{"title":"Circulating miR-18b-3p is a novel biomarker predicting chemo-radiotherapy induced oral mucositis in head and neck cancer.","authors":"Claudio Pulito,Renata Brandi,Rosanna Sestito,Giulia Orlandi,Giuseppe Sanguineti,Giovanni Blandino,Sabrina Strano","doi":"10.1038/s41392-025-02478-3","DOIUrl":"https://doi.org/10.1038/s41392-025-02478-3","url":null,"abstract":"","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"32 1","pages":"380"},"PeriodicalIF":39.3,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145558975","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 : 2025-11-21DOI: 10.1038/s41392-025-02469-4
Byeongsoo Kim,BuHyun Youn
{"title":"Starving tumor, feeding metastasis: a warning about low-carbohydrate diets in cancer therapy.","authors":"Byeongsoo Kim,BuHyun Youn","doi":"10.1038/s41392-025-02469-4","DOIUrl":"https://doi.org/10.1038/s41392-025-02469-4","url":null,"abstract":"","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"79 1","pages":"379"},"PeriodicalIF":39.3,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145558978","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}
Despite advancements in several malignancies, the treatment atlas of natural killer (NK) cell therapy for pancreatic cancer remains inadequate, and the dynamic immune landscape underlying the various responses is still incompletely understood. This phase 1b/2 trial evaluated the safety and efficacy of allogeneic NK cell therapy combined with gemcitabine and S-1 as a first-line treatment for advanced pancreatic cancer (APC) and explored the dynamic responsive immune landscape (ChiCTR1900021764). The administration of 1 × 109 to 8 × 109 NK cells to 24 patients was well tolerated, with no graft-versus-host disease or dose-limiting toxicity. Among the 19 evaluable patients, the objective response rate was 31.6%, and the disease control rate was 73.7%. The median progression-free survival was 6.6 months, and the overall survival was 10.8 months. Further longitudinal single-cell RNA sequencing (scRNA-seq) of 19 paired-blood samples revealed an increased proportion of certain NK cell subsets (c4-ZEB2, c5-IL7, c6-IL15, c10-NCR3, and c11-TNFSF8) and T-cell subsets (CD8+ Teff and CD4+ Tem) in responders, characterized by increased expression of proinflammatory and effector molecules. Bulk T-cell receptor (TCR) Vβ repertoire sequencing of responders indicated potential T-cell clonal expansion, manifested as a greater abundance of large and hyperexpanded clonotypes. Our first-in-human trial demonstrated its safety and potentially preliminary efficacy, warranting further clinical evaluation. Multiomic profiling identified specific circulating NK and T-cell subsets potentially associated with clinical outcomes, providing novel insights into the dynamic transcriptional underpinnings of the immune landscape in response to NK cell-based therapy.
{"title":"Dynamic transcriptional immune landscape in response to NK-cell therapy combined with gemcitabine plus S-1 in advanced pancreatic cancer: a phase 1b/2 trial.","authors":"Qin Tan,Yifei Li,Caixia Liu,Jing Xu,Jinlian Tong,Jiangyong Yu,Yingying Huang,Xueqing Hu,Sen Qin,Fei Xiao,Yunbo Zhao,Jie Ma","doi":"10.1038/s41392-025-02488-1","DOIUrl":"https://doi.org/10.1038/s41392-025-02488-1","url":null,"abstract":"Despite advancements in several malignancies, the treatment atlas of natural killer (NK) cell therapy for pancreatic cancer remains inadequate, and the dynamic immune landscape underlying the various responses is still incompletely understood. This phase 1b/2 trial evaluated the safety and efficacy of allogeneic NK cell therapy combined with gemcitabine and S-1 as a first-line treatment for advanced pancreatic cancer (APC) and explored the dynamic responsive immune landscape (ChiCTR1900021764). The administration of 1 × 109 to 8 × 109 NK cells to 24 patients was well tolerated, with no graft-versus-host disease or dose-limiting toxicity. Among the 19 evaluable patients, the objective response rate was 31.6%, and the disease control rate was 73.7%. The median progression-free survival was 6.6 months, and the overall survival was 10.8 months. Further longitudinal single-cell RNA sequencing (scRNA-seq) of 19 paired-blood samples revealed an increased proportion of certain NK cell subsets (c4-ZEB2, c5-IL7, c6-IL15, c10-NCR3, and c11-TNFSF8) and T-cell subsets (CD8+ Teff and CD4+ Tem) in responders, characterized by increased expression of proinflammatory and effector molecules. Bulk T-cell receptor (TCR) Vβ repertoire sequencing of responders indicated potential T-cell clonal expansion, manifested as a greater abundance of large and hyperexpanded clonotypes. Our first-in-human trial demonstrated its safety and potentially preliminary efficacy, warranting further clinical evaluation. Multiomic profiling identified specific circulating NK and T-cell subsets potentially associated with clinical outcomes, providing novel insights into the dynamic transcriptional underpinnings of the immune landscape in response to NK cell-based therapy.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"1 1","pages":"381"},"PeriodicalIF":39.3,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145558977","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 : 2025-11-19DOI: 10.1038/s41392-025-02466-7
Khalil Mallah, Carsten Krieg, Devin Hatchell, Nahla Hamouda, Tylar Roof, Stephen Walterhouse, Amer Toutonji, Davis Borucki, Christine Couch, Gary Hardiman, Firas Kobeissy, Silvia Guglietta, Stephen Tomlinson
Repeated mild closed head injury (rmCHI) is a significant public health concern, and this type of repetitive injury is garnering increasing attention, not least because of its increasing incidence in sports. The underlying neuroimmune mechanisms secondary to trauma that link rmCHI to cognitive impairment remain to be elucidated, and the contribution of the complement system to the pathological sequelae of this type of brain injury is unexplored. Here, using C57BL/6J mice, we established a repetitive 12-head impact model to investigate the neuroimmune and pathological processes that occur after rmCHI. We specifically studied the role of complement in pathology and cognitive impairment up to 21 days after the cessation of injury in a clinically relevant paradigm using the site-targeted complement inhibitor CR2-Crry. Our analytical methods included mass cytometry, RNA-seq, proteomics, and immunohistological characterization. Mass cytometric analysis revealed that cognitive impairment after rmCHI was associated with major subacute/chronic alterations in local immune cell recruitment, particularly the recruitment and activation of microglia, with marked upregulation of complement receptors and proteins associated with the phagocytic machinery. RNA-seq and proteomic analysis revealed major changes in pathways associated with neurodegeneration, neuronal apoptosis, and the upregulation of complement proteins in animals subjected to rmCHI. Complement inhibition initiated after cessation of injury modulated rmCHI-induced changes and protected against cognitive impairment. In addition to expanding our understanding of the pathological sequelae of rmCHI, these data highlight the therapeutic potential of complement inhibition.
{"title":"Targeted complement inhibition ameliorates the pathological and cognitive outcomes in repetitive mild closed head injury","authors":"Khalil Mallah, Carsten Krieg, Devin Hatchell, Nahla Hamouda, Tylar Roof, Stephen Walterhouse, Amer Toutonji, Davis Borucki, Christine Couch, Gary Hardiman, Firas Kobeissy, Silvia Guglietta, Stephen Tomlinson","doi":"10.1038/s41392-025-02466-7","DOIUrl":"https://doi.org/10.1038/s41392-025-02466-7","url":null,"abstract":"Repeated mild closed head injury (rmCHI) is a significant public health concern, and this type of repetitive injury is garnering increasing attention, not least because of its increasing incidence in sports. The underlying neuroimmune mechanisms secondary to trauma that link rmCHI to cognitive impairment remain to be elucidated, and the contribution of the complement system to the pathological sequelae of this type of brain injury is unexplored. Here, using C57BL/6J mice, we established a repetitive 12-head impact model to investigate the neuroimmune and pathological processes that occur after rmCHI. We specifically studied the role of complement in pathology and cognitive impairment up to 21 days after the cessation of injury in a clinically relevant paradigm using the site-targeted complement inhibitor CR2-Crry. Our analytical methods included mass cytometry, RNA-seq, proteomics, and immunohistological characterization. Mass cytometric analysis revealed that cognitive impairment after rmCHI was associated with major subacute/chronic alterations in local immune cell recruitment, particularly the recruitment and activation of microglia, with marked upregulation of complement receptors and proteins associated with the phagocytic machinery. RNA-seq and proteomic analysis revealed major changes in pathways associated with neurodegeneration, neuronal apoptosis, and the upregulation of complement proteins in animals subjected to rmCHI. Complement inhibition initiated after cessation of injury modulated rmCHI-induced changes and protected against cognitive impairment. In addition to expanding our understanding of the pathological sequelae of rmCHI, these data highlight the therapeutic potential of complement inhibition.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"1 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145554103","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}
Polycystic ovary syndrome (PCOS) is a frequent endocrine and metabolic imbalance that typically occurs in women of reproductive age. Its molecular pathophysiology is yet unknown, especially the ovarian cellular metabolic inefficiency that causes the transcriptional dysregulation of key genes linked to PCOS. Here, we discovered that one transcriptional-like regulator that causes PCOS is nuclear pyruvate kinase M2 (nPKM2). Using multiomics techniques, we show that enhanced lactylation of histone 3 on lysine residues 9 and 18 is linked to nPKM2 binding to the genome, changing the three-dimensional architecture of the genome. Genomic compartment switching, topologically associated domain fusion, and novel enhancer-promoter interactions subsequently enhance the expression of PCOS-related genes, including CYP17A1 and CYP11A1. In mice, ectopic expression of Pkm2 in female GCs consistently presented PCOS-like traits, such as interrupted estrous cycles, hyperandrogenism, and so on. Importantly, whole-organ tracing imaging directly unfolded the number of small follicles, which increased highly in Pkm2-tdtomato transgene mice compared with control. Furthermore, pharmacological inhibition of the nuclear accumulation of PKM2 mitigated PCOS-like symptoms in mice and restored a wild-type-like transcriptome. This study demonstrates the important function of PKM2-mediated histone lactylation in regulating the three-dimensional chromatin architecture and highlights PKM2 as a potential therapeutic target for PCOS treatment.
{"title":"Pyruvate kinase M2 -mediated histone lactylation alters three-dimensional genomic architecture in polycystic ovary syndrome.","authors":"Chuanjin Yu,Tingting Liu,Yishu Wang,Xinghui Guo,Yujie Chen,Yifan Zhao,Xia Liu,Weiwei Huang,Shuoyang Zhao,Jiaying Mo,Hongtao Hu,Pingping Lv,Xiaotao Wang,Zuwei Yang,Jiexue Pan,Guolian Ding,Jianzhong Sheng,Xinmei Liu,Hongbo Yang,He-Feng Huang","doi":"10.1038/s41392-025-02468-5","DOIUrl":"https://doi.org/10.1038/s41392-025-02468-5","url":null,"abstract":"Polycystic ovary syndrome (PCOS) is a frequent endocrine and metabolic imbalance that typically occurs in women of reproductive age. Its molecular pathophysiology is yet unknown, especially the ovarian cellular metabolic inefficiency that causes the transcriptional dysregulation of key genes linked to PCOS. Here, we discovered that one transcriptional-like regulator that causes PCOS is nuclear pyruvate kinase M2 (nPKM2). Using multiomics techniques, we show that enhanced lactylation of histone 3 on lysine residues 9 and 18 is linked to nPKM2 binding to the genome, changing the three-dimensional architecture of the genome. Genomic compartment switching, topologically associated domain fusion, and novel enhancer-promoter interactions subsequently enhance the expression of PCOS-related genes, including CYP17A1 and CYP11A1. In mice, ectopic expression of Pkm2 in female GCs consistently presented PCOS-like traits, such as interrupted estrous cycles, hyperandrogenism, and so on. Importantly, whole-organ tracing imaging directly unfolded the number of small follicles, which increased highly in Pkm2-tdtomato transgene mice compared with control. Furthermore, pharmacological inhibition of the nuclear accumulation of PKM2 mitigated PCOS-like symptoms in mice and restored a wild-type-like transcriptome. This study demonstrates the important function of PKM2-mediated histone lactylation in regulating the three-dimensional chromatin architecture and highlights PKM2 as a potential therapeutic target for PCOS treatment.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"487 1","pages":"376"},"PeriodicalIF":39.3,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145545073","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 : 2025-11-18DOI: 10.1038/s41392-025-02489-0
Yuting Dai, Shaojian Lin, Junchen Wu, Shuangshuang Yang, Yang Lu, Xiaobin Wang, Jun Li, Linfeng Zhao, Desheng Chen, Bo Zhang, Yijun Cheng, Hong Yao, Fan Zhang, Min Xu, Qiang Wang, Xiaojing Lin, Kunjin Chen, Zhen Tian, Xingyan Liu, Pascal Roy, Hai Fang, Gang Lv, Tong Yin, Yun Tan, Bo Jiao, Shengyue Wang, Li Xue, Youqiong Ye, Saijuan Chen, Zhe Bao Wu
Pituitary neuroendocrine tumors (PitNETs) are pathologically characterized by dysregulation of neuroendocrine function and systemic disruption of hormonal homeostasis, yet their regulatory effects on peripheral immune networks remain poorly characterized. Here, we systematically analyzed bulk RNA sequencing (RNA‑seq) from 883 PitNET tumors, 108 PitNET‑associated peripheral blood mononuclear cells (PBMC) samples, and 175 healthy PBMC controls, combined with 69 single‑cell RNA sequencing (scRNA-seq) samples covering tumors, normal pituitaries, as well as tumor‑derived and normal PBMCs. We identified a systemic immune disequilibrium in PitNET patients, characterized by increased circulating lymphocyte proportions, accompanied by upregulated cytokine-receptor interaction signatures. Notably, tumor resection reversed this imbalance, as supported by the normalization of monocyte and neutrophil counts, validated by flow cytometry and routine blood data from 600 samples (200 healthy controls and 200 PitNET patients with paired pre- and post-surgery follow‑up). Trajectory analysis identified terminally differentiated, secretory-specialized cell populations with lineage-specific hormone and cytokine hypersecretion. Ligand-receptor inference suggested these tumor-derived factors potentially engage circulating immune cell receptors. A random‑forest classifier based on PBMC transcriptomes distinguished PitNET subtypes, underscoring the diagnostic potential of peripheral immune signatures. Furthermore, in an estrogen-induced rat model, elevated PRL level coincided with the same peripheral immune skewing. Overall, our work provides a valuable resource and demonstrates PitNETs can be systemic immune modulators, where intrinsic hormone secretory activity and monocyte-lymphocyte imbalance collectively drive peripheral immune dysfunction.
{"title":"Multidimensional tumor-blood profiling uncovers systemic lymphocyte-monocyte imbalance in pituitary neuroendocrine tumors","authors":"Yuting Dai, Shaojian Lin, Junchen Wu, Shuangshuang Yang, Yang Lu, Xiaobin Wang, Jun Li, Linfeng Zhao, Desheng Chen, Bo Zhang, Yijun Cheng, Hong Yao, Fan Zhang, Min Xu, Qiang Wang, Xiaojing Lin, Kunjin Chen, Zhen Tian, Xingyan Liu, Pascal Roy, Hai Fang, Gang Lv, Tong Yin, Yun Tan, Bo Jiao, Shengyue Wang, Li Xue, Youqiong Ye, Saijuan Chen, Zhe Bao Wu","doi":"10.1038/s41392-025-02489-0","DOIUrl":"https://doi.org/10.1038/s41392-025-02489-0","url":null,"abstract":"Pituitary neuroendocrine tumors (PitNETs) are pathologically characterized by dysregulation of neuroendocrine function and systemic disruption of hormonal homeostasis, yet their regulatory effects on peripheral immune networks remain poorly characterized. Here, we systematically analyzed bulk RNA sequencing (RNA‑seq) from 883 PitNET tumors, 108 PitNET‑associated peripheral blood mononuclear cells (PBMC) samples, and 175 healthy PBMC controls, combined with 69 single‑cell RNA sequencing (scRNA-seq) samples covering tumors, normal pituitaries, as well as tumor‑derived and normal PBMCs. We identified a systemic immune disequilibrium in PitNET patients, characterized by increased circulating lymphocyte proportions, accompanied by upregulated cytokine-receptor interaction signatures. Notably, tumor resection reversed this imbalance, as supported by the normalization of monocyte and neutrophil counts, validated by flow cytometry and routine blood data from 600 samples (200 healthy controls and 200 PitNET patients with paired pre- and post-surgery follow‑up). Trajectory analysis identified terminally differentiated, secretory-specialized cell populations with lineage-specific hormone and cytokine hypersecretion. Ligand-receptor inference suggested these tumor-derived factors potentially engage circulating immune cell receptors. A random‑forest classifier based on PBMC transcriptomes distinguished PitNET subtypes, underscoring the diagnostic potential of peripheral immune signatures. Furthermore, in an estrogen-induced rat model, elevated PRL level coincided with the same peripheral immune skewing. Overall, our work provides a valuable resource and demonstrates PitNETs can be systemic immune modulators, where intrinsic hormone secretory activity and monocyte-lymphocyte imbalance collectively drive peripheral immune dysfunction.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"12 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145536069","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 : 2025-11-18DOI: 10.1038/s41392-025-02461-y
Wan Ching Chan, Man Long Kwok, Xinyan Qu, Hazem Abdelkarim, Jonathan Le, Deying Yang, Avik Banerjee, Shuangping Zhao, Jacob Class, Marlen Gonzalez, Harry Hailemeskel, Raman Ghotra Singh, Ricardo Gallardo-Macias, Vadim J. Gurvich, Mark Maienschein-Cline, Matthew Lindeblad, Kasim Kabirov, Alexander V. Lyubimov, Patrick Belvitch, Justin Richner, Vadim Gaponenko, Yulia A. Komarova
Acute respiratory distress syndrome (ARDS) is a severe pulmonary disease characterized by acute, noncardiogenic pulmonary edema and hypoxemia leading to respiratory failure. It is induced by a diverse array of etiologies, including recent SARS-CoV-2 infection. The current standard of care for ARDS remains predominantly supportive, underscoring the urgent need for targeted pharmacological interventions. To address this critical gap, we developed an inhibitor of the microtubule accessory factor end-binding protein 3 (EB3), a key mediator of pathological calcium signaling in endothelial cells. During injury, EB3 facilitates inositol 1,4,5-trisphosphate receptor 3 (IP 3 R3) clustering on the endoplasmic reticulum membrane, activating widespread calcium release from intracellular stores and leading to endothelial barrier disruption. Using nuclear magnetic resonance (NMR)-guided approaches, we designed and optimized a synthetic EB3 inhibitor, termed vascular therapeutics (VT)-109, with enhanced physicochemical properties. We evaluated the therapeutic potential of VT-109 across a wide range of preclinical models in which pathogenic insults target epithelial or endothelial barriers. Treatment with VT-109 promptly restored the tissue‒fluid balance in the injured lung by inducing the reannealing of VE-cadherin junctions and restoring the endothelial barrier. In addition to vascular protection, VT-109 improved lung architecture and function, normalized immune responses, and significantly reduced both morbidity and mortality in ARDS models. At the molecular level, VT-109 blocks inflammatory NFAT and NF κ B signaling while concurrently activating FOXM1-dependent endothelial regeneration. These findings support EB3 inhibition as a promising therapeutic strategy for ARDS and highlight VT-109 as a versatile drug candidate capable of addressing the multifaceted pathophysiology of this disease.
{"title":"Therapeutic targeting of endothelial calcium signaling accelerates the resolution of lung injury","authors":"Wan Ching Chan, Man Long Kwok, Xinyan Qu, Hazem Abdelkarim, Jonathan Le, Deying Yang, Avik Banerjee, Shuangping Zhao, Jacob Class, Marlen Gonzalez, Harry Hailemeskel, Raman Ghotra Singh, Ricardo Gallardo-Macias, Vadim J. Gurvich, Mark Maienschein-Cline, Matthew Lindeblad, Kasim Kabirov, Alexander V. Lyubimov, Patrick Belvitch, Justin Richner, Vadim Gaponenko, Yulia A. Komarova","doi":"10.1038/s41392-025-02461-y","DOIUrl":"https://doi.org/10.1038/s41392-025-02461-y","url":null,"abstract":"Acute respiratory distress syndrome (ARDS) is a severe pulmonary disease characterized by acute, noncardiogenic pulmonary edema and hypoxemia leading to respiratory failure. It is induced by a diverse array of etiologies, including recent SARS-CoV-2 infection. The current standard of care for ARDS remains predominantly supportive, underscoring the urgent need for targeted pharmacological interventions. To address this critical gap, we developed an inhibitor of the microtubule accessory factor end-binding protein 3 (EB3), a key mediator of pathological calcium signaling in endothelial cells. During injury, EB3 facilitates inositol 1,4,5-trisphosphate receptor 3 (IP <jats:sub>3</jats:sub> R3) clustering on the endoplasmic reticulum membrane, activating widespread calcium release from intracellular stores and leading to endothelial barrier disruption. Using nuclear magnetic resonance (NMR)-guided approaches, we designed and optimized a synthetic EB3 inhibitor, termed vascular therapeutics (VT)-109, with enhanced physicochemical properties. We evaluated the therapeutic potential of VT-109 across a wide range of preclinical models in which pathogenic insults target epithelial or endothelial barriers. Treatment with VT-109 promptly restored the tissue‒fluid balance in the injured lung by inducing the reannealing of VE-cadherin junctions and restoring the endothelial barrier. In addition to vascular protection, VT-109 improved lung architecture and function, normalized immune responses, and significantly reduced both morbidity and mortality in ARDS models. At the molecular level, VT-109 blocks inflammatory NFAT and NF <jats:italic>κ</jats:italic> B signaling while concurrently activating FOXM1-dependent endothelial regeneration. These findings support EB3 inhibition as a promising therapeutic strategy for ARDS and highlight VT-109 as a versatile drug candidate capable of addressing the multifaceted pathophysiology of this disease.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"6 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145536075","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 : 2025-11-17DOI: 10.1038/s41392-025-02464-9
Benjamin H Mullish,Lauren A Roberts,Horace R T Williams
{"title":"Microbiota transplants: the concept of 'microbiome mismatching' explored.","authors":"Benjamin H Mullish,Lauren A Roberts,Horace R T Williams","doi":"10.1038/s41392-025-02464-9","DOIUrl":"https://doi.org/10.1038/s41392-025-02464-9","url":null,"abstract":"","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"144 1","pages":"374"},"PeriodicalIF":39.3,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145531266","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 : 2025-11-17DOI: 10.1038/s41392-025-02472-9
Wenhao Zhang, Yanzhi Gai, Mengxue Qiao, Michelle Rowicki, Yong Wei, Xiang Hang, Zhengkai Wei, He Yang, Xifu Ye, Hang Ju, Yi Lu, Yibin Kang, Minhong Shen
Immune checkpoint blockade (ICB) therapy, which has revolutionized cancer treatment, has been approved for the treatment of triple-negative breast cancer (TNBC). Unfortunately, most patients with TNBC are either not eligible for treatment or exhibit resistance, resulting in limited overall survival benefits. There is an urgent need to elucidate the mechanisms of resistance and enhance therapeutic efficacy. Here, via CRISPR activation (CRISPRa) screening, we identified family with sequence similarity 114 member A1 ( FAM114A1 ) as a key mediator of immune evasion and ICB resistance in TNBC. Mechanistically, FAM114A1 binds p85α to disrupt the p85α/p110α protein complex, thus activating the PI3K/AKT pathway and simultaneously preventing condensate formation of E2F Transcription Factor 4 (E2F4) to promote E2F4-driven Metadherin (MTDH) transcription. Upregulation of these FAM114A1-mediated pathways suppresses tumor antigen presentation and consequently attenuates antitumor immunity in TNBC. Moreover, targeting FAM114A1 improves the therapeutic effectiveness of anti-PD-1 therapy in mouse models, and a FAM114A1-based signature shows strong predictive performance for identifying patients with TNBC who may benefit from ICB. Collectively, our findings not only reveal that FAM114A1 is an immune evasion driver but also highlight it as a promising biomarker and therapeutic target. Our study provides new insights into TNBC immune evasion and outlines a potential avenue to improve the effectiveness of ICB.
{"title":"Family with sequence similarity 114 member A1 orchestrates immune evasion in triple-negative breast cancer","authors":"Wenhao Zhang, Yanzhi Gai, Mengxue Qiao, Michelle Rowicki, Yong Wei, Xiang Hang, Zhengkai Wei, He Yang, Xifu Ye, Hang Ju, Yi Lu, Yibin Kang, Minhong Shen","doi":"10.1038/s41392-025-02472-9","DOIUrl":"https://doi.org/10.1038/s41392-025-02472-9","url":null,"abstract":"Immune checkpoint blockade (ICB) therapy, which has revolutionized cancer treatment, has been approved for the treatment of triple-negative breast cancer (TNBC). Unfortunately, most patients with TNBC are either not eligible for treatment or exhibit resistance, resulting in limited overall survival benefits. There is an urgent need to elucidate the mechanisms of resistance and enhance therapeutic efficacy. Here, via CRISPR activation (CRISPRa) screening, we identified <jats:italic>family with sequence similarity 114 member A1</jats:italic> ( <jats:italic>FAM114A1</jats:italic> ) as a key mediator of immune evasion and ICB resistance in TNBC. Mechanistically, FAM114A1 binds p85α to disrupt the p85α/p110α protein complex, thus activating the PI3K/AKT pathway and simultaneously preventing condensate formation of E2F Transcription Factor 4 (E2F4) to promote E2F4-driven Metadherin (MTDH) transcription. Upregulation of these FAM114A1-mediated pathways suppresses tumor antigen presentation and consequently attenuates antitumor immunity in TNBC. Moreover, targeting FAM114A1 improves the therapeutic effectiveness of anti-PD-1 therapy in mouse models, and a FAM114A1-based signature shows strong predictive performance for identifying patients with TNBC who may benefit from ICB. Collectively, our findings not only reveal that FAM114A1 is an immune evasion driver but also highlight it as a promising biomarker and therapeutic target. Our study provides new insights into TNBC immune evasion and outlines a potential avenue to improve the effectiveness of ICB.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"6 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145536082","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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