Cellular &Molecular Immunology最新文献

{"title":"Cathepsin C orchestrates RSV-induced asthma exacerbation through the dual effect of monocyte-derived macrophages.","authors":"Xizi Du, Xinyu Wu, Lin Yuan, Huaiqing Luo, Leyuan Wang, Huijun Liu, Ye Yao, Siqi Yao, Qiuyan Qin, Qianyu Zhao, Dan Liu, Yang Xiang, Xiaoqun Qin, Ming Yang, Weining Xiong, Chi Liu","doi":"10.1038/s41423-026-01423-w","DOIUrl":"https://doi.org/10.1038/s41423-026-01423-w","url":null,"abstract":"<p><p>Asthma exacerbations (AEs), especially those triggered by respiratory syncytial virus (RSV), remain clinically intractable because of limited treatment options and significant immune heterogeneity. In this study, we investigated the central cellular and molecular mechanisms driving RSV-induced AEs using a house dust mite-sensitized mouse model. Through macrophage depletion, transcriptomic profiling, and pathway inhibition, we identified monocyte-derived macrophages (Mo-Mφs) as key orchestrators of both antiviral responses and inflammatory amplification. Mechanistically, Mo-Mφs upregulate and secrete cathepsin C (CTSC), which in turn activates a previously unrecognized PR3/p38/RELB signaling axis. This axis established a positive feedback loop, sustaining macrophage activation and pathogenic inflammation. Pharmacological inhibition of CTSC disrupted this loop, leading to reduced lung inflammation, mucus hypersecretion, and airway hyperresponsiveness. However, this intervention was accompanied by a measurable compromise in antiviral immunity. This study reveals a previously unrecognized CTSC-driven positive feedback loop in Mo-Mφs as a core pathogenic mechanism underlying RSV-induced AE. These findings identify CTSC as a promising mechanism-based therapeutic target, highlighting the need to carefully balance inflammation control against the preservation of antiviral immunity.</p>","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":" ","pages":""},"PeriodicalIF":19.8,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147855935","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":"USP21 drives immune evasion in colorectal cancer via deubiquitination and stabilization of β-catenin.","authors":"Mantang Zhou, Anqi Han, Bingjie Guan, Menghua Zhou, Changsong Zheng, Jianjun Xiang, Yushuai Mi, Bowen Xie, Peng Lian, Sanjun Cai, Xinxiang Li, Jieyun Zhang, Dawei Li, Dongwang Yan, Senlin Zhao","doi":"10.1038/s41423-026-01419-6","DOIUrl":"https://doi.org/10.1038/s41423-026-01419-6","url":null,"abstract":"<p><p>The efficacy of immune checkpoint blockade (ICB) therapy in colorectal cancer (CRC) remains limited. Thus, elucidating the molecular mechanisms underlying tumor immune evasion and identifying novel predictive biomarkers are critical for improving immunotherapy outcomes in CRC patients. Here, we report that ubiquitin-specific peptidase 21 (USP21) is overexpressed in tumor tissues from CRC patients who fail to respond to immunotherapy and that its expression is correlated with CD8⁺ T-cell exclusion and impaired antitumor immunity. To functionally validate these clinical observations, we employed syngeneic mouse models of both microsatellite instability-high (MSI-H) and microsatellite stable (MSS) CRC. Genetic ablation of Usp21 or treatment with the USP21 inhibitor BAY-805 significantly enhanced tumor-reactive CD8⁺ T-cell responses, suppressed tumor progression, and synergized with anti-PD-1 therapy. Mechanistically, USP21 stabilized β-catenin by removing K48-linked ubiquitin chains, enabling its nuclear translocation and binding to the ATF3 promoter to upregulate ATF3 expression. ATF3 subsequently mediated transcriptional repression of the chemokine CCL4, thereby limiting CD8⁺ T-cell trafficking and function via the CCL4-CCR5 axis. Importantly, the therapeutic potential of targeting USP21 to enhance anti-PD-1 efficacy was further validated in huCD34⁺ humanized mice. Collectively, our findings identify USP21 as a pivotal regulator of immune evasion, and inhibiting USP21 represents a promising adjuvant strategy to increase the efficacy of ICB in CRC.</p>","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":" ","pages":""},"PeriodicalIF":19.8,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147833700","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":"Dual CAR-T cell therapy targeting CD19 and BCMA as a novel opportunity for immune reset in systemic lupus erythematosus.","authors":"Sascha Haubner, Michel Sadelain","doi":"10.1038/s41423-026-01403-0","DOIUrl":"https://doi.org/10.1038/s41423-026-01403-0","url":null,"abstract":"","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":" ","pages":""},"PeriodicalIF":19.8,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147833721","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":"Defining the rules of engagement: B cells, antibodies and cancer control.","authors":"Stephen L Nutt, Julie Tellier, Jessica Da Gama Duarte","doi":"10.1038/s41423-026-01422-x","DOIUrl":"https://doi.org/10.1038/s41423-026-01422-x","url":null,"abstract":"<p><p>Immunotherapy has emerged as one of the mainstays of cancer therapy. To date, immunotherapy research has focused heavily on approaches to modulate the anti-tumor activities of T cells, with other immune components of the tumor microenvironment, including B cells, receiving considerably less attention. Mounting evidence has shown that B cells, plasma cells, and the antibodies they produce can impact tumor control. B cells can have both anti-tumor activity, particularly when organized into tertiary lymphoid structures, and pro-tumorigenic roles in some settings. The rules underlying the complex interplay between B cells, other components of the tumor microenvironment, and the cancer cells themselves are only now being elucidated, but anti-tumor activity appears to be associated with distinct B-cell subpopulations and differentiation trajectories, as well as depending on the class of antibodies produced. Thus, the differentiation state of tumor-infiltrating B cells and the quality of antibodies produced may serve as prognostic markers of favorable patient outcomes. This review focuses on recent research that highlights how B-cell heterogeneity influences anti-cancer immunity and how this knowledge could be harnessed to develop B-cell-based immunotherapies and to fully utilize the power of antibody-based cancer diagnosis and patient stratification.</p>","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":" ","pages":""},"PeriodicalIF":19.8,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147833742","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":"Short-, medium-, versus long-chain fatty acids: mechanisms of immunomodulation and disease pathogenesis.","authors":"Chang H Kim","doi":"10.1038/s41423-026-01412-z","DOIUrl":"https://doi.org/10.1038/s41423-026-01412-z","url":null,"abstract":"<p><p>Fatty acids, such as short-chain fatty acids, medium-chain fatty acids and long-chain fatty acids, exist in different chain lengths and with various modifications, which determine their physical, metabolic and biological properties. They serve as important nutrients in energy production via mitochondrial beta-oxidation in various cell types including immune cells. At optimal levels in the body, fatty acids support normal differentiation and function of immune cells. However, at excessive levels, they can cause dysregulation of immune cells and inflammation. The three types of fatty acids regulate cells, in part, via the activation of G protein-coupled receptors, such as GPR41, GPR43, GPR109A, and Olfr78 for short-chain, GPR40 and GPR120 for both medium- and long-chain fatty acids, and GPR84 for medium-chain fatty acids. Activation of these receptors by fatty acids regulates cell proliferation and cell-specific functions. Importantly, fatty acids induce the production of glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide through activation of G-protein coupled receptors. Short-chain fatty acids additionally control epigenetic regulators such as histone deacetylases and histone acetyltransferases. Saturated long-chain fatty acids and omega-6 polyunsaturated fatty acids are implicated in metabolic diseases and inflammatory conditions, whereas short-chain fatty acids, monounsaturated fatty acids, and omega-3 polyunsaturated fatty acids are generally associated with functional immunity with anti-inflammatory effects. This article explores how fatty acids regulate the immune system, focusing on their common and unique roles, as well as their opposing functions.</p>","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":" ","pages":""},"PeriodicalIF":19.8,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147763949","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":"De novo engineered disulfide bond supersedes native interchain linkage to enhance TCR pairing and anti-tumor efficacy in T cell therapy.","authors":"Dan Su, Fan Zhu, Hui Shi, Yang Yuan, Jue Wang, Xiaoqi Yan, Wei Rui, Guangna Liu","doi":"10.1038/s41423-026-01418-7","DOIUrl":"https://doi.org/10.1038/s41423-026-01418-7","url":null,"abstract":"<p><p>T-cell receptor-engineered T (TCR-T) cell therapy is considered highly promising for treating solid tumors. However, it still has significant limitations; one is exogenous-endogenous TCR chain mispairing, which could substantially compromise cell surface expression and the efficacy of the engineered TCR while raising clinical safety concerns. To address this obstacle, we developed a disulfide-substituted TCR (DSS-TCR), in which the native disulfide bond is replaced with artificially designed disulfide bonds within constant domains to increase the fidelity and functionality of TCR pairing. Our study demonstrated that ablation of the native interchain disulfide bond significantly reduces mispairing but severely impairs tumor-killing activity. Using structure-guided computational prediction, we designed nine pairs of artificial interchain disulfide bond-forming sites within TCR constant domains de novo. When introduced into native disulfide-deficient TCRs, four pairs reversed the decrease in cell surface expression. Notably, compared with the wild-type human TCR, two of them significantly enhanced both TCR surface expression and cytotoxic activity. By further combining different pairs of mutations and incorporating hydrophobic substitutions in the α-chain transmembrane domain, DSS-TCRs achieved superior pairing efficiency and antitumor efficacy that were comparable to those of TCRs incorporating mouse-derived constant regions. DSS-TCR significantly decreases the TCR mismatching rate while theoretically reducing immunogenicity. This superior optimization effect was also confirmed for other TCR-based receptors. Therefore, this engineering approach offers a safer and more potent paradigm for TCR-based T-cell therapeutics.</p>","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":" ","pages":""},"PeriodicalIF":19.8,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147763944","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":"Inhibition of glycosphingolipid synthesis overcomes the steric hindrance of CD30 N-glycans to augment CD30-targeted immunotherapeutic efficacy.","authors":"Yuting Pan, Yixin Chang, Wanjun Zhang, Xueting Qin, Chunmeng Wang, Nannan Lu, Jing Nie, Weidong Han","doi":"10.1038/s41423-026-01421-y","DOIUrl":"https://doi.org/10.1038/s41423-026-01421-y","url":null,"abstract":"<p><p>CD30-targeted chimeric antigen receptor (CAR) T-cell therapy faces clinical challenges in classical Hodgkin lymphoma (cHL). While current optimization strategies focus on CAR design, manufacturing protocols, and preconditioning regimens, tumor-intrinsic resistance mechanisms remain poorly understood. Our study revealed that CD30 in cHL cells is associated with N-glycans at Asn101 and Asn276, which are essential for protein stability but do not affect cell proliferation or apoptosis. Genetic ablation of these N-glycans or enzymatic deglycosylation significantly enhanced CD30-targeted CAR-T-cell accessibility to tumor cells, leading to improved T-cell activation and cytotoxic function. Notably, pretreatment with eliglustat, an FDA-approved glycosphingolipid synthesis inhibitor, selectively potentiated the antitumor activity of CD30-targeted CAR-T cells in wild-type CD30-expressing tumors but had minimal effects on CD30 glycosylation-deficient variants. Eliglustat combined with CD30-targeted CAR-T cells resulted in superior tumor control in xenograft models without additional toxicity. Mechanistically, eliglustat trimmed terminal sialic acids from CD30 N-glycans while preserving the core N-glycan structure. Furthermore, the addition of eliglustat also enhanced the tumor-killing activity of brentuximab vedotin (BV), a CD30-directed antibody-drug conjugate, both in vitro and in vivo. This glycoimmunotherapy paradigm represents a clinically actionable approach to overcome glycan-mediated immune evasion and enhance therapeutic efficacy in CD30-positive lymphomas.</p>","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":" ","pages":""},"PeriodicalIF":19.8,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147763947","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":"Commentary: Yin and Yang of MAITs in HCC: balancing type 1 vs. type 17 signaling.","authors":"Sarah Beyer, Benjamin Ruf","doi":"10.1038/s41423-026-01416-9","DOIUrl":"https://doi.org/10.1038/s41423-026-01416-9","url":null,"abstract":"","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":" ","pages":""},"PeriodicalIF":19.8,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147763951","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":"Interleukin enhancer binding factor 3 exacerbates cardiac inflammation and injury following myocardial infarction by inhibiting Lys48-linked ubiquitination on HNRNPA2B1 in macrophages.","authors":"Xu Zhang, Peng Wang, Long-Hao Liu, Qiu-Ting Zhang, Yuan-Qing Lv, Hong-Rui Yang, Ya-Min Hou, Na Li, Jie Cheng, Ze-Ying Wang, Ying Wang, Yuan-Fei Zhao, Zhi-Wei Zhao, Ming-Xiang Zhang","doi":"10.1038/s41423-026-01417-8","DOIUrl":"https://doi.org/10.1038/s41423-026-01417-8","url":null,"abstract":"<p><p>Changes in the immune microenvironment are key features of ischemic heart disease. In particular, excessive inflammatory responses driven by macrophages are the primary cause of myocardial injury, impaired repair and deterioration of cardiac function following myocardial infarction (MI). We report that interleukin enhancer binding factor 3 (ILF3) is a key regulator that mediates immune responses in macrophages. We found that ILF3 expression was significantly upregulated in macrophages from AMI patients and animal models. This was accompanied by increased levels of inflammation and cardiac dysfunction. ILF3 deficiency in myocardial infarction mice promoted the resolution of inflammatory responses while improving cardiac function and mitigating adverse remodeling. Mechanistically, macrophage ILF3 inhibits Trim21-mediated ubiquitination and degradation of HNRNPA2B1 (heterogeneous nuclear ribonucleoprotein A2B1) at lysine 112 through binding to the RRM1 and RRM2 domains of HNRNPA2B1. The ILF3/HNRNPA2B1 axis enhances the stability of Irak4 mRNA through m6A modification, activating the c-jun/c-fos pathway, leading to early inflammatory responses following MI, and promoting myocardial injury and adverse remodeling after infarction. Finally, our results suggest that targeting HNRNPA2B1 and Irak4 effectively improves myocardial injury and cardiac repair post-MI. In summary, our findings underscore the critical role of macrophage ILF3 in mediating postinfarction inflammation in myocardial injury. These findings suggest that inhibition of macrophage ILF3 may be an important target for the treatment of ischemic myocardial injury and inflammation. During the inflammatory phase of myocardial infarction, ILF3 levels are elevated in macrophages. Macrophage ILF3 inhibits the ubiquitination and degradation of HNRNPA2B1. The latter increases the stability of Irak4 mRNA through m6A modification, activating the c-jun/c-fos pathway, leading to early inflammatory responses, and promoting myocardial injury and adverse remodeling. When ILF3 is absent in macrophages, HNRNPA2B1 is degraded by Trim21-mediated ubiquitination, subsequently inhibiting inflammation-related signaling pathways, alleviating myocardial damage, and promoting repair.</p>","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":" ","pages":""},"PeriodicalIF":19.8,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147763893","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":"EZH2 and intracellular Ca²⁺ signals interdependently coordinate alloreactive and CAR-T-cell responses.","authors":"Ying Wang, Qingrong Huang, Yan Zhou, Robert Hooper, Ruqayyah Sanders-Braggs, Mimi Chen, Yuanyuan Tian, Tatiana Kent, Richard Pomerantz, Gennaro Clando, Woonbok Chung, Jean-Pierre J Issa, Jonathan Soboloff, Yi Zhang","doi":"10.1038/s41423-026-01413-y","DOIUrl":"https://doi.org/10.1038/s41423-026-01413-y","url":null,"abstract":"<p><p>In graft-versus-host disease (GVHD), Ca²⁺ signals in alloreactive T cells are carefully controlled to determine whether cells survive or thrive, although how this is accomplished during GVHD remains poorly defined. We demonstrate that EZH2, a chromatin-modifying enzyme, promotes alloreactive T-cell survival in GVHD by acting as a Ca²⁺ signaling brake to limit excessive intracellular Ca²⁺ responses. Ezh2 loss led to the upregulation of gene programs that promote effector differentiation in activated T cells, coincident with enhanced intracellular Ca²⁺ responses that ultimately caused massive cell death. Conditional deletion of Stim1 (required for cytosolic Ca²⁺ entry) led to \"synthetic rescue\" of Ezh2-null T cells by protecting them from cell death without interfering with effector differentiation, resulting in severe GVHD. Interestingly, Stim1 expression was unaffected by EZH2, whereas the expression of the endoplasmic reticulum Ca²⁺ release channel inositol 1,4,5-trisphosphate receptor 2 (Itpr2) was suppressed by EZH2. Notably, EZH2 and Ca²⁺ signals served mutually opposing roles in controlling the expression of genes in chimeric antigen receptor (CAR) T cells. Inhibiting Ca²⁺ signaling restored EZH2 function in CAR-T cells, significantly improving their antitumor activity. Our findings reveal the interdependent roles of EZH2 and Ca²⁺ signals in coordinating antigen-activated T-cell responses that mediate alloimmunity and tumor immunity.</p>","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":" ","pages":""},"PeriodicalIF":19.8,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147763891","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}