Radiation therapy (RT) is a key treatment strategy for lung cancer, yet its efficacy is frequently compromised by radioresistance. The combination of RT with targeted therapies enhances treatment outcomes for non-small cell lung cancer (NSCLC). This study aims to investigate new mechanisms of metastasis after RT for NSCLC and improve the durability of the benefits of radiotherapy for lung cancer patients. This integrative study utilized human NSCLC tissue arrays, bulk RNA-sequencing, CUT&Tag sequencing, and single-cell RNA-sequencing to identify gene alterations induced by RT. In vitro experiments and animal studies were used to investigate the role of Jumonji domain-containing 6 (JMJD6)/ETS homologous factor (EHF) axis in post-RT metastasis of NSCLC. RT triggered the upregulation of JMJD6 in NSCLC tissues. This upregulation led to the activation of EHF and the subsequent transcription of pluripotency factor genes through the demethylation of H4R3me2s. JMJD6/EHF axis plays a critical role in NSCLC cell metastasis, potentially through the TGF-β/SMAD and AKT/ERK signaling pathways. These findings suggest JMJD6 as a potential therapeutic target to combat post-RT metastasis in NSCLC.
{"title":"Integrative analysis of non-small cell lung cancer identifies Jumonji domain-containing 6/ETS homologous factor axis as a target to overcome radioresistance.","authors":"Manni Wang,Li Xu,Aqu Alu,Peiheng Li,Jian Liu,Siyuan Chen,Xuemei He,Xuejiao Han,Li Yang,Qiang Pu,Xiawei Wei","doi":"10.1038/s41392-025-02471-w","DOIUrl":"https://doi.org/10.1038/s41392-025-02471-w","url":null,"abstract":"Radiation therapy (RT) is a key treatment strategy for lung cancer, yet its efficacy is frequently compromised by radioresistance. The combination of RT with targeted therapies enhances treatment outcomes for non-small cell lung cancer (NSCLC). This study aims to investigate new mechanisms of metastasis after RT for NSCLC and improve the durability of the benefits of radiotherapy for lung cancer patients. This integrative study utilized human NSCLC tissue arrays, bulk RNA-sequencing, CUT&Tag sequencing, and single-cell RNA-sequencing to identify gene alterations induced by RT. In vitro experiments and animal studies were used to investigate the role of Jumonji domain-containing 6 (JMJD6)/ETS homologous factor (EHF) axis in post-RT metastasis of NSCLC. RT triggered the upregulation of JMJD6 in NSCLC tissues. This upregulation led to the activation of EHF and the subsequent transcription of pluripotency factor genes through the demethylation of H4R3me2s. JMJD6/EHF axis plays a critical role in NSCLC cell metastasis, potentially through the TGF-β/SMAD and AKT/ERK signaling pathways. These findings suggest JMJD6 as a potential therapeutic target to combat post-RT metastasis in NSCLC.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"9 1","pages":"391"},"PeriodicalIF":39.3,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145644893","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}
The role of preoperative anti-PD-1 antibody (pembrolizumab) plus chemoradiotherapy (PPCT) in locally advanced, resectable esophageal squamous cell carcinoma (ESCC) is still unclear. We aimed to investigate the therapeutic effect and safety of PPCT followed by surgery in this study (NCT03792347, NCT04435197). Patients with histologically confirmed, locally advanced, and surgically resectable ESCC were enrolled. They received PPCT with paclitaxel/carboplatin or nab-paclitaxel/carboplatin, followed by esophagectomy 4–6 weeks after treatment. The primary endpoint was the pathologic complete response (pCR) rate. Tumor specimens, blood samples and subcutaneous tumor mouse models were utilized to explore and validate the dynamic characteristics of the tumor microenvironment (TME) of ESCC after PPCT. Among the 143 patients enrolled, 140 received neoadjuvant treatment, and 125 underwent surgery. The pCR rate reached 43.2% (54/125). During neoadjuvant period, 75.7% (106/140) of patients experienced grade three or higher-grade adverse events. After a median follow-up of 17.4 months, patients showed a one-year disease-free survival rate of 91.1%, and an overall survival rate of 96.5%. Using scRNA-seq and cytokine profiling, we identified high IL-6 levels as a predictor of response to PPCT. In vivo experiment revealed that IL-6 neutralization enhanced the efficacy of immunotherapy by increasing CD4 + T-cell cytotoxicity. This is the first large-scale, multicenter, phase 1/2 trial reporting the short-term results of PPCT for locally advanced resectable ESCC. Although the short-term efficacy was not superior to that of neoadjuvant chemoradiotherapy, PPCT demonstrated acceptable safety and comparable one-year survival. We also revealed an association between the therapeutic response and the ability of anti-IL-6 blockade to enhance the efficacy of immunotherapy.
{"title":"Preoperative pembrolizumab (anti-PD-1 antibody) combined with chemoradiotherapy for esophageal squamous cell carcinoma: a phase 1/2 trial (PALACE-2)","authors":"Chengqiang Li, Yichao Han, Shengguang Zhao, Xiaozheng Kang, Yuyan Zheng, Yuqin Cao, Yan Yan, Liqiang Shi, Xipeng Wang, Tong Lu, Guowen Zou, Huan Li, Jiaming Che, Jie Xiang, Lianggang Zhu, Junbiao Hang, Yajie Zhang, Runsen Jin, Dingpei Han, Xueyu Chen, Hui Jing, Wei Guo, Zenghui Cheng, Liqin Zhao, Xiaoyan Chen, Bentong Yu, Jian Li, Bin Li, Yin Li, Hecheng Li","doi":"10.1038/s41392-025-02477-4","DOIUrl":"https://doi.org/10.1038/s41392-025-02477-4","url":null,"abstract":"The role of preoperative anti-PD-1 antibody (pembrolizumab) plus chemoradiotherapy (PPCT) in locally advanced, resectable esophageal squamous cell carcinoma (ESCC) is still unclear. We aimed to investigate the therapeutic effect and safety of PPCT followed by surgery in this study (NCT03792347, NCT04435197). Patients with histologically confirmed, locally advanced, and surgically resectable ESCC were enrolled. They received PPCT with paclitaxel/carboplatin or nab-paclitaxel/carboplatin, followed by esophagectomy 4–6 weeks after treatment. The primary endpoint was the pathologic complete response (pCR) rate. Tumor specimens, blood samples and subcutaneous tumor mouse models were utilized to explore and validate the dynamic characteristics of the tumor microenvironment (TME) of ESCC after PPCT. Among the 143 patients enrolled, 140 received neoadjuvant treatment, and 125 underwent surgery. The pCR rate reached 43.2% (54/125). During neoadjuvant period, 75.7% (106/140) of patients experienced grade three or higher-grade adverse events. After a median follow-up of 17.4 months, patients showed a one-year disease-free survival rate of 91.1%, and an overall survival rate of 96.5%. Using scRNA-seq and cytokine profiling, we identified high IL-6 levels as a predictor of response to PPCT. In vivo experiment revealed that IL-6 neutralization enhanced the efficacy of immunotherapy by increasing CD4 <jats:sup>+</jats:sup> T-cell cytotoxicity. This is the first large-scale, multicenter, phase 1/2 trial reporting the short-term results of PPCT for locally advanced resectable ESCC. Although the short-term efficacy was not superior to that of neoadjuvant chemoradiotherapy, PPCT demonstrated acceptable safety and comparable one-year survival. We also revealed an association between the therapeutic response and the ability of anti-IL-6 blockade to enhance the efficacy of immunotherapy.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"3 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145611263","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}
Resistance of NSCLCs to osimertinib, an EGFR tyrosine kinase inhibitor (TKI), is mediated by pleotropic mechanisms that pose a significant challenge for subsequent treatment. We report that the oncogenic MUC1-C/M1C protein confers resistance to osimertinib by regulating the STAT1 and interferon (IFN) type I/II pathways. Studies of osimertinib-resistant NSCLC cell lines selected for growth in the absence of drug demonstrate dependence on MUC1-C and the STAT1 pathway for memory of the refractory phenotype. This inflammatory memory of TKI resistance is mediated through activation of the MUC1 gene at (i) a proximal enhancer-like signature 1 (pELS-1) by MUC1-C and STAT1 and (ii) a pELS-2 by MUC1-C, JUN/AP-1, and PBAF. Our results further reveal that the MUC1-C-driven STAT1 inflammatory response promotes resistance of patient-derived (i) EGFR mutant NSCLC cells with MET amplification to the combination of osimertinib+MET TKIs, and (ii) EGFR(T790M/C797S) NSCLC cells to the 4th generation EGFR TKI TQB3804. Of clinical significance, we report that NSCLC cells dependent on MUC1-C for TKI resistance are druggable with an antibody-drug conjugate (M1C ADC) in vitro and in a PDX tumor model. These findings demonstrate that MUC1-C (i) is essential for TKI resistance of NSCLC cells by driving an inflammatory memory response and (ii) is a target for M1C ADC treatment of TKI-refractory NSCLCs.
{"title":"MUCIN 1 confers inflammatory memory of tyrosine kinase inhibitor resistance in non-small cell lung cancer","authors":"Shinkichi Takamori, Naoki Haratake, Atrayee Bhattacharya, Chie Kikutake, Hiroki Ozawa, Keisuke Shigeta, Ayako Nakashoji, Hideko Isozaki, Mototsugu Shimokawa, Mikita Suyama, Asato Hashinokuchi, Kazuki Takada, Gouji Toyokawa, Yuichi Yamada, Tomoyoshi Takenaka, Kenichi Taguchi, Masafumi Yamaguchi, Tomoharu Yoshizumi, Aaron N. Hata, Donald Kufe","doi":"10.1038/s41392-025-02482-7","DOIUrl":"https://doi.org/10.1038/s41392-025-02482-7","url":null,"abstract":"Resistance of NSCLCs to osimertinib, an EGFR tyrosine kinase inhibitor (TKI), is mediated by pleotropic mechanisms that pose a significant challenge for subsequent treatment. We report that the oncogenic MUC1-C/M1C protein confers resistance to osimertinib by regulating the STAT1 and interferon (IFN) type I/II pathways. Studies of osimertinib-resistant NSCLC cell lines selected for growth in the absence of drug demonstrate dependence on MUC1-C and the STAT1 pathway for memory of the refractory phenotype. This inflammatory memory of TKI resistance is mediated through activation of the <jats:italic>MUC1</jats:italic> gene at (i) a proximal enhancer-like signature 1 (pELS-1) by MUC1-C and STAT1 and (ii) a pELS-2 by MUC1-C, JUN/AP-1, and PBAF. Our results further reveal that the MUC1-C-driven STAT1 inflammatory response promotes resistance of patient-derived (i) EGFR mutant NSCLC cells with <jats:italic>MET</jats:italic> amplification to the combination of osimertinib+MET TKIs, and (ii) EGFR(T790M/C797S) NSCLC cells to the 4th generation EGFR TKI TQB3804. Of clinical significance, we report that NSCLC cells dependent on MUC1-C for TKI resistance are druggable with an antibody-drug conjugate (M1C ADC) in vitro and in a PDX tumor model. These findings demonstrate that MUC1-C (i) is essential for TKI resistance of NSCLC cells by driving an inflammatory memory response and (ii) is a target for M1C ADC treatment of TKI-refractory NSCLCs.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"378 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145611259","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}
Pub Date : 2025-11-27DOI: 10.1038/s41392-025-02473-8
Khalil Choucair, Hafsa Imtiaz, Md Hafiz Uddin, Misako Nagasaka, Mohammad Najeeb Al-Hallak, Philip A. Philip, Bassel El-Rayes, Boris C. Pasche, Asfar S. Azmi
Activating KRAS mutations are highly relevant to various cancers, and KRAS is the most frequently altered oncogenic protein in solid tumors. While historically considered undruggable, two KRAS G12C inactive state-selective inhibitors are currently approved for treating patients with non-small cell lung cancer. However, these agents only demonstrate a 30–40% response rate and a median progression-free survival of approximately 6 months, with the inevitable emergence of resistance mechanisms, hence remaining far from achieving a cure. Additionally, several cancers with poor prognostic outcomes, such as pancreatic adenocarcinoma, are driven by other non-G12C KRAS mutations and thus have no effective targeted therapies. Improvements in understanding RAS signaling, RNA, and nucleic acid chemistry, as well as the role of the tumor microenvironment, have sparked a paradigm shift in the approach to KRAS inhibition and suggested the potential for several novel combination therapies. In this review, we provide an overview of the RAS pathway and discuss the ongoing development and status of therapeutic strategies for targeting the oncogenic RAS. We further delve into the challenges of resistance mechanisms to better understand the rationale behind these developing strategies, describe their mechanisms of action, and offer insights into the current clinical trial status of each of these approaches.
{"title":"Targeting KRAS mutations: orchestrating cancer evolution and therapeutic challenges","authors":"Khalil Choucair, Hafsa Imtiaz, Md Hafiz Uddin, Misako Nagasaka, Mohammad Najeeb Al-Hallak, Philip A. Philip, Bassel El-Rayes, Boris C. Pasche, Asfar S. Azmi","doi":"10.1038/s41392-025-02473-8","DOIUrl":"https://doi.org/10.1038/s41392-025-02473-8","url":null,"abstract":"Activating <jats:italic>KRAS</jats:italic> mutations are highly relevant to various cancers, and KRAS is the most frequently altered oncogenic protein in solid tumors. While historically considered undruggable, two KRAS <jats:sup>G12C</jats:sup> inactive state-selective inhibitors are currently approved for treating patients with non-small cell lung cancer. However, these agents only demonstrate a 30–40% response rate and a median progression-free survival of approximately 6 months, with the inevitable emergence of resistance mechanisms, hence remaining far from achieving a cure. Additionally, several cancers with poor prognostic outcomes, such as pancreatic adenocarcinoma, are driven by other non-G12C <jats:italic>KRAS</jats:italic> mutations and thus have no effective targeted therapies. Improvements in understanding RAS signaling, RNA, and nucleic acid chemistry, as well as the role of the tumor microenvironment, have sparked a paradigm shift in the approach to KRAS inhibition and suggested the potential for several novel combination therapies. In this review, we provide an overview of the RAS pathway and discuss the ongoing development and status of therapeutic strategies for targeting the oncogenic RAS. We further delve into the challenges of resistance mechanisms to better understand the rationale behind these developing strategies, describe their mechanisms of action, and offer insights into the current clinical trial status of each of these approaches.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"206 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145611261","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}
Pub Date : 2025-11-27DOI: 10.1038/s41392-025-02479-2
Hongxin Cheng, Qing Zhang, Wen Zhong, Hanbin Li, Lu Wang, Shiqi Wang, Chengqi He, Chenying Fu, Quan Wei
Atherosclerosis serves as the core pathological basis of cardiovascular, cerebrovascular, and peripheral arterial diseases, posing a serious threat to human health. However, current mainstream treatments such as statin drugs and stent implantation are associated with significant side effects or limited efficacy, highlighting the urgent need for new therapeutic strategies. Pulsed electromagnetic fields (PEMFs), due to their noninvasive nature and anti-inflammatory properties, show potential in the treatment of atherosclerosis. This study utilized ApoE-/- mice, ApoE-/-NLRP3-/- knockout mice, human umbilical vein endothelial cells (HUVECs), human aortic endothelial cells (HAECs), and human plasma samples for experiments, revealing significant endothelial cell (EC) inflammation and pyroptosis during the progression of atherosclerosis. PEMFs were found to effectively inhibit the activation of the NLRP3 inflammasome, reduce plaque formation, and delay the progression of atherosclerosis. Proteomic analysis of plasma from atherosclerosis patients further indicated elevated expression levels of proteins related to inflammation and pyroptosis, with particularly notable changes in membrane proteins. Mechanistic studies demonstrated that PEMFs improve mitochondrial dysfunction in ECs by regulating membrane tension and the mechanosensitive tension-mediated transient receptor potential vanilloid 4 (TRPV4) channels, thereby reducing pyroptosis. This discovery not only reveals a novel mechanobiological pathway but also provides a solid theoretical foundation for the development of PEMF-based therapies for atherosclerosis.
{"title":"Pulsed electromagnetic fields inhibit atherosclerosis by regulating pyroptosis through membrane tension-mediated mechanosensitive channels","authors":"Hongxin Cheng, Qing Zhang, Wen Zhong, Hanbin Li, Lu Wang, Shiqi Wang, Chengqi He, Chenying Fu, Quan Wei","doi":"10.1038/s41392-025-02479-2","DOIUrl":"https://doi.org/10.1038/s41392-025-02479-2","url":null,"abstract":"Atherosclerosis serves as the core pathological basis of cardiovascular, cerebrovascular, and peripheral arterial diseases, posing a serious threat to human health. However, current mainstream treatments such as statin drugs and stent implantation are associated with significant side effects or limited efficacy, highlighting the urgent need for new therapeutic strategies. Pulsed electromagnetic fields (PEMFs), due to their noninvasive nature and anti-inflammatory properties, show potential in the treatment of atherosclerosis. This study utilized ApoE-/- mice, ApoE-/-NLRP3-/- knockout mice, human umbilical vein endothelial cells (HUVECs), human aortic endothelial cells (HAECs), and human plasma samples for experiments, revealing significant endothelial cell (EC) inflammation and pyroptosis during the progression of atherosclerosis. PEMFs were found to effectively inhibit the activation of the NLRP3 inflammasome, reduce plaque formation, and delay the progression of atherosclerosis. Proteomic analysis of plasma from atherosclerosis patients further indicated elevated expression levels of proteins related to inflammation and pyroptosis, with particularly notable changes in membrane proteins. Mechanistic studies demonstrated that PEMFs improve mitochondrial dysfunction in ECs by regulating membrane tension and the mechanosensitive tension-mediated transient receptor potential vanilloid 4 (TRPV4) channels, thereby reducing pyroptosis. This discovery not only reveals a novel mechanobiological pathway but also provides a solid theoretical foundation for the development of PEMF-based therapies for atherosclerosis.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"115 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145611262","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}
Pub Date : 2025-11-26DOI: 10.1038/s41392-025-02480-9
Yi-Bo Gao, Jia-Ming Xie, Yan-Nan Yang, Xiao-Xiang Zhou, Jie He
{"title":"Induction of cuproptosis enhances sensitivity and overcomes resistance to osimertinib in lung cancer","authors":"Yi-Bo Gao, Jia-Ming Xie, Yan-Nan Yang, Xiao-Xiang Zhou, Jie He","doi":"10.1038/s41392-025-02480-9","DOIUrl":"https://doi.org/10.1038/s41392-025-02480-9","url":null,"abstract":"","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"13 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145599275","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}
Pub Date : 2025-11-25DOI: 10.1038/s41392-025-02476-5
Julius C. Fischer, Sascha Göttert, Maximilian Giller, Paul Heinrich, Kaiji Fan, Omer Khalid, Caroline N. Walther, Maria Drießlein, Sophie M. Nefzger, Gabriel Eisenkolb, Vincent R. Timnik, Sebastian Jarosch, Lena Klostermeier, Thomas Engleitner, Nicholas Strieder, Claudia Gebhard, Sarah Diederich, Nicole A. Schmid, Laura Lansink Rotgerink, Laura Joachim, Sakhila Ghimire, Eva Vonbrunn, Maike Büttner-Herold, Marianne Remke, Katja Steiger, Rupert Öllinger, Roland Rad, Daniel Wolff, Markus Feuerer, Petra Hoffmann, Matthias Edinger, Michael Rehli, Markus Tschurtschenthaler, Oliver Kepp, Guido Kroemer, Erik Thiele Orberg, Stephanie E. Combs, Wolfgang Herr, Florian Bassermann, Dirk H. Busch, Ernst Holler, Simon Heidegger, Hendrik Poeck
Intestinal stem cells (ISCs) promote tissue repair after genotoxic or immune-mediated injury. However, ISCs are particularly sensitive to various stressors and primary targets of overwhelming immune responses, such as interferon γ (IFNγ)-mediated killing. In mouse models of radiation therapy-induced gut damage and in biopsies from patients who underwent allogeneic hematopoietic stem cell transplantation, we observed IFNγ expression by intestinal T reg cells. T reg cells leverage combined IFNγ and interleukin 10 (IL-10) stimulation of ISCs to nurture the growth of intestinal organoids through the activation of the mTORC1 and Myc pathways. Similarly, T reg cells or the combined addition of recombinant IFNγ and IL-10 promoted the regeneration of organoids after irradiation, and both cytokines were essential for ensuring epithelial regeneration following acute intestinal tissue injury in vivo. The exposure of organoids to growth factor-free culture conditions revealed distinct EGF-like properties of IFNγ and Wnt-like properties of IL-10. While IFNγ rapidly induced epithelial proliferation, it depleted the pool of ISCs in vitro. Only the combination of IFNγ and IL-10 led to epithelial proliferation and organoid growth while simultaneously ensuring ISC maintenance over time. Our results reveal a context-dependent role of inflammatory signaling in ISCs, through which T reg cells promote epithelial repair following therapy-induced injury.
{"title":"Tissue-adapted Tregs harness inflammatory signals to promote intestinal repair from therapy-related injury","authors":"Julius C. Fischer, Sascha Göttert, Maximilian Giller, Paul Heinrich, Kaiji Fan, Omer Khalid, Caroline N. Walther, Maria Drießlein, Sophie M. Nefzger, Gabriel Eisenkolb, Vincent R. Timnik, Sebastian Jarosch, Lena Klostermeier, Thomas Engleitner, Nicholas Strieder, Claudia Gebhard, Sarah Diederich, Nicole A. Schmid, Laura Lansink Rotgerink, Laura Joachim, Sakhila Ghimire, Eva Vonbrunn, Maike Büttner-Herold, Marianne Remke, Katja Steiger, Rupert Öllinger, Roland Rad, Daniel Wolff, Markus Feuerer, Petra Hoffmann, Matthias Edinger, Michael Rehli, Markus Tschurtschenthaler, Oliver Kepp, Guido Kroemer, Erik Thiele Orberg, Stephanie E. Combs, Wolfgang Herr, Florian Bassermann, Dirk H. Busch, Ernst Holler, Simon Heidegger, Hendrik Poeck","doi":"10.1038/s41392-025-02476-5","DOIUrl":"https://doi.org/10.1038/s41392-025-02476-5","url":null,"abstract":"Intestinal stem cells (ISCs) promote tissue repair after genotoxic or immune-mediated injury. However, ISCs are particularly sensitive to various stressors and primary targets of overwhelming immune responses, such as interferon γ (IFNγ)-mediated killing. In mouse models of radiation therapy-induced gut damage and in biopsies from patients who underwent allogeneic hematopoietic stem cell transplantation, we observed IFNγ expression by intestinal T <jats:sub>reg</jats:sub> cells. T <jats:sub>reg</jats:sub> cells leverage combined IFNγ and interleukin 10 (IL-10) stimulation of ISCs to nurture the growth of intestinal organoids through the activation of the mTORC1 and Myc pathways. Similarly, T <jats:sub>reg</jats:sub> cells or the combined addition of recombinant IFNγ and IL-10 promoted the regeneration of organoids after irradiation, and both cytokines were essential for ensuring epithelial regeneration following acute intestinal tissue injury in vivo. The exposure of organoids to growth factor-free culture conditions revealed distinct EGF-like properties of IFNγ and Wnt-like properties of IL-10. While IFNγ rapidly induced epithelial proliferation, it depleted the pool of ISCs in vitro. Only the combination of IFNγ and IL-10 led to epithelial proliferation and organoid growth while simultaneously ensuring ISC maintenance over time. Our results reveal a context-dependent role of inflammatory signaling in ISCs, through which T <jats:sub>reg</jats:sub> cells promote epithelial repair following therapy-induced injury.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"120 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145599296","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}
CD38 is highly expressed on various immune cells, including long-lived plasma cells, making it a potential therapeutic target in autoimmune diseases. This phase Ib/IIa study aimed to explore the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of CM313, an anti-CD38 antibody, in patients with systemic lupus erythematosus (SLE). Eligible patients were sequentially enrolled in four ascending dose groups (2, 4, 8, and 16 mg/kg) and randomized 4:1 to receive CM313 or placebo intravenously at days 1, 29, 36, 43, and 50. The primary endpoint was safety, and efficacy was exploratorily investigated. Between October 14, 2022, and March 7, 2024, 40 patients were enrolled, including 8 patients in each CM313 dose group and the pooled placebo group. Adverse events occurred in 90.6% and 62.5% of participants receiving CM313 and placebo, all of which were mild or moderate. Upper respiratory tract infection (87.5%/62.5% vs. 12.5%), urinary tract infection (12.5%/25.0% vs. 0), and herpes zoster (25.0%/0 vs. 0) were more frequent in CM313 8 and 16 mg/kg groups than the placebo group. The CM313 groups had greater reductions in anti-ds-DNA antibodies, immunoglobulin G (IgG), IgA, IgM, IgE, and greater increases in complement C3 and C4 compared with placebo. Systemic Lupus Erythematosus Responder Index-4 response rates were 33.3%, 40.0%, 62.5%, 71.4%, and 37.5% in CM313 2, 4, 8, 16 mg/kg, and placebo groups at day 57, respectively. CM313 showed a manageable safety profile in SLE patients at 2–16 mg/kg and encouraging clinical efficacy at 8 and 16 mg/kg. The results support further investigation of CM313 for treating SLE patients (ClinicalTrials.gov ID: NCT05465707).
CD38在多种免疫细胞上高度表达，包括长寿命的浆细胞，使其成为自身免疫性疾病的潜在治疗靶点。这项Ib/IIa期研究旨在探讨CM313（一种抗cd38抗体）在系统性红斑狼疮（SLE）患者中的安全性、药代动力学、药效学和初步疗效。符合条件的患者依次入组4个递增剂量组（2、4、8和16 mg/kg），在第1、29、36、43和50天静脉注射CM313或安慰剂，随机分为4:1组。主要终点是安全性，并对疗效进行探索性研究。在2022年10月14日至2024年3月7日期间，共入组40例患者，CM313剂量组和联合安慰剂组各8例。接受CM313和安慰剂治疗的参与者中，不良事件发生率分别为90.6%和62.5%，均为轻度或中度。CM313 8和16 mg/kg组上呼吸道感染（87.5%/62.5% vs. 12.5%）、尿路感染（12.5%/25.0% vs. 0）和带状疱疹（25.0%/0 vs. 0）发生率高于安慰剂组。与安慰剂组相比，CM313组抗ds- dna抗体、免疫球蛋白G （IgG）、IgA、IgM、IgE的降低幅度更大，补体C3和C4的增加幅度更大。第57天，CM313 2、4、8、16 mg/kg组和安慰剂组的系统性红斑狼疮反应指数-4反应率分别为33.3%、40.0%、62.5%、71.4%和37.5%。CM313在2-16 mg/kg的SLE患者中显示出可控的安全性，在8和16 mg/kg的SLE患者中显示出令人鼓舞的临床疗效。这些结果支持CM313治疗SLE患者的进一步研究（ClinicalTrials.gov ID: NCT05465707）。
{"title":"Anti-CD38 monoclonal antibody CM313 for systemic lupus erythematosus: a randomized, double-blind, placebo-controlled phase Ib/IIa trial","authors":"Jiuliang Zhao, Changsong Lin, Qibing Xie, Qiang Shu, Yang Cui, Hui Luo, Wenqiang Fan, Anbin Huang, Yi Zhao, Zili Fu, Changhao Xie, Huaxiang Wu, Niansheng Yang, Lan He, Ping Feng, Tiandong Zhang, Huan Zhou, Wei Liu, Qiaoyun Hou, Xihua Mao, Jing Sun, Bo Chen, Xiaofeng Zeng","doi":"10.1038/s41392-025-02487-2","DOIUrl":"https://doi.org/10.1038/s41392-025-02487-2","url":null,"abstract":"CD38 is highly expressed on various immune cells, including long-lived plasma cells, making it a potential therapeutic target in autoimmune diseases. This phase Ib/IIa study aimed to explore the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of CM313, an anti-CD38 antibody, in patients with systemic lupus erythematosus (SLE). Eligible patients were sequentially enrolled in four ascending dose groups (2, 4, 8, and 16 mg/kg) and randomized 4:1 to receive CM313 or placebo intravenously at days 1, 29, 36, 43, and 50. The primary endpoint was safety, and efficacy was exploratorily investigated. Between October 14, 2022, and March 7, 2024, 40 patients were enrolled, including 8 patients in each CM313 dose group and the pooled placebo group. Adverse events occurred in 90.6% and 62.5% of participants receiving CM313 and placebo, all of which were mild or moderate. Upper respiratory tract infection (87.5%/62.5% vs. 12.5%), urinary tract infection (12.5%/25.0% vs. 0), and herpes zoster (25.0%/0 vs. 0) were more frequent in CM313 8 and 16 mg/kg groups than the placebo group. The CM313 groups had greater reductions in anti-ds-DNA antibodies, immunoglobulin G (IgG), IgA, IgM, IgE, and greater increases in complement C3 and C4 compared with placebo. Systemic Lupus Erythematosus Responder Index-4 response rates were 33.3%, 40.0%, 62.5%, 71.4%, and 37.5% in CM313 2, 4, 8, 16 mg/kg, and placebo groups at day 57, respectively. CM313 showed a manageable safety profile in SLE patients at 2–16 mg/kg and encouraging clinical efficacy at 8 and 16 mg/kg. The results support further investigation of CM313 for treating SLE patients (ClinicalTrials.gov ID: NCT05465707).","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"90 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145599278","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}
Proper social behaviors are essential for survival and success, and deficits in these behaviors are associated with many brain disorders. However, the mechanisms underlying the formation and maintenance of social memory remain poorly understood. In this study, we demonstrate that social interaction with unfamiliar mouse induces α- and γ-secretase-dependent proteolysis of Neuroligin 1 (NLG1) in the ventral hippocampus (vHPC). The intracellular hydrolysate fragment, NLG1-CTD, regulates synaptic plasticity, spine strengthening, and the maintenance of social memory through its PDZ binding domain (PBD) and the cofilin signaling pathway. Both γ-secretase inhibition and deletion of the secretase recognition site on NLG1 prevent cofilin phosphorylation and impair the maintenance of social memory by inhibiting the production of NLG1-CTD. Injection of the Tat-PBD peptide into the vHPC inhibits cofilin activity and rescues deficits in social memory maintenance in mouse models. Additionally, our findings indicate that deficits in maintaining memory for sequentially presented social objects within a short temporal interval may be associated with insufficient levels of NLG1-CTD. Supplementation of Tat-PBD into the vHPC promotes maturation of dendritic spines and restores the maintenance of memory for the second social object. We also discovered that NLG1-CTD/PBD may play a role in maintaining novel object recognition memory. In summary, this work uncovers a novel mechanism that links extracellular and intracellular signal transduction processes to synaptic remodeling during learning and memory maintenance, providing a systematic perspective that connects memory formation, maintenance, and synaptic structural and functional plasticity.
{"title":"Social memory maintenance relies on social interaction-induced proteolytic products of neuroligin 1","authors":"An Liu, Xingcan Li, Mei Zhuang, Qiaoyun Ren, Jinglei Zhang, Dandan Lv, Miao Wu, Xingjie Bian, Chengyan Zhu, Xiuqi Yang, Moyi Li, Yanan Wang, Zhengping Jia, Wei Xie","doi":"10.1038/s41392-025-02467-6","DOIUrl":"https://doi.org/10.1038/s41392-025-02467-6","url":null,"abstract":"Proper social behaviors are essential for survival and success, and deficits in these behaviors are associated with many brain disorders. However, the mechanisms underlying the formation and maintenance of social memory remain poorly understood. In this study, we demonstrate that social interaction with unfamiliar mouse induces α- and γ-secretase-dependent proteolysis of Neuroligin 1 (NLG1) in the ventral hippocampus (vHPC). The intracellular hydrolysate fragment, NLG1-CTD, regulates synaptic plasticity, spine strengthening, and the maintenance of social memory through its PDZ binding domain (PBD) and the cofilin signaling pathway. Both γ-secretase inhibition and deletion of the secretase recognition site on NLG1 prevent cofilin phosphorylation and impair the maintenance of social memory by inhibiting the production of NLG1-CTD. Injection of the Tat-PBD peptide into the vHPC inhibits cofilin activity and rescues deficits in social memory maintenance in mouse models. Additionally, our findings indicate that deficits in maintaining memory for sequentially presented social objects within a short temporal interval may be associated with insufficient levels of NLG1-CTD. Supplementation of Tat-PBD into the vHPC promotes maturation of dendritic spines and restores the maintenance of memory for the second social object. We also discovered that NLG1-CTD/PBD may play a role in maintaining novel object recognition memory. In summary, this work uncovers a novel mechanism that links extracellular and intracellular signal transduction processes to synaptic remodeling during learning and memory maintenance, providing a systematic perspective that connects memory formation, maintenance, and synaptic structural and functional plasticity.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"29 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145583105","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}
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