Signal Transduction and Targeted Therapy最新文献

{"title":"Single amino acid substitution in Hendra virus attachment glycoprotein induces cross-neutralizing antibodies against Nipah virus","authors":"Yaohui Li, Xiaoyan Huang, Ruihua Li, Xiaodong Zai, Yilong Yang, Yue Zhang, Zhang Zhang, Jun Zhang, Junjie Xu, Wei Chen","doi":"10.1038/s41392-025-02370-0","DOIUrl":"https://doi.org/10.1038/s41392-025-02370-0","url":null,"abstract":"<p>Nipah virus (NiV) and Hendra virus (HeV) are highly pathogenic henipaviruses within the Paramyxoviridae family, causing severe respiratory and neurological diseases in humans and animals with fatality rates up to 75%, and no licensed human vaccines or therapeutics. In this study, we identified a unique vulnerable epitope on the NiV attachment glycoprotein (G) recognized by the potent neutralizing antibody 14F8, which targets a receptor-binding site and neutralizes NiV effectively. Using the 2.8 Å crystal structure of the 14F8 Fab–NiV-G complex as a guide, we reconstructed this epitope on HeV-G via a single amino acid substitution (S586N), creating the HeV-G_S586N mutant. Immunization with HeV-G_S586N in BALB/c mice and cynomolgus monkeys elicited robust, broadly neutralizing antibody responses against both NiV and HeV, achieving higher NiV-neutralizing titers post-prime compared to wild-type HeV-G, as confirmed by pseudovirus and live-virus assays. Crystal structures of HeV-G_S586N (3.3 Å) and its 14F8 complex (3.2 Å) showed the S586N substitution induced a 9 Å conformational rearrangement in β-propeller blade 6, reshaping the molecular skeleton and solvent-accessible surface without direct N586–14F8 interaction, thus mimicking the NiV epitope. These findings position HeV-G_S586N as a promising broad-spectrum antigen for henipavirus prevention and demonstrate the value of structure-guided epitope reconstruction in universal vaccine design for emerging viral threats.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"55 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144915406","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":"Disarming a molecular brake: cAMP-responsive element modulator deletion supercharges CAR-NK cells","authors":"Sudheendra Hebbar Subramanyam, Klaus Tenbrock","doi":"10.1038/s41392-025-02362-0","DOIUrl":"https://doi.org/10.1038/s41392-025-02362-0","url":null,"abstract":"<p>In a recent study published in <i>Nature</i>, Rafei and colleagues identified the transcription factor cAMP responsive element modulator (CREM) as an important regulator in natural killer (NK) cells that have been engineered with Chimeric antigen receptors (CARs). Their study demonstrated that CREM integrates signals from CAR activation and from interleukin-15 (IL-15) stimulation and serves as a molecular brake that limits CAR-NK functionality.¹</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"22 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144910844","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":"Transforming acidic coiled-coil-containing protein 3-mediated lipid metabolism reprogramming impairs CD8+ T-cell cytotoxicity in hepatocellular carcinoma","authors":"Ying Li, Zule Chen, Dongdong Wang, Wei Du, Ningqi Zhu, Xiaotian Shen, Xiang Mao, Yinghan Su, Lunxiu Qin, Diyu Chen, Huliang Jia","doi":"10.1038/s41392-025-02367-9","DOIUrl":"https://doi.org/10.1038/s41392-025-02367-9","url":null,"abstract":"<p>Recent evidence has highlighted immune checkpoint inhibitors as among the most promising immunotherapies for various malignancies. However, a significant proportion of HCC patients exhibit poor responses. Lipid metabolic heterogeneity is considered a key driver of cancer progression. However, the role of lipid metabolic reprogramming in HCC immunotherapy resistance remains poorly understood. Herein, we aimed to illuminate the potential relationship between lipid metabolic reprogramming and ICI resistance and provide novel strategies to increase the HCC immunotherapy response. Patients who received PD-1/PD-L1 inhibitors were enrolled. The effect of TACC3 on the tumor microenvironment was validated via single-cell RNA sequencing in HCC-bearing mouse models. Targeted metabolomics was performed to analyze the regulatory role of TACC3 in HCC metabolism. To address HCC immunotherapy resistance, we developed a targeted nucleic acid therapeutic utilizing N-acetylgalactosamine (GalNAc) to conjugate siTACC3. Through clinical cohort analysis, we found that TACC3 was overexpressed in HCC patients with poor response to immunotherapy. Furthermore, we demonstrated that silencing tumor-derived TACC3 optimizes the cytotoxicity of infiltrating CD8⁺ T lymphocytes. Both in vitro and in vivo assays suggested that TACC3 maintains ACSL4-mediated polyunsaturated fatty acid (PUFA) metabolism in HCC cells. Additionally, TACC3 accelerates ACSL4 expression by interacting with LARP1 and PABPC1, which stabilize ACSL4 mRNA. The results of preclinical models demonstrated the satisfactory efficacy of GalNAc-conjugated siTACC3 combined with PD-1 inhibitor therapy for HCC. In summary, tumor-derived TACC3 impairs the tumor-killing activity of CD8⁺ T lymphocytes through PUFA metabolism-associated crosstalk. Targeting TACC3 represents a novel and practicable strategy to augment ICI efficacy against HCC.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"24 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144910845","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":"Adjuvant icotinib for resected EGFR-mutated stage II–IIIA non-small-cell lung cancer (ICTAN, GASTO1002): a randomized comparison study","authors":"Ning Li, Wei Ou, Chao Cheng, Jian You, Lin Yang, Feng-Xia Chen, Yi Liang, Zhixiong Yang, Bao-Xiao Wang, Zeng-Hao Chang, Yao-Bin Lin, Weixiong Yang, Feng Xu, Guanggui Ding, Xian-Shan Chen, Ronggui Hu, Shujun Li, Hao Jiang, Xin-Xin Hu, Hao Long, Si-Yu Wang","doi":"10.1038/s41392-025-02358-w","DOIUrl":"https://doi.org/10.1038/s41392-025-02358-w","url":null,"abstract":"<p>The efficacy, safety and ideal treatment duration of an adjuvant epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) for patients with resected EGFR-mutated non-small-cell lung cancer (NSCLC) were not known until 2014, when this study was initiated. In this phase 3 ICTAN trial (GASTO1002, NCT01996098), patients with completely resected, EGFR-mutated, stage II-IIIA NSCLC after adjuvant chemotherapy were assigned in a 1:1:1 ratio to receive icotinib (125 mg, three times daily) for 12 months, to receive icotinib for 6 months, or to undergo observation. The primary endpoint was disease-free survival (DFS). This trial was terminated early. A total of 251 patients were randomized. Adjuvant icotinib for 12 months significantly improved DFS (hazard ratio [HR]: 0.40, 95% confidence interval [CI], 0.27–0.61; <i>P</i> &lt; 0.001) and overall survival (OS; HR: 0.55, 95% CI, 0.32–0.96; <i>P</i> = 0.032) compared with observation. Adjuvant icotinib of 6 months also significantly improved DFS (HR: 0.41, 95% CI, 0.27–0.62; <i>P</i> &lt; 0.001) and OS (HR: 0.56, 95% CI, 0.32–0.98; <i>P</i> = 0.038) compared with observation. Adjuvant icotinib for 12 months did not improve DFS (HR: 0.97; <i>P</i> = 0.89) or OS (HR: 1.00; <i>P</i> = 0.99) compared with 6 months of this drug. Rates of adverse events of grade 3 or higher were 8.3%, 6.0% and 2.4% for the 12-month icotinib, 6-month icotinib, and observation groups, respectively. Adjuvant icotinib for 12 months or 6 months following adjuvant chemotherapy improved DFS and OS compared with observation in patients with resected EGFR-mutated stage II-IIIA NSCLC with a manageable safety profile, supporting it as a potential treatment option.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"1 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144910847","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":"Enrichment of Streptococcus oralis in respiratory microbiome enhance innate immunity and protects against influenza infection","authors":"Xiaohui Zou, Hongyun Cao, Lizhe Hong, Lijun Suo, Chun Wang, Kang Chang, Yawen Ni, Bo Liu, Bin Cao","doi":"10.1038/s41392-025-02365-x","DOIUrl":"https://doi.org/10.1038/s41392-025-02365-x","url":null,"abstract":"<p>Respiratory microbial dysbiosis has been implicated in the occurrence and progression of community-acquired pneumonia (CAP). However, the dynamic variation in the respiratory microbiota and its interaction with the host response remain poorly understood. Here, we performed metagenomic analysis of respiratory and gut microbiota, along with blood transcriptomics, using longitudinally collected samples from 38 CAP patients. CAP patients presented disrupted sputum microbiota at the early, middle, and late stages of hospitalization. Microbial pathways involved in peptidoglycan biosynthesis and immune evasion, particularly contributed by the <i>Streptococcus</i> genus, were enriched in CAP patients. Additionally, several <i>Streptococcus</i> strains demonstrated correlation between respiratory and gut microbiota in CAP patients. By incorporating host response data, we revealed that <i>Streptococcus oralis</i> (SOR) was associated with host pathways involved in the innate immune response to infection, and this microbe‒host interaction was reproduced in a newly enrolled CAP cohort consisting of 22 patients with influenza infection. The host-SOR interaction was validated in a mouse model, where SOR demonstrated protective efficacy against influenza virus infection comparable to that of the well-established respiratory probiotic <i>Lactobacillus rhamnosus GG</i>. Preaspiration of SOR in mice significantly mitigated body weight loss, reduced lung inflammation, and lowered viral loads following influenza virus challenge. Host response profiling indicated that SOR priming activated a greater innate immune response at the early stage of infection and that this response resolved timely as the host began to recover. These findings suggest that respiratory commensals play an immune-protective role by inducing a timely innate immune response to prevent CAP progression.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"21 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144905811","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":"Pain management beyond opioids: a β-arrestin2-biased allosteric GPCR modulator opens new avenues for drug development","authors":"Eline Pottie, Sophie A. M. Steinmüller, Michael Decker","doi":"10.1038/s41392-025-02361-1","DOIUrl":"https://doi.org/10.1038/s41392-025-02361-1","url":null,"abstract":"","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"37 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144905809","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":"High fructose consumption aggravates inflammation by promoting effector T cell generation via inducing metabolic reprogramming","authors":"Xiao Ma, Jiao Chen, Fang Wang, Xinzou Fan, Zhenhong Li, Hantian Liang, Hao Cheng, Fang Nan, Yubin Lin, Xiaoshuang Song, Jianan Zhang, Fan Gao, Wei Zhang, Wenwen Jin, Huiyuan Zhang, Jiyu Tong, Hong Jiang, Xikun Zhou, Qiang Zou, Hongbo Hu, Aiping Tong, WanJun Chen, Dunfang Zhang","doi":"10.1038/s41392-025-02359-9","DOIUrl":"https://doi.org/10.1038/s41392-025-02359-9","url":null,"abstract":"<p>The intake of sugars, especially glucose and fructose, has significantly increased with the change of lifestyle. Excessive intake of sugar has been proven to be associated with tumors and inflammatory diseases. Fructose directly mediates innate immune responses; however, whether it can directly regulate T-cell immunity remains unknown. We show that high fructose consumption accelerates the development of inflammatory bowel disease (IBD) by promoting the generation of T helper 1 (Th1) and T helper 17 (Th17) cells. It was demonstrated that fructose promotes the differentiation of Th1 and Th17 cells directly by enhancing mechanistic target of rapamycin complex 1 (mTORC1) activation through the glutamine metabolism-dependent pathway. Reactive oxygen species (ROS)-induced activation of transforming growth factor-β (TGF-β) is also involved in fructose-induced Th17 cell generation. Moreover, metformin can reverse Th1 and Th17 cell generation induced by fructose by suppressing mTORC1 activation and reducing ROS-mediated TGF-β activation. Finally, we identified metformin as an in vivo therapeutic drug for relieving high fructose consumption-induced T-cell inflammation and colitis aggravation. Our study revealed a previously unknown adverse effect of high fructose consumption in disrupting immune homeostasis and exacerbating IBD by directly promoting T-cell immunity, and showed metformin is a potential therapeutic for reversing the T cell immune imbalance caused by long-term high fructose consumption.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"15 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144899059","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":"Ultrasound-enhanced Pt-coordinated polymer immunopotentiators and heterogenic fusion membrane-based multifunctional tumor vaccine nanoplatforms for melanoma treatment","authors":"Ruiqian Guo, Fangxue Du, Xi Xiang, Ziyan Feng, Jianbo Huang, Chuanxiong Nie, Lang Ma, Li Qiu","doi":"10.1038/s41392-025-02355-z","DOIUrl":"https://doi.org/10.1038/s41392-025-02355-z","url":null,"abstract":"<p>A tumor cell membrane (CM)-based biomimetic membrane tumor vaccine is an emerging prevention and treatment strategy in tumor immunotherapy. However, a single CM mostly has a weak immune-boosting effect. Here, a heterogenic fusion membrane tumor vaccine, EV–CM, was successfully constructed by fusing extracellular vesicles (EVs) from <i>S. aureus</i> and CM from B16F10 melanoma cells. Inheriting the advantages of parental components, the EV–CM combines tumor antigens with natural adjuvants that can be used for immunotherapy and can be easily synergistic with complementary therapies. In vivo vaccine tests have shown that EV–CM can activate immune antitumor responses and prevent tumorigenesis. To further enhance the immunotherapeutic and antimetastatic effects of EV–CM, Pt-porphyrin coordination polymer as an immunopotentiator (CPIP) was implanted into an EV<b>–</b>CM nanoplatform (CPIP@EV–CM), which combines localized sonodynamic/chemodynamic therapy-induced immunogenic cell death with heterogenic fusion membrane-mediated antigen-presenting functions. In vitro performance tests, cell experiments, and in vivo animal models have confirmed that the CPIP@EV–CM combined with US has better ROS production, tumor cell killing, and antimetastasis abilities. The heterogenic fusion membrane strategy and ultrasound-augmented nanoplatform present exciting prospects for designing tumor-immunogenic, self-adjuvant, and expandable vaccines, providing new ideas for exploring new melanoma immunotherapy and antimetastasis strategies, which is expected to be used as a safe and effective treatment in clinical practice.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"14 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144899048","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":"Bone marrow microenvironment in autoimmune hemolytic anemia: from trephine biopsy to single cell RNA sequencing","authors":"Bruno Fattizzo, Matteo Claudio Da Vià, Francesca Lazzaroni, Alfredo Marchetti, Alessio Marella, Akihiro Maeda, Antonio Giovanni Solimando, Loredana Pettine, Francesco Passamonti, Niccolò Bolli, Wilma Barcellini","doi":"10.1038/s41392-025-02348-y","DOIUrl":"https://doi.org/10.1038/s41392-025-02348-y","url":null,"abstract":"<p>The role of bone marrow (BM) compensatory response in autoimmune hemolytic anemias (AIHAs) is emerging and inadequate reticulocytosis has been associated with more severe disease and adverse outcomes. However, few is known about the BM immunologic microenvironment composition in these diseases. Here we investigated BM features in a large cohort of 97 patients with autoimmune hemolytic anemia (AIHA) and observed a high prevalence of hypercellularity, dyserythropoiesis, reticulin fibrosis, and T-cell infiltration (65%, 29%, 76%, and 69% of patients, respectively). These findings were associated with inadequate bone marrow compensation, more severe anemia at onset, and need of multiple treatments. In a subset of warm type AIHA patients we investigated BM microenvironment by single-cell RNA sequencing. We found distinct immune cell profiles across disease stages (diagnosis, remission, relapse). In particular, upregulation of inflammatory response pathways was noted in CD8 + , CD4 + , and monocyte subsets during relapse compared to diagnosis and remission. Moreover, by single-cell TCR sequencing, we found small T cell clones at diagnosis that may either disappeared or expanded at remission. Disappearing clones exhibited a naive CD8+ phenotype and were more likely to respond to glucocorticoid treatment. Expanding clones showed upregulation of cytotoxic T cell markers and may play a role in the transition to a chronic/relapsing phase. Finally, cytokine gene expression differed across disease phases. At relapse, pro-inflammatory cytokines such as TNF-alpha, IL-1, and IL-6 were upregulated in CD4+ and CD8 + T cells, while TGF-beta was downregulated, potentially in an attempt to counteract the transition to chronic phase. This is the largest study evaluating BM histology and clinical characteristics, and the first evaluation of BM microenvironment by single-cell RNA sequencing in AIHA. We showed a complex scenario encompassing T-cell infiltration, clonality, and up/down-regulation of cytokine genes, associated with a more severe and relapsing disease.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"20 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144899015","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":"Focal neuropathologies in the brain of COVID-19-infected humans: inflammation, primary gliovascular failure and microglial dysfunction","authors":"Peter Illes, Hai-Yan Yin, Yong Tang","doi":"10.1038/s41392-025-02351-3","DOIUrl":"https://doi.org/10.1038/s41392-025-02351-3","url":null,"abstract":"<p>Dénes and his co-workers recently published a paper in <i>Nature Neuroscience</i>, documenting that neurological abnormalities in COVID are based on microglial dysfunction in the brain.¹ In case of acute respiratory syndrome of COVID infection, the central nervous system symptomatology significantly contribute to the severity of this disease. The authors used an autopsy platform allowing morphological and biochemical/molecular biological investigations in postmortem mirror blocks prepared from the brain and peripheral organs of 13 COVID and 23 non- COVID-infected patients.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"17 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144899117","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}