Signal Transduction and Targeted Therapy最新文献

{"title":"Progress in pain mechanisms and management.","authors":"Yong-Chang Li, Qian-Qian Chen, Fu-Chao Zhang, Rui-Xia Weng, Timothy W Xu, Hong-Hong Zhang, Rong Gao, Lian Lian, Rui Li, Guang-Yin Xu","doi":"10.1038/s41392-026-02931-x","DOIUrl":"10.1038/s41392-026-02931-x","url":null,"abstract":"<p><p>Pain is a multifaceted sensory and emotional experience that profoundly affects human health and quality of life. It functions as a double-edged sword: while acute pain serves as a protective warning signal, chronic pain compromises physiological and psychological well-being. Pain is now widely regarded as the \"fifth vital sign,\" and given its rising prevalence and substantial global burden, chronic pain may also be considered a major chronic disease entity. Accordingly, elucidating the neural and molecular underpinnings of pain and developing effective analgesic strategies remain urgent priorities. This review provides a comprehensive overview of the molecular and neural circuit mechanisms that govern pain. At the molecular level, ion channels, diverse receptor systems, and intricate signaling pathways play central roles in the transduction and modulation of nociceptive signals. At the circuit level, pain processing involves ascending pathways, descending modulatory systems, and distributed brain regions that collectively encode the sensory and affective dimensions of pain. Building on these mechanistic insights, we discuss current therapeutic strategies, including pharmacological and nonpharmacological interventions, as well as emerging approaches such as gene therapy, stem cell-based therapies and neuromodulation. Despite notable progress, several challenges remain, including the adverse effects associated with existing analgesics and an incomplete understanding of visceral pain mechanisms. Future research should prioritize the integration of multiomics approaches, advanced neural circuit mapping technologies, and artificial intelligence to refine mechanistic insights and enable the development of more precise and effective pain management strategies.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"11 1","pages":""},"PeriodicalIF":81.2,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13658816/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149168460","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":"Back to youth: flipping the switch on tissue-resident macrophages.","authors":"Priya Veluswamy, Jens Wippermann, Max Wacker","doi":"10.1038/s41392-026-03068-7","DOIUrl":"10.1038/s41392-026-03068-7","url":null,"abstract":"","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"11 1","pages":""},"PeriodicalIF":81.2,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13655176/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149168009","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":"Hydrogen peroxide sensing and signaling in physiology and disease: implications for therapy.","authors":"Ryan J Mailloux","doi":"10.1038/s41392-026-02905-z","DOIUrl":"10.1038/s41392-026-02905-z","url":null,"abstract":"<p><p>Free radicals are highly reactive molecules that are ubiquitous in aerobic organisms. Among them, oxyradicals like superoxide (O₂^•-), hydrogen peroxide (H₂O₂), and hydroxyl radical (OH^•), collectively called reactive oxygen species (ROS), have drawn the most attention from researchers in the life sciences and biomedicine because these are the byproducts of aerobic metabolism that are responsible for the oxidative burden experienced by mammalian cells. However, it is now known this oxidative stress only occurs when cells are overwhelmed with ROS and that controlled bursts in free radical production orchestrate signaling pathways essential for organismal health. ROS like H₂O₂ is now a well-characterized second messenger that transmits signals through protein sulfur switches to activate cell stress coping strategies and induce pathways involved in proliferation, growth, and development. Additionally, defects in these redox systems have been found to be related to many diseases, which has led to the development of new therapeutic modalities to treat and prevent various disorders. In this Review, I will discuss the history of the Redox Biology and Medicine field and how these findings led to the discovery of the three known H₂O₂ signaling pathways that occur in cells; the floodgate, redox relay, and S-glutathionylation signaling mechanisms. Using this information and new findings generated with advanced molecular biology techniques that have quantified the cellular distance traveled by H₂O₂, I then propose that cells use these three redox signaling mechanisms to sense and transmit H₂O₂ signals over short and long cellular distances in mammalian cells.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"11 1","pages":""},"PeriodicalIF":81.2,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13658818/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149172047","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":"COVID-19 triggers pulmonary tumor outgrowth through hypoxia- and inflammation-induced VEGF-dependent angiogenesis","authors":"Xu Jing, Mingwei Ma, Yan Bai, Yaping Wu, Xiaoting Sun, Jing Wu, Kristian Holgersson, Xiaolu Wang, Lijuan Chen, Siwen Long, Gerald M. McInerney, Mikael Adner, Laszlo Szekely, Yunjian Zhang, Meiyun Wang, Jiaojiao Pang, Yuguo Chen, Yihai Cao","doi":"10.1038/s41392-026-02952-6","DOIUrl":"https://doi.org/10.1038/s41392-026-02952-6","url":null,"abstract":"Pulmonary nodules are highly prevalent in adult human populations, with a substantial proportion representing dormant cancerous lesions. We hypothesized that these pulmonary dormant cancers debilitate in growth owing to the lack of an angiogenic switch in tumors. In this study, we comprehensively investigated the hypothesis that specific pathological triggers can activate this angiogenic switch utilizing severe acute respiratory coronavirus 2 (SARS-CoV-2) infection-induced hypoxia as a primary physiological stimulus. Our findings provide compelling experimental evidence demonstrating that SARS-CoV-2 infection induces profound pulmonary hypoxia and severe tissue inflammation in animal models. This microenvironmental disruption markedly upregulates the expression of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor 2 (VEGFR2) within lung tissues. The resulting hyperactivation of the downstream VEGF-VEGFR2 signaling pathway effectively drives robust pulmonary neovascularization, a phenomenon frequently documented in clinical observations of COVID-19 patients. Furthermore, employing an established experimental tumor model, we demonstrated that SARS-CoV-2 infection directly accelerates tumor outgrowth via this specific VEGF angiogenesis-dependent cascade. Crucially, the targeted administration of a neutralizing antibody to block VEGF significantly suppressed tumor progression and outgrowth in SARS-CoV-2-infected, tumor-bearing animals. Our data show that the COVID-19-induced hypoxia-VEGF-angiogenesis axis serves as one of the mechanisms for initiating tumor outgrowth in pulmonary tissues.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"44 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149151724","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":"Targeting receptor tyrosine kinases: from molecular mechanisms to clinical therapeutics.","authors":"Kai Wu, Jia Ji, Ting Sun, Dan Lv, Jingying Pan, Mudan Wei, Miaojin Zhu, Minghai Wang, Lanjuan Li, Hangping Yao","doi":"10.1038/s41392-026-02840-z","DOIUrl":"10.1038/s41392-026-02840-z","url":null,"abstract":"<p><p>Receptor tyrosine kinases (RTKs), constituting a major family of cell-surface transmembrane receptors, are essential for intracellular tyrosine phosphorylation and signal transduction. RTK signaling is crucial for cellular fate regulation and tissue homeostasis, and its disruption is linked to numerous diseases. Herein, we present a comprehensive review of signaling pathways involving RTKs, with a focus on their signal transduction mechanisms and key components, along with their interactions with major signaling cascades such as G protein-coupled receptors, Wnt, and transforming growth factor β pathways. We also elucidate the multidimensional roles of RTKs in cancer development and progression, highlighting their key effects on cancer stem cell maintenance, tumor microenvironment modulation, and other factors. Furthermore, we systematically summarize the roles of RTKs in noncancerous diseases, including cardiovascular disorders, neurodegenerative diseases, metabolic syndrome, autoimmune conditions, and fibrotic disorders. We then examine current RTK-targeted therapeutics, including small-molecule inhibitors and monoclonal antibodies, for the treatment of various cancers. Finally, novel therapeutic strategies, along with the challenges associated with their development and application, are discussed. In summary, this review will enhance the understanding of the mechanistic aspects of RTK signaling in major disease pathways and provide a detailed overview of recent advancements in targeted therapeutic interventions.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"11 1","pages":""},"PeriodicalIF":81.2,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13654986/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149170668","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":"Chimeric antigen receptor T (CAR-T) cell therapy in non-oncological diseases","authors":"Zhuolin Fan, Xu Zheng, Chuan Jin, Jingting Zhang, Ningqiang Gong, Xuexin Li","doi":"10.1038/s41392-026-02783-5","DOIUrl":"https://doi.org/10.1038/s41392-026-02783-5","url":null,"abstract":"The application of chimeric antigen receptor T (CAR-T) cells in hematologic malignancies has driven significant advancements in this form of immunotherapy. The therapeutic strategy of CAR-T cells targeting specific cell populations has opened new avenues for treating non-oncological diseases, such as autoimmune diseases, aging-related conditions, and infections. For instance, in non-oncological diseases like systemic lupus erythematosus (SLE), abnormal B cell development or dysfunction leads to the production of autoantibodies, triggering localized deposition of immune complexes and resulting in tissue or organ damage and dysfunction. Relevant studies have identified disease-specific surface antigens or pathogenic cell subsets, making CAR-T cell therapy a feasible treatment approach. Moreover, in non-oncological diseases, CAR-T cells can mediate immune remodeling for certain conditions, thereby achieving long-term therapeutic remission. Although no CAR-T therapies have yet been approved for non-oncological diseases, multiple clinical trials have been initiated, with some achieving interim successes (e.g., allogeneic CAR-T cells have demonstrated efficacy in treating rheumatic diseases). Meanwhile, ongoing research into the pathogenesis of non-neoplastic diseases further supports the potential application of CAR-T cells. With this background, this article aims to introduce the latest research, mechanisms, and applications of CAR-T cell therapy in non-oncological diseases, summarize the pathogenesis of related disorders, and discuss the advantages, challenges, and future prospects of CAR-T cell therapy.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"465 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2026-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149086463","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":"Targeting the HPGDS-PGD2 axis to treat Th17 cell-mediated autoimmunity in multiple sclerosis","authors":"Yuxin Zhuang, Kawai Lei, Yan Li, Wende Deng, Jianmin Yue, Jianbo Wan, Qibiao Wu, Qianjin Lu, Yun Tang, John E. J. Rasko, Juan Liu, Olivia Monteiro, Xiqing Bian, Wei Qiu, Ting Li","doi":"10.1038/s41392-026-02937-5","DOIUrl":"https://doi.org/10.1038/s41392-026-02937-5","url":null,"abstract":"Th17 cells are central drivers of autoimmune pathology, including multiple sclerosis (MS), yet the endogenous metabolic signals that shape their pathogenic differentiation remain incompletely defined. Prostaglandin D₂ (PGD₂) is traditionally viewed as an extracellular mediator in allergic diseases. Here, we identify PGD₂ as a cell-intrinsic antagonist of the nuclear receptor PPAR<italic>γ</italic>, thereby promoting Th17 cell differentiation and exacerbating EAE pathology. PGD₂ is selectively elevated in patients with MS compared with healthy individuals. Within the MS cohort, PGD₂ correlates with Th17 cell frequency and disease severity. Consistent with this association, administration of PGD₂ increases the severity of experimental autoimmune encephalomyelitis (EAE) in mice. CD4⁺ T cell-specific deletion of <italic>Hpgds</italic>, the key synthase for PGD₂, impairs Th17 cell polarization and protects against EAE, whereas exogenous PGD₂ restores both Th17 cell responses and disease susceptibility. Importantly, pharmacological inhibition of HPGDS alleviates EAE symptoms in mice. Consistently, HPGDS inhibition suppresses Th17 cell differentiation in both murine and human CD4⁺ T cells, highlighting its translational potential. Mechanistically, PGD₂ binds directly to histidine 266 and serine 342 within the PPAR<italic>γ</italic> ligand-binding domain and suppresses its transcriptional activity, as demonstrated by site-directed mutagenesis and structure-function rescue assays in <italic>Pparg</italic>^{<italic>-/-</italic>} T cells. Collectively, our findings define a crucial role for the HPGDS-PGD₂ axis in Th17 cell-mediated autoimmunity, establishing HPGDS as a promising therapeutic target for Th17 cell-mediated autoimmune diseases such as MS.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"35 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2026-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149086461","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":"Carbon nanoparticle-Fe (II) complex for ferroptosis therapy in refractory solid tumors: a phase I trial","authors":"Huashan Shi, Ping Xie, Xiaoyu Li, Lin Lai, Qi Dang, Zehui Gou, Zhengyin Liao, Qing He, Wenhao Guo, Zhenyu Ding, Songpu Wu, Yueyun Chen, Zhen Lin, Ying Wen, Yuanfang Huang, Yan Chen, Jianqiang Xu, Chuying Huang, Yongsheng Wang","doi":"10.1038/s41392-026-02929-5","DOIUrl":"https://doi.org/10.1038/s41392-026-02929-5","url":null,"abstract":"We developed a novel carbon nanoparticle-Fe (II) complex prepared via suspension injection (CNSI-Fe) to induce cancer cell ferroptosis through direct intratumoral delivery of ferrous iron. Preclinical studies have demonstrated that CNSI-Fe has promising antitumour effects, thereby prompting this first-in-human, single-arm, open-label, dose-escalation phase I trial in patients with refractory solid tumors. Primary objectives included assessments of safety and tolerability and the determination of dose-limiting toxicity (DLT) and the maximum tolerated dose (MTD). Secondary objectives included the determination of preliminary antitumour efficacy and pharmacokinetics. Applying a 3 + 3 design across five doses (30–150 mg), a total of 19 enrolled patients received CNSI-Fe treatment. The MTD was not reached, and only one patient (in the 90 mg cohort) experienced DLT events. For all treated patients (<italic>n</italic> = 19), the common adverse events included injection site pain (89.5%), hypertension (52.6%), elevated serum iron levels (47.4%), and anemia (47.4%). Pharmacokinetic analysis revealed rapid iron absorption (peak time: 0.15–0.41 h) and clearance (half-life: 1.96–5.06 h), with peak serum concentrations ranging from 3520.33 to 13961.67 ng/mL. Preliminary efficacy estimates revealed an overall response rate of 10.5% and a disease control rate (DCR) of 84.2%. Notably, the DCR reached 100% in patients with lymph node and sarcoma lesions. Overall, CNSI-Fe demonstrated a favorable safety profile and promising antitumour activity (ClinicalTrials.gov identifier: NCT06048367), supporting further investigations in a phase II trial.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"22 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2026-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149086462","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":"Genome instability goes mobile: damaged DNA transfer between human cells.","authors":"Ashutosh Choudhury, Mathilde Courtes, Nitika Taneja","doi":"10.1038/s41392-026-03030-7","DOIUrl":"10.1038/s41392-026-03030-7","url":null,"abstract":"","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"11 1","pages":""},"PeriodicalIF":81.2,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13649729/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149138297","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":"Metabolic immune checkpoints (MICs) in cancer: from molecular mechanisms to challenges and opportunities in clinical translation.","authors":"Jinru Yang, Xing Cai, Fajian He, Junhong Zhang, Ziqiang Zhang, Zongbi Yi, Conghua Xie, Binghe Xu","doi":"10.1038/s41392-026-02903-1","DOIUrl":"10.1038/s41392-026-02903-1","url":null,"abstract":"<p><p>Metabolic reprogramming is a core feature of tumor cells in adapting to microenvironmental stress and acquiring malignant phenotypes. It not only supports rapid proliferation but also mediates immune escape by reshaping the immune microenvironment. In recent years, the \"metabolism-immune axis\", serving as a central hub for the crosstalk between metabolic regulation and immune suppression, has provided a new perspective for understanding tumor immune evasion. This review systematically discusses how metabolic pathways, including glucose, lipid, and amino acid metabolism, along with mitochondrial function and other related processes, shape the immunosuppressive tumor microenvironment by regulating immune cell function, immune checkpoint expression, and immune signaling networks, thereby promoting tumor immune escape. The concept of \"metabolic immune checkpoints (MICs)\" is innovatively proposed and classified into three categories based on their mechanisms of action: (1) MIC-I: metabolic modification-type immune checkpoints, exemplified by posttranslational modifications of immune checkpoint molecules such as PD-L1 lactylation, acetylation and glycosylation, etc.; (2) MIC-II: metabolic enzyme-dependent immune regulatory nodes, represented by enzymes such as indoleamine 2,3-dioxygenase 1 and others that directly influence immune cell function; and (3) MIC-III: microbial metabolite-coupled immune regulatory targets, including receptors for microbe-derived metabolites such as short-chain fatty acid receptors. By integrating molecular interaction networks of key targets such as lactate dehydrogenase A and ATP citrate lyase, this review explores synergistic therapeutic strategies that combine small-molecule inhibitors targeting MICs with immune checkpoint blockade. This highlights how metabolic intervention can restore immune cell function and reverse exhaustion. Current key challenges in clinical translation include limitations in metabolic dynamic monitoring technologies, lack of patient stratification biomarkers and insufficient specificity in microbiome regulation. Future directions will focus on personalized treatment guided by multiomics, integrating single-cell metabolic flux analysis, deep learning-driven target prediction, and synthetic microbiome engineering, driving tumor immunotherapy into the era of precision metabolic regulation. By integrating the fundamental mechanisms of MICs with translational medical research, this review not only provides a systematic paradigm but also establishes a foundation for the development of new-generation precision combination therapies.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"11 1","pages":""},"PeriodicalIF":81.2,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13650150/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149138309","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}