Cellular &Molecular Immunology最新文献

{"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":"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":"712-729"},"PeriodicalIF":21.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12206924/pdf/","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":"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":"https://doi.org/10.1038/s41423-025-01313-7","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":" ","pages":""},"PeriodicalIF":21.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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, Yong Ki Choi, Yong Taik Lim","doi":"10.1038/s41423-025-01306-6","DOIUrl":"https://doi.org/10.1038/s41423-025-01306-6","url":null,"abstract":"<p><p>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 (T_FH) 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 T_FH 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.</p>","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":" ","pages":""},"PeriodicalIF":21.8,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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":"<p><p>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.</p>","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":" ","pages":""},"PeriodicalIF":21.8,"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":"https://doi.org/10.1038/s41423-025-01310-w","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":" ","pages":""},"PeriodicalIF":21.8,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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":"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":"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}