Signal Transduction and Targeted Therapy最新文献

{"title":"Extracellular vesicle-based drug overview: research landscape, quality control and nonclinical evaluation strategies","authors":"Gangling Xu, Jing Jin, Zhihao Fu, Guangming Wang, Xinhua Lei, Jun Xu, Junzhi Wang","doi":"10.1038/s41392-025-02312-w","DOIUrl":"https://doi.org/10.1038/s41392-025-02312-w","url":null,"abstract":"<p>Extracellular vesicles share lipid‒protein membranes with their parent cells, allowing for the targeted transfer of bioactive cargo to recipient cells for functional modulation. The biological features allow extracellular vesicles to serve both as intrinsic therapeutics and as engineered delivery vehicles for targeted molecule transport. In recent years, extracellular vesicle-based therapy has shown great potential as a new therapeutic approach for traumatic conditions and degenerative, acute, and refractory diseases. As extracellular vesicle engineering continues to evolve, more innovative drugs are expected to receive investigational new drug approvals and marketing approvals from regulatory agencies in the future. However, many challenges exist in terms of mechanistic understanding, engineering modifications, manufacturing processes, quality control, and nonclinical research, and no drug regulatory authorities have currently issued specific technical evaluation guidelines for extracellular vesicle-based drugs, all of which have hindered the clinical translation of these drugs. In this article, which is focused primarily on extracellular vesicles derived from mammalian cells, we summarize the clinical translation and process development research status of extracellular vesicle-based drugs and propose both general considerations and key aspects of quality control strategies and nonclinical evaluations in the development process. The aim of this review is to provide valuable references for the development and evaluation of extracellular vesicle-based products, accelerate the clinical translation process, and benefit patients as soon as possible.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"114 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144840112","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":"Both inhibitory and activating KIRs recognize RIFINs: a dual-edged mechanism of NK cell control in malaria","authors":"Angelica Cuapio, Hans-Gustaf Ljunggren","doi":"10.1038/s41392-025-02341-5","DOIUrl":"https://doi.org/10.1038/s41392-025-02341-5","url":null,"abstract":"<p>In a recent publication in <i>Nature</i>, Sakoguchi et al. reveal a long-sought missing link between pathogen-derived ligands and activating human natural killer (NK) cell receptors.¹ The study identifies a clade of <i>Plasmodium falciparum</i> (<i>P. falciparum</i>) repetitive interspersed family (RIFIN) proteins that not only bind to the inhibitory KIR2DL1 receptor but, strikingly, also engage the activating KIR2DS1 receptor, thereby offering new insight into NK cell regulation in malaria and expanding our understanding of host–pathogen interaction in innate immune responses.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"19 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144825661","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":"Single-cell RNA sequencing identifies the prolactin receptor as a therapeutic target in adenomyosis","authors":"Runze Wang, Shuai Xu, Qionghua Cui, Xin Chen, Xuelian Wang, Jinghao Liu, Jie Liu, Yuxuan Xin, Hao Shen, Fengxiang Lv, Lan Zhu, Xinli Hu, Rui-Ping Xiao","doi":"10.1038/s41392-025-02339-z","DOIUrl":"https://doi.org/10.1038/s41392-025-02339-z","url":null,"abstract":"<p>Adenomyosis is a complex gynecological disease characterized by endometrial tissue invasion into the myometrium. Current interventions, such as hormonal therapy or hysterectomy, are associated with significant side effects and compromise fertility, underscoring the urgent need for safe and effective treatments. Using single-cell RNA sequencing (scRNA-seq) of uterine samples from patients, we identified prolactin (PRL) signaling as a key pathological driver of adenomyosis. Specifically, scRNA-seq revealed a distinct epithelial subcluster with enriched PRL receptor (PRLR) expression. PRL signaling is overactivated in this epithelial subcluster, promoting cellular survival and proliferation, which contributes to lesion formation and expansion in adenomyosis. Concurrently, PRLR is also highly expressed in a fibroblast subcluster characterized by strong expression of inflammation-related genes. Pathological PRL hyperactivation was further validated in preclinical animal models, where transgenic overexpression of PRL or pituitary transplantation induced an adenomyosis phenotype. Importantly, we demonstrated that dysregulation of local PRL signaling led to the development and progression of adenomyosis, whereas inhibition of PRLR with the monoclonal antibody HMI-115 markedly ameliorated pathological manifestations. These findings establish PRL signaling as a critical driver of adenomyosis pathogenesis, highlighting PRLR inhibition as a promising therapeutic strategy and demonstrating the translational potential of HMI-115 for treating adenomyosis, a gynecological condition that has long been neglected in drug development.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"186 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144825703","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":"Immunological synapse: structures, molecular mechanisms and therapeutic implications in disease","authors":"Zheng Chao, Qi Mei, Chunguang Yang, Jing Luo, Peikun Liu, Hao Peng, Xiangdong Guo, Zhinan Yin, Le Li, Zhihua Wang","doi":"10.1038/s41392-025-02332-6","DOIUrl":"https://doi.org/10.1038/s41392-025-02332-6","url":null,"abstract":"<p>The immunological synapse (IS) serves as the fundamental architectural framework for direct interactions and secretory crosstalk between immune cells, as well as between immune cells and other cells. Its dysregulation is thought to be a key underlying cause of immune evasion or inflammation observed in various diseases, including tumors and infections. Numerous recent studies have addressed key signaling mechanisms and reported novel targets related to IS, further broadening our understanding of its function and regulatory factors. However, a comprehensive review that highlights recent progress and consolidates past knowledge is still lacking. In this study, we delineated the pre- and postsynaptic structures constituting the IS between T cells, natural killer (NK) cells, dendritic cells (DCs), and macrophages. We also detail the specific signaling mechanisms and pathways that modulate the formation and disassembly of the IS, including cytoskeletal remodeling, membrane reshaping, integrin signaling, and force transduction. Following these experimental findings, we systematically review the central roles of IS in maintaining homeostasis and health and outline various diseases arising from IS disorders. Finally, we thoroughly explore targets and treatments related to IS on the basis of preclinical evidence and clinical trials, with the aim of providing further investigatory and therapeutic insights for researchers and clinicians.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"44 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144813039","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":"AAV for gene therapy drives a nephrotoxic response via NFκB in kidney organoids.","authors":"Navin Gupta,Ke Zhang,Venkata Sabbisetti,Jian Shu,Ryuji Morizane","doi":"10.1038/s41392-025-02336-2","DOIUrl":"https://doi.org/10.1038/s41392-025-02336-2","url":null,"abstract":"","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"78 1","pages":"252"},"PeriodicalIF":39.3,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144796849","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":"Novel atypical G protein-coupled receptor (GPCR)-arrestin complexes: a structural snapshot of the barcode hypothesis.","authors":"Jenny C Filor,Edda S F Matthees,Carsten Hoffmann","doi":"10.1038/s41392-025-02338-0","DOIUrl":"https://doi.org/10.1038/s41392-025-02338-0","url":null,"abstract":"","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"1 1","pages":"251"},"PeriodicalIF":39.3,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144791967","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":"Finotonlimab (PD-1 inhibitor) plus bevacizumab (bevacizumab biosimilar) as first-tier therapy for late-stage hepatocellular carcinoma: a randomized phase 2/3 trial","authors":"Chuanhua Zhao, Yanqiao Zhang, Gang Wang, Jinfang Zheng, Weiqing Chen, Zheng Lu, Li Zhuang, Shanzhi Gu, Lei Han, Zhendong Zheng, Zujiang Yu, Yongsheng Yang, Hongmei Sun, Xiaoyong Wei, Ying Cheng, Hailan Lin, Bo Zhu, Guicheng Wu, Kaijian Lei, Wei Wang, Yuwen Wang, Kehe Chen, Ximing Xu, Cuiping Zheng, Yanzhi Bi, Sijuan Ding, Jingdong Zhang, Wei Li, Hailong Liu, Jun Wang, Xianling Liu, Yangfeng Du, Lianming Cai, Jingran Wang, Zhanxiong Luo, Baocai Xing, Jie Shen, Lin Yang, Jianbing Wu, Ou Jiang, Zhigang Peng, Xiuli Liu, Bangwei Cao, Liangfang Shen, Aibing Xu, Aimin Li, Shaojun Chen, Ting Fu, Jian Chen, Chuan Jin, Lei Zhang, Jun Lv, Chengwu Zhang, Xiaoman Zhang, Yu Wang, Huo Su, Qiang Zhou, Wenlin Gai, Liangzhi Xie, Jianming Xu","doi":"10.1038/s41392-025-02333-5","DOIUrl":"https://doi.org/10.1038/s41392-025-02333-5","url":null,"abstract":"<p>We aimed to assess the tolerability and efficacy of finotonlimab (an anti-programmed cell death protein-1 antibody) in combination with SCT510, a bevacizumab biosimilar, versus sorafenib in unresectable advanced HCC. This randomized phase 2 and 3 study (ClinicalTrials.gov, NCT04560894; Chinadrugtrials.org.cn, CTR20201976 and CTR20201974) was performed at 67 hospitals in China. HCC patients (<i>n</i> = 398) were included between 11 November 2020 and 28 September 2022. In phase 2, patients received intravenous finotonlimab (200 mg every 3 weeks) combined with SCT510 (15 mg/kg every 3 weeks). In phase 3, 346 patients were randomized (2:1) to either the finotonlimab plus SCT510 (dual-agent) group or the sorafenib group. The median follow-up time for the dual-agent therapy and sorafenib groups was 19.9 and 19.0 months, respectively. Median PFS, assessed by BICR according to RECIST 1.1, was significantly longer in the dual-agent group (7.1 months [95% confidence intervals {CI}: 6.1, 8.4]) than in the sorafenib group (2.9 months [95% CI: 2.8, 4.1]; stratified hazard ratio [HR]: 0.5, 95% CI: 0.38, 0.65, <i>p</i> &lt; 0.0001). Median OS was also significantly longer in patients receiving finotonlimab plus SCT510 (22.1 months [18.6, not available]) than in those receiving sorafenib (14.2 months [95% CI: 10.2, 15.8]; HR: 0.60 [95% CI: 0.44, 0.81], <i>p</i> &lt; 0.0008). Finotonlimab in combination with bevacizumab demonstrated favorable efficacy, in comparison to sorafenib, as a first-line treatment for unresectable HCC, with a manageable safety profile.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"27 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144786750","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":"Immunosenescence: signaling pathways, diseases and therapeutic targets","authors":"Yichu Fu, Binhan Wang, Aqu Alu, Weiqi Hong, Hong Lei, Xuemei He, Huashan Shi, Ping Cheng, Xiangliang Yang","doi":"10.1038/s41392-025-02371-z","DOIUrl":"https://doi.org/10.1038/s41392-025-02371-z","url":null,"abstract":"<p>Immunosenescence refers to the abnormal activation or dysfunction of the immune system as people age. Inflammaging is a typical pathological inflammatory state associated with immunosenescence and is characterized by excessive expression of proinflammatory cytokines in aged immune cells. Chronic inflammation contributes to a variety of age-related diseases, such as neurodegenerative disease, cancer, infectious disease, and autoimmune diseases. Although not fully understood, recent studies contribute greatly to uncovering the underlying mechanisms of immunosenescence at the molecular and cellular levels. Immunosenescence is associated with dysregulated signaling pathways (e.g., overactivation of the NF-κB signaling pathway and downregulation of the melatonin signaling pathway) and abnormal immune cell responses with functional alterations and phenotypic shifts. These advances remarkably promote the development of countermeasures against immunosenescence for the treatment of age-related diseases. Some anti-immunosenescence treatments have already shown promising results in clinical trials. In this review, we discuss the molecular and cellular mechanisms of immunosenescence and summarize the critical role of immunosenescence in the pathogenesis of age-related diseases. Potential interventions to mitigate immunosenescence, including reshaping immune organs, targeting different immune cells or signaling pathways, and nutritional and lifestyle interventions, are summarized. Some treatment strategies have already launched into clinical trials. This study aims to provide a systematic and comprehensive introduction to the basic and clinical research progress of immunosenescence, thus accelerating research on immunosenescence in related diseases and promoting the development of targeted therapy.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"15 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144786751","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":"Islet environment and development of type 1 diabetes in the biobreeding rat model.","authors":"Patricia Recio-López,Per-Olof Berggren,Montserrat Visa Majoral,Ismael Valladolid-Acebes,Lisa Juntti-Berggren","doi":"10.1038/s41392-025-02330-8","DOIUrl":"https://doi.org/10.1038/s41392-025-02330-8","url":null,"abstract":"","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"58 1","pages":"247"},"PeriodicalIF":39.3,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144777873","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":"Cancer stem cells: landscape, challenges and emerging therapeutic innovations.","authors":"Haksoo Lee,Byeongsoo Kim,Junhyeong Park,Sujin Park,Gaeun Yoo,Soomin Yum,Wooseok Kang,Jae-Myung Lee,HyeSook Youn,BuHyun Youn","doi":"10.1038/s41392-025-02360-2","DOIUrl":"https://doi.org/10.1038/s41392-025-02360-2","url":null,"abstract":"Cancer stem cells (CSCs) constitute a highly plastic and therapy-resistant cell subpopulation within tumors that drives tumor initiation, progression, metastasis, and relapse. Their ability to evade conventional treatments, adapt to metabolic stress, and interact with the tumor microenvironment makes them critical targets for innovative therapeutic strategies. Recent advances in single-cell sequencing, spatial transcriptomics, and multiomics integration have significantly improved our understanding of CSC heterogeneity and metabolic adaptability. Metabolic plasticity allows CSCs to switch between glycolysis, oxidative phosphorylation, and alternative fuel sources such as glutamine and fatty acids, enabling them to survive under diverse environmental conditions. Moreover, interactions with stromal cells, immune components, and vascular endothelial cells facilitate metabolic symbiosis, further promoting CSC survival and drug resistance. Despite substantial progress, major hurdles remain, including the lack of universally reliable CSC biomarkers and the challenge of targeting CSCs without affecting normal stem cells. The development of 3D organoid models, CRISPR-based functional screens, and AI-driven multiomics analysis is paving the way for precision-targeted CSC therapies. Emerging strategies such as dual metabolic inhibition, synthetic biology-based interventions, and immune-based approaches hold promise for overcoming CSC-mediated therapy resistance. Moving forward, an integrative approach combining metabolic reprogramming, immunomodulation, and targeted inhibition of CSC vulnerabilities is essential for developing effective CSC-directed therapies. This review discusses the latest advancements in CSC biology, highlights key challenges, and explores future perspectives on translating these findings into clinical applications.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"15 1","pages":"248"},"PeriodicalIF":39.3,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144777875","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}