Signal Transduction and Targeted Therapy最新文献

{"title":"Cancer cell reprogramming: turning the enemy into an ally","authors":"Severin Guetter, Kaiji Fan, Hendrik Poeck","doi":"10.1038/s41392-024-02102-w","DOIUrl":"https://doi.org/10.1038/s41392-024-02102-w","url":null,"abstract":"","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"50 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142987357","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":"Chimeric antigen receptor with novel intracellular modules improves antitumor performance of T cells","authors":"Pengju Wang, Yiyi Wang, Xiaojuan Zhao, Rui Zheng, Yiting Zhang, Ruotong Meng, Hao Dong, Sixin Liang, Xinyi He, Yang Song, Haichuan Su, Bo Yan, An-Gang Yang, Lintao Jia","doi":"10.1038/s41392-024-02096-5","DOIUrl":"https://doi.org/10.1038/s41392-024-02096-5","url":null,"abstract":"<p>The excessive cytokine release and limited persistence represent major challenges for chimeric antigen receptor T (CAR-T) cell therapy in diverse tumors. Conventional CARs employ an intracellular domain (ICD) from the ζ subunit of CD3 as a signaling module, and it is largely unknown how alternative CD3 chains potentially contribute to CAR design. Here, we obtained a series of CAR-T cells against HER2 and mesothelin using a domain comprising a single immunoreceptor tyrosine-based activation motif from different CD3 subunits as the ICD of CARs. While these reconstituted CARs conferred sufficient antigen-specific cytolytic activity on equipped T cells, they elicited low tonic signal, ameliorated the exhaustion and promoted memory differentiation of these cells. Intriguingly, the CD3ε-derived ICD outperformed others in generation of CAR-T cells that produced minimized cytokines. Mechanistically, CD3ε-based CARs displayed a restrained cytomembrane expression on engineered T cells, which was ascribed to endoplasmic reticulum retention mediated by the carboxyl terminal basic residues. The present study demonstrated the applicability of CAR reconstitution using signaling modules from different CD3 subunits, and depicted a novel pattern of CAR expression that reduces cytokine release, thus paving a way for preparation of CAR-T cells displaying improved safety and persistence against diverse tumor antigens.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"28 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142981179","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":"Digestive cancers: mechanisms, therapeutics and management","authors":"Tianzuo Zhan, Johannes Betge, Nadine Schulte, Lena Dreikhausen, Michael Hirth, Moying Li, Philip Weidner, Antonia Leipertz, Andreas Teufel, Matthias P. Ebert","doi":"10.1038/s41392-024-02097-4","DOIUrl":"https://doi.org/10.1038/s41392-024-02097-4","url":null,"abstract":"<p>Cancers of the digestive system are major contributors to global cancer-associated morbidity and mortality, accounting for 35% of annual cases of cancer deaths. The etiologies, molecular features, and therapeutic management of these cancer entities are highly heterogeneous and complex. Over the last decade, genomic and functional studies have provided unprecedented insights into the biology of digestive cancers, identifying genetic drivers of tumor progression and key interaction points of tumor cells with the immune system. This knowledge is continuously translated into novel treatment concepts and targets, which are dynamically reshaping the therapeutic landscape of these tumors. In this review, we provide a concise overview of the etiology and molecular pathology of the six most common cancers of the digestive system, including esophageal, gastric, biliary tract, pancreatic, hepatocellular, and colorectal cancers. We comprehensively describe the current stage-dependent pharmacological management of these malignancies, including chemo-, targeted, and immunotherapy. For each cancer entity, we provide an overview of recent therapeutic advancements and research progress. Finally, we describe how novel insights into tumor heterogeneity and immune evasion deepen our understanding of therapy resistance and provide an outlook on innovative therapeutic strategies that will shape the future management of digestive cancers, including CAR-T cell therapy, novel antibody-drug conjugates and targeted therapies.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"42 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142981180","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":"Beyond incretins: targeting neurokinin receptors for obesity treatment","authors":"Doreen Thor, Simone Prömel","doi":"10.1038/s41392-024-02100-y","DOIUrl":"https://doi.org/10.1038/s41392-024-02100-y","url":null,"abstract":"<p>In a study published recently in <i>Nature</i>, Sass, Ma, and colleagues describe the neurokinin 2 receptor (NK2R), a G protein-coupled receptor (GPCR), as a novel regulator of food intake as well as energy expenditure, and develop and characterize selective agonists that effectively activate NK2R to promote weight loss. Most interestingly, the authors bridge the gap between rodents and primates, raising hopes for novel treatment options.¹</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"31 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142981337","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":"A multicenter, randomized, double-blind, placebo-controlled phase 3 study of Socazolimab or placebo combined with carboplatin and etoposide in the first-line treatment of extensive-stage small cell lung cancer","authors":"Zhiwei Chen, Jianhua Chen, Dingzhi Huang, Wei Zhang, Lin Wu, Tienan Yi, Qiming Wang, Liang Han, Liping Tan, Yinyin Li, Zhihong Zhang, Na Li, Jie li, Tongmei Zhang, Ying Hu, Hongmei Sun, Youhua Wu, Zhiyong He, Runxiang Yang, Peng Cheng, Xingya Li, Jianhua Shi, Guohua Yu, Daiyuan Ma, Benjamin Xiaoyi Li, Xiangrong Dai, Michael Wong, Yujie Li, Xiaohui Yu, Shun Lu","doi":"10.1038/s41392-024-02115-5","DOIUrl":"https://doi.org/10.1038/s41392-024-02115-5","url":null,"abstract":"<p>This is a randomized, double-blind, placebo-controlled phase 3 clinical trial (ClinicalTrials.gov, NCT04878016) conducted in 54 hospitals in China. Adults who were histologically diagnosed and never treated for extensive-stage small cell lung cancer (ES-SCLC) were enrolled. Eligible Patients were randomly assigned (1:1) to receive four cycles (21 days as one cycle) of intravenous carboplatin (area under the curve of 5 mg/mL per min, day 1 of each cycle) and etoposide (100 mg/m² of body-surface area, on days 1–3 of each cycle) with either socazolimab (5 mg/kg, day 1 of each cycle) or matching placebo, following maintenance therapy with socazolimab or placebo. From July 15, 2021, to May 12, 2022, 498 eligible patients were randomly assigned to receive socazolimab (250 patients) or placebo (248 patients) combined with chemotherapy. As of October 13, 2023, patients treated with socazolimab presented significant overall survival (OS) benefit (13.90 months) compared with the placebo plus EC group (11.58 months) (hazard ratio for death, 0.799; 95% CI, 0.652–0.979; <i>p</i> = 0.0158). The median progression free survival (PFS) was 5.55 months in the socazolimab plus EC group, prolonging disease progression or death by nearly 1.2 months (5.55 months vs 4.37 months, hazard ratio for progression or death, 0.569; 95% CI, 0.457–0.708; <i>p</i> &lt; 0.0001). 200 (80.3%) patients in the socazolimab plus EC group experienced ≥ grade 3 treatment-related adverse events and 187 (75.7%) patients occurred in the placebo plus EC group. Socazolimab combined with standard EC regimen chemotherapy for first-line treatment of ES-SCLC significantly prolonged overall survival and did not increase the safety risk of treatment.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"22 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142967891","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":"Cyclin-dependent protein kinases and cell cycle regulation in biology and disease","authors":"Ilenia Pellarin, Alessandra Dall’Acqua, Andrea Favero, Ilenia Segatto, Valentina Rossi, Nicole Crestan, Javad Karimbayli, Barbara Belletti, Gustavo Baldassarre","doi":"10.1038/s41392-024-02080-z","DOIUrl":"https://doi.org/10.1038/s41392-024-02080-z","url":null,"abstract":"<p>Cyclin Dependent Kinases (CDKs) are closely connected to the regulation of cell cycle progression, having been first identified as the kinases able to drive cell division. In reality, the human genome contains 20 different CDKs, which can be divided in at least three different sub-family with different functions, mechanisms of regulation, expression patterns and subcellular localization. Most of these kinases play fundamental roles the normal physiology of eucaryotic cells; therefore, their deregulation is associated with the onset and/or progression of multiple human disease including but not limited to neoplastic and neurodegenerative conditions. Here, we describe the functions of CDKs, categorized into the three main functional groups in which they are classified, highlighting the most relevant pathways that drive their expression and functions. We then discuss the potential roles and deregulation of CDKs in human pathologies, with a particular focus on cancer, the human disease in which CDKs have been most extensively studied and explored as therapeutic targets. Finally, we discuss how CDKs inhibitors have become standard therapies in selected human cancers and propose novel ways of investigation to export their targeting from cancer to other relevant chronic diseases. We hope that the effort we made in collecting all available information on both the prominent and lesser-known CDK family members will help in identify and develop novel areas of research to improve the lives of patients affected by debilitating chronic diseases.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"36 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142967893","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":"A broadly neutralizing antibody against the SARS-CoV-2 Omicron sub-variants BA.1, BA.2, BA.2.12.1, BA.4, and BA.5","authors":"Zhe Chen, Leilei Feng, Lei Wang, Li Zhang, Binyang Zheng, Hua Fu, Fengdi Li, Ligai Liu, Qi Lv, Ran Deng, YanLi Xu, Yongfeng Hu, Jianhua Zheng, Chuan Qin, Linlin Bao, Xiangxi Wang, Qi Jin","doi":"10.1038/s41392-024-02114-6","DOIUrl":"https://doi.org/10.1038/s41392-024-02114-6","url":null,"abstract":"<p>The global spread of Severe Acute Respiratory Syndrome Coronavirus 2. (SARS-CoV-2) and its variant strains, including Alpha, Beta, Gamma, Delta, and now Omicron, pose a significant challenge. With the constant evolution of the virus, Omicron and its subtypes BA.1, BA.2, BA.3, BA.4, and BA.5 have developed the capacity to evade neutralization induced by previous vaccination or infection. This evasion highlights the urgency in discovering new monoclonal antibodies (mAbs) with neutralizing activity, especially broadly neutralizing antibodies (bnAbs), to combat the virus.In the current study, we introduced a fully human neutralizing mAb, CR9, that targets Omicron variants. We demonstrated the mAb’s effectiveness in inhibiting Omicron replication both in vitro and in vivo. Structural analysis using cryo-electron microscopy (cryo-EM) revealed that CR9 binds to an epitope formed by RBD residues, providing a molecular understanding of its neutralization mechanism. Given its potency and specificity, CR9 holds promise as a potential adjunct therapy for treating Omicron infections. Our findings highlight the importance of continuous mAb discovery and characterization in addressing the evolving threat of COVID-19.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"9 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142967892","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":"Comparing acute versus AIDS ART initiation on HIV-1 integration sites and clonal expansion.","authors":"Jun Wang, Nan Xiao, Zhengnong Zhu, Haiyan Qiao, Fang Zhao, Lukun Zhang, Jizhou Gou, Mengji Lu, Yun He, Hongzhou Lu, Qian Li","doi":"10.1038/s41392-024-02113-7","DOIUrl":"10.1038/s41392-024-02113-7","url":null,"abstract":"<p><p>Early antiretroviral therapy (ART) initiation is known to limit the establishment of the HIV reservoir, with studies suggesting benefits such as a reduced number of infected cells and a smaller latent reservoir. However, the long-term impact of early ART initiation on the dynamics of the infected cell pool remains unclear, and clinical evidence directly comparing proviral integration site counts between early and late ART initiation is limited. In this study, we used Linear Target Amplification-PCR (LTA-PCR) and Next Generation Sequencing to compare unique integration site (UIS) clonal counts between individuals who initiated ART during acute HIV infection stage (Acute-ART group) and those in the AIDS stage (AIDS-ART group). Our analysis revealed distinct clonal distribution patterns, with greater UIS heterogeneity in Acute-ART group and more homogeneity in AIDS-ART group. Monoclonal UIS accumulation, predominantly in-gene regions, was influenced by ART timing and duration, with early treatment delaying this process. Host cell genes integrated by HIV provirus as monoclonal types were enriched in cell cycle and lymphocyte activation pathways. Tumor suppressor genes (TSGs) were more frequently integrated as monoclonal types in AIDS-ART group, suggesting potential risk factors. Overall, we introduced a sequencing method to assess provirus size in human peripheral blood and identified the widespread presence of monoclonal distribution of UIS in AIDS-ART group after long-term treatment. The early intervention helps slow the progress of clonal expansion of infected cells, reducing the formation of stable and persistent reservoirs, and ultimately posing fewer barriers to achieving a functional cure.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"10 1","pages":"23"},"PeriodicalIF":40.8,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11718275/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142954673","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":"Mitochondrial diseases: from molecular mechanisms to therapeutic advances.","authors":"Haipeng Wen, Hui Deng, Bingyan Li, Junyu Chen, Junye Zhu, Xian Zhang, Shigeo Yoshida, Yedi Zhou","doi":"10.1038/s41392-024-02044-3","DOIUrl":"10.1038/s41392-024-02044-3","url":null,"abstract":"<p><p>Mitochondria are essential for cellular function and viability, serving as central hubs of metabolism and signaling. They possess various metabolic and quality control mechanisms crucial for maintaining normal cellular activities. Mitochondrial genetic disorders can arise from a wide range of mutations in either mitochondrial or nuclear DNA, which encode mitochondrial proteins or other contents. These genetic defects can lead to a breakdown of mitochondrial function and metabolism, such as the collapse of oxidative phosphorylation, one of the mitochondria's most critical functions. Mitochondrial diseases, a common group of genetic disorders, are characterized by significant phenotypic and genetic heterogeneity. Clinical symptoms can manifest in various systems and organs throughout the body, with differing degrees and forms of severity. The complexity of the relationship between mitochondria and mitochondrial diseases results in an inadequate understanding of the genotype-phenotype correlation of these diseases, historically making diagnosis and treatment challenging and often leading to unsatisfactory clinical outcomes. However, recent advancements in research and technology have significantly improved our understanding and management of these conditions. Clinical translations of mitochondria-related therapies are actively progressing. This review focuses on the physiological mechanisms of mitochondria, the pathogenesis of mitochondrial diseases, and potential diagnostic and therapeutic applications. Additionally, this review discusses future perspectives on mitochondrial genetic diseases.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"10 1","pages":"9"},"PeriodicalIF":40.8,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11724432/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142954676","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":"Targeting pathological brain activity-related to neuroinflammation through scRNA-seq for new personalized therapies in Parkinson's disease.","authors":"Daniela Mirzac, Manuel Bange, Sebastian Kunz, Phil L de Jager, Sergiu Groppa, Gabriel Gonzalez-Escamilla","doi":"10.1038/s41392-024-02086-7","DOIUrl":"10.1038/s41392-024-02086-7","url":null,"abstract":"","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"10 1","pages":"10"},"PeriodicalIF":40.8,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11718261/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142954678","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}