Signal Transduction and Targeted Therapy最新文献

{"title":"Discovery of biosynthetic enzymes for β-D-manno-heptoses across kingdoms: novel agonists for ALPK1/NF-κB-dependent immune response","authors":"Gunter Maubach, Michelle C. C. Lim, Michael Naumann","doi":"10.1038/s41392-024-02003-y","DOIUrl":"https://doi.org/10.1038/s41392-024-02003-y","url":null,"abstract":"<p>A recent study by Tang et al. ¹ in <i>Science</i> reveals the cross-kingdom widespread occurrence of functional nucleotide-diphosphate (NDP)-heptose biosynthetic enzymes (HBEs) that accounts for the synthesis of NDP-heptoses to activate the alpha-protein kinase 1 (ALPK1)-dependent innate immune response. This study not only highlights the importance of the metabolite β-D-<i>manno</i>-heptose as pathogen-associated molecular patterns (PAMPs) but also raises the question of possibly other biological roles, especially in the different kingdoms (Fig. 1).</p><figure><figcaption><b data-test=\"figure-caption-text\">Fig. 1</b></figcaption><picture><source srcset=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fs41392-024-02003-y/MediaObjects/41392_2024_2003_Fig1_HTML.png?as=webp\" type=\"image/webp\"/><img alt=\"figure 1\" aria-describedby=\"Fig1\" height=\"511\" loading=\"lazy\" src=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fs41392-024-02003-y/MediaObjects/41392_2024_2003_Fig1_HTML.png\" width=\"685\"/></picture><p>New findings on NDP-heptoses as agonists for the immune response. Small molecule metabolites such as ADP-heptose are synthesized by HBEs exhibiting isomerase, kinase, phosphatase, and nucleotidyltransferase activities. Of note, three subgroups of HBEs with nucleotidyltransferase activity (HENases) exist, exhibiting solely this activity or combined with kinase, or isomerase/kinase activities. In bacteria, where HBEs were first reported, they catalyzed the four-step biosynthesis of ADP-heptose starting from D-sedoheptulose 7-phosphate. Functional HBEs are prevalent in bacteria, archaea, viruses, and some eukaryotes. The authors discovered the presence of a widely conserved arginine residue at the fifth N-terminal position of the (F/L)XXGXSTT motif (STT_R5) in HENases that enable them to synthesize also CDP- and UDP-heptoses. A striking feature of the NDP-heptoses is their ability to act as immunostimulants. Pathogenic organisms deliver NDP-heptoses into mammalian cells, where they are detected by ALPK1, triggering its kinase activity. The ensuing TIFA phosphorylation initiates a signaling cascade to activate NF-κB, leading to the release of cytokines and chemokines that result in the recruitment of immune cells. In addition, NDP-heptoses could also serve as building blocks for protein glycosylation, or the production of LPS or antibiotics. The figure is created with BioRender.com</p><span>Full size image</span><svg aria-hidden=\"true\" focusable=\"false\" height=\"16\" role=\"img\" width=\"16\"><use xlink:href=\"#icon-eds-i-chevron-right-small\" xmlns:xlink=\"http://www.w3.org/1999/xlink\"></use></svg></figure>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":null,"pages":null},"PeriodicalIF":39.3,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142384127","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 borders: the choroid plexus-immune communication during neuroinflammation","authors":"Anaelle Aurelie Dumas, Adrià Dalmau Gasull, Marco Prinz","doi":"10.1038/s41392-024-01997-9","DOIUrl":"https://doi.org/10.1038/s41392-024-01997-9","url":null,"abstract":"<p>In their paper published in Cell,¹ Xu et al. leveraged single-cell sequencing and cell lineage tracing tools combined with two-photon live imaging to characterise the spatiotemporal immune recruitment and infiltration to the choroid plexus (ChP). They provide seminal insights into the communication between specialised ChP epithelial and macrophage populations, which coordinate the stepwise response to inflammation and its resolution.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":null,"pages":null},"PeriodicalIF":39.3,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142384128","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":"Allogeneic CAR T cells for autoimmune diseases: a glimpse into the future","authors":"Dimitrios Mougiakakos","doi":"10.1038/s41392-024-01998-8","DOIUrl":"https://doi.org/10.1038/s41392-024-01998-8","url":null,"abstract":"<p>In a recent study published in <i>Cell</i>, Wang X et al.¹ reported the first use of allogeneic anti-CD19 CAR T cells in patients with therapy-resistant autoimmune diseases, demonstrating their effectiveness in reducing disease activity, with good tolerability and persistence. These findings suggest that allogeneic CAR T cells could offer a scalable, off-the-shelf treatment option for autoimmune disorders.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":null,"pages":null},"PeriodicalIF":39.3,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142384178","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 microglial compliment: controlling neuronal function from within","authors":"Dilara Hasavci, Thomas Blank","doi":"10.1038/s41392-024-01989-9","DOIUrl":"https://doi.org/10.1038/s41392-024-01989-9","url":null,"abstract":"<p>A recent study published in <i>Cell</i> revealed that in the aging brain, the microglia-derived complement component C1q is internalized into neurons through endocytosis, integrates into ribonucleoprotein (RNP) complexes where it inhibits neuronal protein synthesis and alters the protein content. These findings demonstrate an unexpected intracellular function of C1q in neurons with significant implications for understanding age-related changes in brain function and potentially neurodegenerative diseases.¹</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":null,"pages":null},"PeriodicalIF":39.3,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142379324","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":"Signaling pathways involved in colorectal cancer: pathogenesis and targeted therapy","authors":"Qing Li, Shan Geng, Hao Luo, Wei Wang, Ya-Qi Mo, Qing Luo, Lu Wang, Guan-Bin Song, Jian-Peng Sheng, Bo Xu","doi":"10.1038/s41392-024-01953-7","DOIUrl":"https://doi.org/10.1038/s41392-024-01953-7","url":null,"abstract":"<p>Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality worldwide. Its complexity is influenced by various signal transduction networks that govern cellular proliferation, survival, differentiation, and apoptosis. The pathogenesis of CRC is a testament to the dysregulation of these signaling cascades, which culminates in the malignant transformation of colonic epithelium. This review aims to dissect the foundational signaling mechanisms implicated in CRC, to elucidate the generalized principles underpinning neoplastic evolution and progression. We discuss the molecular hallmarks of CRC, including the genomic, epigenomic and microbial features of CRC to highlight the role of signal transduction in the orchestration of the tumorigenic process. Concurrently, we review the advent of targeted and immune therapies in CRC, assessing their impact on the current clinical landscape. The development of these therapies has been informed by a deepening understanding of oncogenic signaling, leading to the identification of key nodes within these networks that can be exploited pharmacologically. Furthermore, we explore the potential of integrating AI to enhance the precision of therapeutic targeting and patient stratification, emphasizing their role in personalized medicine. In summary, our review captures the dynamic interplay between aberrant signaling in CRC pathogenesis and the concerted efforts to counteract these changes through targeted therapeutic strategies, ultimately aiming to pave the way for improved prognosis and personalized treatment modalities in colorectal cancer.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":null,"pages":null},"PeriodicalIF":39.3,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142379322","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":"The phage anti-restriction induced system: new insights into bacterial immunity and bacteriophage escape strategies","authors":"Yi Zhong, Volker M. Lauschke","doi":"10.1038/s41392-024-01995-x","DOIUrl":"https://doi.org/10.1038/s41392-024-01995-x","url":null,"abstract":"","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":null,"pages":null},"PeriodicalIF":39.3,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142377334","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":"Correction: CDK4/6 inhibition blocks cancer metastasis through a USP51-ZEB1-dependent deubiquitination mechanism","authors":"Zhen Zhang, Jianjun Li, Yang Ou, Guang Yang, Kaiyuan Deng, Qiong Wang, Zhaoyang Wang, Wenhao Wang, Quansheng Zhang, Hang Wang, Wei Sun, Peiqing Sun, Shuang Yang","doi":"10.1038/s41392-024-01972-4","DOIUrl":"https://doi.org/10.1038/s41392-024-01972-4","url":null,"abstract":"<p>Correction to: <i>Signal Transduction and Targeted Therapy</i> (2020) <b>5</b>:25; https://doi.org/10.1038/s41392-020-0118-x, published online 11 March 2020</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":null,"pages":null},"PeriodicalIF":39.3,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142374182","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":"Evolving understanding of autoimmune mechanisms and new therapeutic strategies of autoimmune disorders","authors":"Yi Song, Jian Li, Yuzhang Wu","doi":"10.1038/s41392-024-01952-8","DOIUrl":"https://doi.org/10.1038/s41392-024-01952-8","url":null,"abstract":"<p>Autoimmune disorders are characterized by aberrant T cell and B cell reactivity to the body’s own components, resulting in tissue destruction and organ dysfunction. Autoimmune diseases affect a wide range of people in many parts of the world and have become one of the major concerns in public health. In recent years, there have been substantial progress in our understanding of the epidemiology, risk factors, pathogenesis and mechanisms of autoimmune diseases. Current approved therapeutic interventions for autoimmune diseases are mainly non-specific immunomodulators and may cause broad immunosuppression that leads to serious adverse effects. To overcome the limitations of immunosuppressive drugs in treating autoimmune diseases, precise and target-specific strategies are urgently needed. To date, significant advances have been made in our understanding of the mechanisms of immune tolerance, offering a new avenue for developing antigen-specific immunotherapies for autoimmune diseases. These antigen-specific approaches have shown great potential in various preclinical animal models and recently been evaluated in clinical trials. This review describes the common epidemiology, clinical manifestation and mechanisms of autoimmune diseases, with a focus on typical autoimmune diseases including multiple sclerosis, type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosus, and sjögren’s syndrome. We discuss the current therapeutics developed in this field, highlight the recent advances in the use of nanomaterials and mRNA vaccine techniques to induce antigen-specific immune tolerance.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":null,"pages":null},"PeriodicalIF":39.3,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142369920","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":"Neoadjuvant toripalimab plus axitinib for clear cell renal cell carcinoma with inferior vena cava tumor thrombus: NEOTAX, a phase 2 study","authors":"Liangyou Gu, Cheng Peng, Qiyang Liang, Qingbo Huang, Deqiang Lv, Houming Zhao, Qi Zhang, Yu Zhang, Peng Zhang, Shichao Li, Junnan Xu, Luyao Chen, Yongpeng Xie, Jinhang Li, Gang Guo, Xu Zhang, Baojun Wang, Xin Ma","doi":"10.1038/s41392-024-01990-2","DOIUrl":"https://doi.org/10.1038/s41392-024-01990-2","url":null,"abstract":"<p>The potential benefit of neoadjuvant toripalimab plus axitinib in cases with clear cell renal cell carcinoma (ccRCC) and inferior vena cava tumor thrombus (IVC-TT) remains unclear. NEOTAX was a phase 2 study to investigate the efficacy and safety of neoadjuvant toripalimab plus axitinib in patients with ccRCC and IVC-TT (ChiCTR2000030405). The primary endpoint was the down-staging rate of IVC-TT level. Secondary endpoints included change in TT length, response rate, percentage change in surgical approach, surgical morbidity, progression-free survival (PFS), safety, and biomarker analyses. In all, 25 patients received study treatment, 44.0% (11/25) patients had a reduction in thrombus level, and none experienced an increase in Mayo level. The median change in tumor thrombus length was −2.3 cm (range: −7.1 to 1.1 cm). Overall, 61.9% (13/21) patients experienced changes in surgical strategy compared with planned surgery, three patients experienced major complications. The median PFS was 25.3 months (95% CI: 17.0-NE). The 1-year PFS was 89.1% (95% CI: 62.7–97.2). No any of grade 4 or 5 treatment-related adverse event was identified. Biopsy samples of non-responders exhibited increased T cytotoxic cell infiltration, but these cells were predominantly PD-1 positive. Biopsy samples of responders exhibited lower T helper cells, however, their subtype, regulatory T cells remained unchanged. In surgical samples of the TT, non-responders exhibited increased CD8T_01_GZMK_CXCR4 subset T cells. NEOTAX met preset endpoints proving that toripalimab in combination with axitinib downstages IVC-TT in a significant proportion of patients leading to simplification in the procedure of surgery.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":null,"pages":null},"PeriodicalIF":39.3,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142369921","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":"Mechanism exploration and model construction for small cell transformation in EGFR-mutant lung adenocarcinomas.","authors":"Yan Li, Tongji Xie, Shouzheng Wang, Lin Yang, Xuezhi Hao, Yan Wang, Xingsheng Hu, Lin Wang, Junling Li, Jianming Ying, Puyuan Xing","doi":"10.1038/s41392-024-01981-3","DOIUrl":"10.1038/s41392-024-01981-3","url":null,"abstract":"<p><p>Small-cell lung cancer (SCLC) transformation accounts for 3-14% of resistance in EGFR-TKI relapsed lung adenocarcinomas (LUADs), with unknown molecular mechanisms and optimal treatment strategies. We performed transcriptomic analyses (including bulk and spatial transcriptomics) and multiplex immunofluorescence on pre-treated samples from LUADs without transformation after EGFR-TKI treatment (LUAD-NT), primary SCLCs (SCLC-P) and LUADs with transformation after EGFR-TKI treatment (before transformation: LUAD-BT; after transformation: SCLC-AT). Our study found that LUAD-BT exhibited potential transcriptomic characteristics for transformation compared with LUAD-NT. We identified several pathways that shifted during transformation, and the transformation might be promoted by epigenetic alterations (such as HDAC10, HDAC1, DNMT3A) within the tumor cells instead of within the tumor microenvironment. For druggable pathways, transformed-SCLC were proved to be less dependent on EGF signaling but more relied on FGF signaling, while VEGF-VEGFR pathway remained active, indicating potential treatments after transformation. We also found transformed-SCLC showed an immuno-exhausted status which was associated with the duration of EGFR-TKI before transformation. Besides, SCLC-AT exhibited distinct molecular subtypes from SCLC-P. Moreover, we constructed an ideal 4-marker model based on transcriptomic and IHC data to predict SCLC transformation, which obtained a sensitivity of 100% and 87.5%, a specificity of 95.7% and 100% in the training and test cohorts, respectively. We provided insights into the molecular mechanisms of SCLC transformation and the differences between SCLC-AT and SCLC-P, which might shed light on prevention strategies and subsequent therapeutic strategies for SCLC transformation in the future.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":null,"pages":null},"PeriodicalIF":40.8,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11445518/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142361975","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}