Signal Transduction and Targeted Therapy最新文献

{"title":"MEK inhibition prevents CAR-T cell exhaustion and differentiation via downregulation of c-Fos and JunB","authors":"Xiujian Wang, Xiao Tao, Pengjie Chen, Penglei Jiang, Wenxiao Li, Hefeng Chang, Cong Wei, Xinyi Lai, Hao Zhang, Yihan Pan, Lijuan Ding, Zuyu Liang, Jiazhen Cui, Mi Shao, Xinyi Teng, Tianning Gu, Jieping Wei, Delin Kong, Xiaohui Si, Yingli Han, Huarui Fu, Yu Lin, Jian Yu, Xia Li, Dongrui Wang, Yongxian Hu, Pengxu Qian, He Huang","doi":"10.1038/s41392-024-01986-y","DOIUrl":"https://doi.org/10.1038/s41392-024-01986-y","url":null,"abstract":"<p>Clinical evidence supports the notion that T cell exhaustion and terminal differentiation pose challenges to the persistence and effectiveness of chimeric antigen receptor-T (CAR-T) cells. MEK1/2 inhibitors (MEKIs), widely used in cancer treatment due to their ability to inhibit aberrant MAPK signaling, have shown potential synergistic effects when combined with immunotherapy. However, the impact and mechanisms of MEKIs on CAR-T cells remain uncertain and controversial. To address this, we conducted a comprehensive investigation to determine whether MEKIs enhance or impair the efficacy of CAR-T cells. Our findings revealed that MEKIs attenuated CAR-T cell exhaustion and terminal differentiation induced by tonic signaling and antigen stimulation, thereby improving CAR-T cell efficacy against hematological and solid tumors. Remarkably, these effects were independent of the specific scFvs and costimulatory domains utilized in CARs. Mechanistically, analysis of bulk and single-cell transcriptional profiles demonstrates that the effect of MEK inhibition was related to diminish anabolic metabolism and downregulation of c-Fos and JunB. Additionally, the overexpression of c-Fos or JunB in CAR-T cells counteracted the effects of MEK inhibition. Furthermore, our Cut-and-Tag assay revealed that MEK inhibition downregulated the JunB-driven gene profiles associated with exhaustion, differentiation, anergy, glycolysis, and apoptosis. In summary, our research unveil the critical role of the MAPK-c-Fos-JunB axis in driving CAR-T cell exhaustion and terminal differentiation. These mechanistic insights significantly broaden the potential application of MEKIs to enhance the effectiveness of CAR-T therapy.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":null,"pages":null},"PeriodicalIF":39.3,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142486724","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":"Corynebacterium parakroppenstedtii secretes a novel glycolipid to promote the development of granulomatous lobular mastitis","authors":"Ran Liu, Zixuan Luo, Chong Dai, Yuchen Wei, Shuqing Yan, Xinwen Kuang, Kuan Qi, Aisi Fu, Yinxin Li, Shuai Fu, Zhengning Ma, Wen Dai, Xiao Xiao, Qing Wu, Haokui Zhou, Yan Rao, Jingping Yuan, Ting Shi, Zixin Deng, Chuang Chen, Tiangang Liu","doi":"10.1038/s41392-024-01984-0","DOIUrl":"https://doi.org/10.1038/s41392-024-01984-0","url":null,"abstract":"<p>Granulomatous lobular mastitis (GLM) is a chronic idiopathic granulomatous mastitis of the mammary gland characterized by significant pain and a high propensity for recurrence, the incidence rate has gradually increased, and has become a serious breast disease that should not be ignored. GLM is highly suspected relative to microbial infections, especially those of <i>Corynebacterium</i> species; however, the mechanisms involved are unclear, and prevention and treatment are difficult. In this study, we demonstrated the pathogenicity of <i>Corynebacterium parakroppenstedtii</i> in GLM using Koch’s postulates. Based on the drug sensitization results of <i>C. parakroppenstedtii</i>, and utilizing a retrospective study in conjunction with a comprehensive literature review, we suggested an efficacious, targeted antibiotic treatment strategy for GLM. Subsequently, we identified the pathogenic factor as a new type of glycolipid (named corynekropbactins) secreted by <i>C. parakroppenstedtii</i>. Corynekropbactins may chelate iron, cause the death of mammary cells and other mammary -gland-colonizing bacteria, and increase the levels of inflammatory cytokines. We further analyzed the prevalence of <i>C. parakroppenstedtii</i> infection in patients with GLM. Finally, we suggested that the lipophilicity of <i>C. parakroppenstedtii</i> may be associated with its infection route and proposed a possible model for the development of GLM. This research holds significant implications for the clinical diagnosis and therapeutic management of GLM, offering new insights into targeted treatment approaches.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":null,"pages":null},"PeriodicalIF":39.3,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142451590","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":"Sequential responsive nano-PROTACs for precise intracellular delivery and enhanced degradation efficacy in colorectal cancer therapy","authors":"Liuqing Yang, Ye Yang, Jing Zhang, Minghui Li, Long Yang, Xing Wang, Meifang Chen, Hua Zhang, Bing He, Xueqing Wang, Wenbing Dai, Yiguang Wang, Qiang Zhang","doi":"10.1038/s41392-024-01983-1","DOIUrl":"https://doi.org/10.1038/s41392-024-01983-1","url":null,"abstract":"<p>PROteolysis TArgeting Chimeras (PROTACs) have been considered the next blockbuster therapies. However, due to their inherent limitations, the efficacy of PROTACs is frequently impaired by limited tissue penetration and particularly insufficient cellular internalization into their action sites. Herein, based on the ultra-pH-sensitive and enzyme-sensitive nanotechnology, a type of polymer PROTAC conjugated and pH/cathepsin B sequential responsive nanoparticles (PSRNs) are deliberately designed, following the construction of the PROTAC for Cyclin-dependent kinase 4 and 6 (CDK4/6). Colorectal cancer (CRC) which hardly responds to many treatments even immune checkpoint blockades was selected as the tumor model in this study. As a result, PSRNs were found to maintain nanostructure (40 nm) in circulation and efficiently accumulated in tumors via enhanced permeation and retention effect. Then, they were dissociated into unimers (&lt;10 nm) in response to an acidic tumor microenvironment, facilitating tumor penetration and cellular internalization. Eventually, the CDK4/6 degrading PROTACs were released intracellularly following the cleavage of cathepsin B. Importantly, PSRNs led to the enhanced degradation of target protein in vitro and in vivo. The degradation of CDK4/6 also augmented the efficacy of immune checkpoint blockades, through the upregulation of programmed cell death-ligand 1 (PD-L1) expression in cancer cells and the suppression of regulatory T cells cell proliferation in tumor microenvironment. By combination with α-PD-1, an enhanced anti-tumor outcome is well achieved in CT26 tumor model. Overall, our study verifies the significance of precise intracellular delivery of PROTACs and introduces a promising therapeutic strategy for the targeted combination treatment of CRC.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":null,"pages":null},"PeriodicalIF":39.3,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142448209","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":"Cold and hot tumors: from molecular mechanisms to targeted therapy","authors":"Bo Wu, Bo Zhang, Bowen Li, Haoqi Wu, Meixi Jiang","doi":"10.1038/s41392-024-01979-x","DOIUrl":"https://doi.org/10.1038/s41392-024-01979-x","url":null,"abstract":"<p>Immunotherapy has made significant strides in cancer treatment, particularly through immune checkpoint blockade (ICB), which has shown notable clinical benefits across various tumor types. Despite the transformative impact of ICB treatment in cancer therapy, only a minority of patients exhibit a positive response to it. In patients with solid tumors, those who respond well to ICB treatment typically demonstrate an active immune profile referred to as the “hot” (immune-inflamed) phenotype. On the other hand, non-responsive patients may exhibit a distinct “cold” (immune-desert) phenotype, differing from the features of “hot” tumors. Additionally, there is a more nuanced “excluded” immune phenotype, positioned between the “cold” and “hot” categories, known as the immune “excluded” type. Effective differentiation between “cold” and “hot” tumors, and understanding tumor intrinsic factors, immune characteristics, TME, and external factors are critical for predicting tumor response and treatment results. It is widely accepted that ICB therapy exerts a more profound effect on “hot” tumors, with limited efficacy against “cold” or “altered” tumors, necessitating combinations with other therapeutic modalities to enhance immune cell infiltration into tumor tissue and convert “cold” or “altered” tumors into “hot” ones. Therefore, aligning with the traits of “cold” and “hot” tumors, this review systematically delineates the respective immune characteristics, influencing factors, and extensively discusses varied treatment approaches and drug targets based on “cold” and “hot” tumors to assess clinical efficacy.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":null,"pages":null},"PeriodicalIF":39.3,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142448208","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":"PD-1 and LAG-3: synergistic fostering of T cell exhaustion","authors":"Maike Hofmann, Robert Thimme, Wolfgang W. Schamel","doi":"10.1038/s41392-024-02000-1","DOIUrl":"https://doi.org/10.1038/s41392-024-02000-1","url":null,"abstract":"","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":null,"pages":null},"PeriodicalIF":39.3,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142448206","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: The JAK-STAT pathway: from structural biology to cytokine engineering","authors":"You Lv, Jianxun Qi, Jeffrey J. Babon, Longxing Cao, Guohuang Fan, Jiajia Lang, Jin Zhang, Pengbing Mi, Bostjan Kobe, Faming Wang","doi":"10.1038/s41392-024-01975-1","DOIUrl":"https://doi.org/10.1038/s41392-024-01975-1","url":null,"abstract":"<p><b>Correction to:</b> <i>Signal Transduction and Targeted Therapy</i> https://doi.org/10.1038/s41392-024-01934-w, published online 21 August 2024</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":null,"pages":null},"PeriodicalIF":39.3,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142440840","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":"Cardiomyocyte-specific knockout of ADAM17 alleviates doxorubicin-induced cardiomyopathy via inhibiting TNFα–TRAF3–TAK1–MAPK axis","authors":"Lin Xie, Fei Xue, Cheng Cheng, Wenhai Sui, Jie Zhang, Linlin Meng, Yue Lu, Wenjing Xiong, Peili Bu, Feng Xu, Xiao Yu, Bo Xi, Lin Zhong, Jianmin Yang, Cheng Zhang, Yun Zhang","doi":"10.1038/s41392-024-01977-z","DOIUrl":"https://doi.org/10.1038/s41392-024-01977-z","url":null,"abstract":"<p>The pathogenesis of doxorubicin-induced cardiomyopathy remains unclear. This study was carried out to test our hypothesis that ADAM17 aggravates cardiomyocyte apoptosis induced by doxorubicin and inhibition of ADAM17 may ameliorate doxorubicin-induced cardiomyopathy. C57BL/6J mice were intraperitoneally injected with a cumulative dose of doxorubicin to induce cardiomyopathy. Cardiomyocyte-specific ADAM17-knockout (A17^α-MHCKO) and ADAM17-overexpressing (AAV9-oeA17) mice were generated. In addition, RNA sequencing of the heart tissues in different mouse groups and in vitro experiments in neonatal rat cardiomyocytes (NRCMs) receiving different treatment were performed. Mouse tumor models were constructed in A17^fl/fl and A17^α-MHCKO mice. In addition, cardiomyocyte-specific TRAF3-knockdown and TRAF3-overexpressing mice were generated. ADAM17 expression and activity were markedly upregulated in doxorubicin-treated mouse hearts and NRCMs. A17^α-MHCKO mice showed less cardiomyocyte apoptosis induced by doxorubicin than A17^fl/fl mice, and cardiomyocyte ADAM17 deficiency did not affect the anti-tumor effect of doxorubicin. In contrast, AAV9-oeA17 mice exhibited markedly aggravated cardiomyocyte apoptosis relative to AAV9-oeNC mice after doxorubicin treatment. Mechanistically, doxorubicin enhanced the expression of transcription factor C/EBPβ, leading to increased expression and activity of ADAM17 in cardiomyocyte, which enhanced TNF-α shedding and upregulated the expression of TRAF3. Increased TRAF3 promoted TAK1 autophosphorylation, resulting in activated MAPKs pathway and cardiomyocyte apoptosis. ADAM17 acted as a positive regulator of cardiomyocyte apoptosis and cardiac remodeling and dysfunction induced by doxorubicin by upregulating TRAF3/TAK1/MAPKs signaling. Thus, targeting ADAM17/TRAF3/TAK1/MAPKs signaling holds a promising potential for treating doxorubicin-induced cardiotoxicity.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":null,"pages":null},"PeriodicalIF":39.3,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142439244","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":"Integrate and conquer: pan-cancer proteogenomics uncovers cancer vulnerabilities and therapeutic opportunities","authors":"Debomita Chakraborty, Rossana Romero, Krishnaraj Rajalingam","doi":"10.1038/s41392-024-02009-6","DOIUrl":"https://doi.org/10.1038/s41392-024-02009-6","url":null,"abstract":"<p>In a recent article published in <i>Cell</i> by Savage et al., the authors developed a computational workflow for integrating multi-omics data from readily available public online databases to provide novel insights into the proteogenomic landscape of several types of cancers and reveal new druggable targets for drug development or repurposing.¹</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":null,"pages":null},"PeriodicalIF":39.3,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142435968","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 breath of fresh air: targeted non-viral in vivo gene correction in the mammalian lung","authors":"Jixin Liu, Dirk Grimm","doi":"10.1038/s41392-024-01994-y","DOIUrl":"https://doi.org/10.1038/s41392-024-01994-y","url":null,"abstract":"<p>In a recent study published in <i>Science</i>,¹ Sun and colleagues showcase the power and potential of lung SORT LNPs, <i>i.e</i>., lipid nanoparticles that upon systemic delivery in mice specifically and efficiently target cells in the lung, most likely facilitated by their binding to plasma vitronectin and uptake via the vitronectin receptor. Most remarkably, when engineered to deliver a base editor, peripheral injection of SORT LNPs enabled highly efficient gene correction in lung stem cells, whole lung and trachea in a mouse model of cystic fibrosis, illustrating the enormous promise of this novel technology for human patients suffering from this devastating disease (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%2Fs41392-024-01994-y/MediaObjects/41392_2024_1994_Fig1_HTML.png?as=webp\" type=\"image/webp\"/><img alt=\"figure 1\" aria-describedby=\"Fig1\" height=\"144\" loading=\"lazy\" src=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fs41392-024-01994-y/MediaObjects/41392_2024_1994_Fig1_HTML.png\" width=\"685\"/></picture><p>Lipid nanoparticles (LNPs) bind to vitronectin, which facilitates their uptake by vitronectin receptors (VtnR) in the lungs. The figure illustrates the efficiency of gene editing in various lung cell types and the restoration of CFTR function. This figure was created with BioRender</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":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142431126","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":"Iron homeostasis and ferroptosis in human diseases: mechanisms and therapeutic prospects","authors":"Qin Ru, Yusheng Li, Lin Chen, Yuxiang Wu, Junxia Min, Fudi Wang","doi":"10.1038/s41392-024-01969-z","DOIUrl":"https://doi.org/10.1038/s41392-024-01969-z","url":null,"abstract":"<p>Iron, an essential mineral in the body, is involved in numerous physiological processes, making the maintenance of iron homeostasis crucial for overall health. Both iron overload and deficiency can cause various disorders and human diseases. Ferroptosis, a form of cell death dependent on iron, is characterized by the extensive peroxidation of lipids. Unlike other kinds of classical unprogrammed cell death, ferroptosis is primarily linked to disruptions in iron metabolism, lipid peroxidation, and antioxidant system imbalance. Ferroptosis is regulated through transcription, translation, and post-translational modifications, which affect cellular sensitivity to ferroptosis. Over the past decade or so, numerous diseases have been linked to ferroptosis as part of their etiology, including cancers, metabolic disorders, autoimmune diseases, central nervous system diseases, cardiovascular diseases, and musculoskeletal diseases. Ferroptosis-related proteins have become attractive targets for many major human diseases that are currently incurable, and some ferroptosis regulators have shown therapeutic effects in clinical trials although further validation of their clinical potential is needed. Therefore, in-depth analysis of ferroptosis and its potential molecular mechanisms in human diseases may offer additional strategies for clinical prevention and treatment. In this review, we discuss the physiological significance of iron homeostasis in the body, the potential contribution of ferroptosis to the etiology and development of human diseases, along with the evidence supporting targeting ferroptosis as a therapeutic approach. Importantly, we evaluate recent potential therapeutic targets and promising interventions, providing guidance for future targeted treatment therapies against human diseases.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":null,"pages":null},"PeriodicalIF":39.3,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142431139","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}