. These pathological functions of NF-κB highlight its potential as a therapeutic target for both inflammatory diseases and cancer. In this review, we summarize recent findings regarding the role of NF-κB in these pathological processes and discuss the underlying mechanisms. We also explore potential therapeutic strategies aimed at targeting the NF-κB pathway for disease treatment, along with an analysis of possible challenges.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 8","pages":"811-839"},"PeriodicalIF":19.8,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12310982/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144494922","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":"CD39 as a metabolic rheostat of immunoregulation","authors":"Vincenzo Barnaba, Silvano Sozzani","doi":"10.1038/s41423-025-01302-w","DOIUrl":"10.1038/s41423-025-01302-w","url":null,"abstract":"","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 7","pages":"806-808"},"PeriodicalIF":19.8,"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":"10.1038/s41423-025-01296-5","url":null,"abstract":"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. Our study uncovers a dynamic immunoregulatory role of dermal white adipose tissue (dWAT) in the progression and resolution of neutrophilic skin inflammation in an imiquimod-induced psoriatic mouse model. Initially, dWAT undergoes lipolysis and expands preadipocytes (pAds) secreting CXCL1/SAA3 to recruit neutrophils, which amplify inflammation via IL1β and activate pAds through the IL1-NFκB-C/EBPδ pathway. Prolonged IL1β exposure triggers PPARγ-dependent differentiation of pAds into early adipocytes, producing anti-inflammatory lipids that resolve neutrophilic inflammation. We also observed a negative correlation between neutrophil-related inflammatory response with dermal lipogenesis is also observed in human psoriasis. These findings highlight dWAT as an immunomodulatory hub, suggesting adipogenic reprogramming or lipid delivery as novel psoriasis therapies.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 8","pages":"901-917"},"PeriodicalIF":19.8,"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":"10.1038/s41423-025-01305-7","url":null,"abstract":"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.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 8","pages":"918-934"},"PeriodicalIF":19.8,"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}