Aortic dissection (AD) is a life-threatening vascular disease with a high mortality rate. Surgery is essential in the acute phase but carries significant risks, whereas elective surgery during the chronic phase yields better outcomes. However, no pharmacological therapy has been proven effective in slowing AD progression. In our recent pilot clinical study, an association between higher plasma fibrinogen levels and improved clinical outcomes was observed in AD patients, suggesting a potential protective role of fibrinogen. However, direct evidence supporting this hypothesis is lacking. In this study, a population-based analysis of nonsurgically managed patients with acute AD revealed a distinct association: fibrinogen levels <2 g/L were significantly associated with increased mortality, whereas levels >4 g/L were significantly associated with reduced mortality. Notably, fibrinogen was undetectable in aortic samples from control individuals without AD but accumulated in the aortic media of both AD patients and model mice. Importantly, fibrinogen accumulation was more pronounced in mice with advanced but unruptured AD, suggesting its role in maintaining vascular stability. AAV8-mediated fibrinogen knockdown significantly exacerbated AD, whereas exogenous supplementation with fibrinogen alleviated AD in mice, as evidenced by changes in the survival rate, aortic dilation, AD incidence, elastic fiber degradation, and collagen accumulation. Mechanistically, fibrinogen inhibited Bmal1 signaling, preventing detrimental vascular smooth muscle cell (VSMC) phenotypic transformation and contractility impairment. Finally, exogenous supplementation with the optimal dose of fibrinogen mitigates the progression of AD in mice. This study identified fibrinogen as a key regulator of VSMC contractility and aortic structural integrity, highlighting its potential as a novel therapeutic target to delay AD progression and extend the window for elective surgery.
{"title":"Fibrinogen-Bmal1 signaling as a therapeutic target to limit aortic dissection by preserving VSMC contractility.","authors":"Xiaohan Zhong,Dongjie Li,Yuanfei Zhao,Lu Dai,Jinzhang Li,Zhiqi Ji,Bojing Zuo,Hongshan Liu,Haixia Huang,Wei Wang,Haiyang Li,Yuyong Liu,Ming Gong,Xinliang Ma,Wenjian Jiang,Meili Wang,Hongjia Zhang","doi":"10.1038/s41392-026-02610-x","DOIUrl":"https://doi.org/10.1038/s41392-026-02610-x","url":null,"abstract":"Aortic dissection (AD) is a life-threatening vascular disease with a high mortality rate. Surgery is essential in the acute phase but carries significant risks, whereas elective surgery during the chronic phase yields better outcomes. However, no pharmacological therapy has been proven effective in slowing AD progression. In our recent pilot clinical study, an association between higher plasma fibrinogen levels and improved clinical outcomes was observed in AD patients, suggesting a potential protective role of fibrinogen. However, direct evidence supporting this hypothesis is lacking. In this study, a population-based analysis of nonsurgically managed patients with acute AD revealed a distinct association: fibrinogen levels <2 g/L were significantly associated with increased mortality, whereas levels >4 g/L were significantly associated with reduced mortality. Notably, fibrinogen was undetectable in aortic samples from control individuals without AD but accumulated in the aortic media of both AD patients and model mice. Importantly, fibrinogen accumulation was more pronounced in mice with advanced but unruptured AD, suggesting its role in maintaining vascular stability. AAV8-mediated fibrinogen knockdown significantly exacerbated AD, whereas exogenous supplementation with fibrinogen alleviated AD in mice, as evidenced by changes in the survival rate, aortic dilation, AD incidence, elastic fiber degradation, and collagen accumulation. Mechanistically, fibrinogen inhibited Bmal1 signaling, preventing detrimental vascular smooth muscle cell (VSMC) phenotypic transformation and contractility impairment. Finally, exogenous supplementation with the optimal dose of fibrinogen mitigates the progression of AD in mice. This study identified fibrinogen as a key regulator of VSMC contractility and aortic structural integrity, highlighting its potential as a novel therapeutic target to delay AD progression and extend the window for elective surgery.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"102 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147483384","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}
SHR-A1811, an antibody‒drug conjugate consisting of the anti-HER2 antibody trastuzumab conjugated via a cleavable linker to a topoisomerase I inhibitor payload, demonstrated substantial antitumor activity in patients with heavily treated HER2-expressing or mutated advanced solid tumors. The main analysis was reported, and this is a long-term follow-up of the HORIZON-X trial (NCT04446260). This global, multicenter, first-in-human, phase 1 trial enrolled patients aged ≥ 18 years with unresectable, advanced, or metastatic HER2-expressing or mutated solid tumors refractory or intolerant to standard therapies across 38 hospitals. SHR-A1811 was administered intravenously at doses ranging from 1.0 to 8.0 mg/kg every three weeks. The primary endpoints included dose-limiting toxicity, safety, and the recommended phase 2 dose. From September 7, 2020, to June 4, 2024, 396 patients with a median of three prior treatment regimens (IQR 2-5) received SHR-A1811. As of March 12, 2025, the median follow-up was 17.1 months for HER2-positive breast cancer, 10.6 months for HER2-low expressing breast cancer, and 4.3 to 8.2 months in non-breast cancers. The safety profile remained consistent with that of previous reports. Grade 3 or higher treatment-related adverse events occurred in 261 patients (65.9%), and any grade interstitial lung disease was observed in 10 patients (2.5%). The median progression-free survival was 25.0 months (95% CI 17.2-33.6) for HER2-positive breast cancer, 11.0 months (95% CI 8.2-13.8) for HER2-low expressing breast cancer, and 3.5 to 17.2 months for non-breast tumors. This final analysis further confirmed the long-term efficacy and favorable safety profile of SHR-A1811 among heavily prior-treated advanced solid tumors, reinforcing its potential as an effective HER2-targeted therapy.
SHR-A1811是一种抗体-药物偶联物，由抗her2抗体曲妥珠单抗通过可切割连接物偶联到拓扑异构酶I抑制剂有效载荷组成，在重度治疗的表达her2或突变的晚期实体瘤患者中显示出显著的抗肿瘤活性。报告了主要分析，这是对HORIZON-X试验（NCT04446260）的长期随访。这项全球性、多中心、首次人体i期临床试验招募了年龄≥18岁的不可切除、晚期或转移性her2表达或突变实体瘤患者，这些患者难治性或对标准治疗不耐受，来自38家医院。SHR-A1811以每三周1.0至8.0 mg/kg的剂量静脉注射。主要终点包括剂量限制性毒性、安全性和推荐的2期剂量。从2020年9月7日至2024年6月4日，396名患者接受了shrr - a1811治疗，其中中位数为三种先前治疗方案（IQR 2-5）。截至2025年3月12日，her2阳性乳腺癌的中位随访时间为17.1个月，her2低表达乳腺癌为10.6个月，非乳腺癌为4.3至8.2个月。安全概况与以前的报告保持一致。261名患者（65.9%）发生了3级或以上的治疗相关不良事件，10名患者（2.5%）出现了任何级别的间质性肺疾病。her2阳性乳腺癌的中位无进展生存期为25.0个月（95% CI 17.2-33.6）， her2低表达乳腺癌的中位无进展生存期为11.0个月（95% CI 8.2-13.8），非乳腺肿瘤的中位无进展生存期为3.5 - 17.2个月。这一最终分析进一步证实了SHR-A1811在重度既往治疗的晚期实体瘤中的长期疗效和良好的安全性，增强了其作为一种有效的her2靶向治疗的潜力。
{"title":"SHR-A1811, a novel HER2-targeting antibody-drug conjugate, in advanced solid tumors (HORIZON-X): a global phase 1 trial.","authors":"Herui Yao,Min Yan,Zhongsheng Tong,Xinhong Wu,Yongmei Yin,Min-Hee Ryu,John J Park,Shusuan Jiang,Jee Hyun Kim,Shouman Wang,Yahua Zhong,Mark Voskoboynik,Jian Zhang,Andreas Kaubisch,Caigang Liu,Yu Chen,Seock-Ah Im,Lingying Wu,Yingbin Liu,Vinod Ganju,Minal Barve,Hui Li,Guangyu Yao,Mudan Yang,Lequn Bao,Yiming Zhao,Jianli Zhao,Kaijing Zhao,Yu Shen,Shangyi Rong,Xiaoyu Zhu,Erwei Song","doi":"10.1038/s41392-026-02612-9","DOIUrl":"https://doi.org/10.1038/s41392-026-02612-9","url":null,"abstract":"SHR-A1811, an antibody‒drug conjugate consisting of the anti-HER2 antibody trastuzumab conjugated via a cleavable linker to a topoisomerase I inhibitor payload, demonstrated substantial antitumor activity in patients with heavily treated HER2-expressing or mutated advanced solid tumors. The main analysis was reported, and this is a long-term follow-up of the HORIZON-X trial (NCT04446260). This global, multicenter, first-in-human, phase 1 trial enrolled patients aged ≥ 18 years with unresectable, advanced, or metastatic HER2-expressing or mutated solid tumors refractory or intolerant to standard therapies across 38 hospitals. SHR-A1811 was administered intravenously at doses ranging from 1.0 to 8.0 mg/kg every three weeks. The primary endpoints included dose-limiting toxicity, safety, and the recommended phase 2 dose. From September 7, 2020, to June 4, 2024, 396 patients with a median of three prior treatment regimens (IQR 2-5) received SHR-A1811. As of March 12, 2025, the median follow-up was 17.1 months for HER2-positive breast cancer, 10.6 months for HER2-low expressing breast cancer, and 4.3 to 8.2 months in non-breast cancers. The safety profile remained consistent with that of previous reports. Grade 3 or higher treatment-related adverse events occurred in 261 patients (65.9%), and any grade interstitial lung disease was observed in 10 patients (2.5%). The median progression-free survival was 25.0 months (95% CI 17.2-33.6) for HER2-positive breast cancer, 11.0 months (95% CI 8.2-13.8) for HER2-low expressing breast cancer, and 3.5 to 17.2 months for non-breast tumors. This final analysis further confirmed the long-term efficacy and favorable safety profile of SHR-A1811 among heavily prior-treated advanced solid tumors, reinforcing its potential as an effective HER2-targeted therapy.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"12 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147483385","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}
Head and neck squamous cell carcinoma (HNSCC) is one of the most prevalent and lethal cancers worldwide. Despite multimodal therapeutic advances, long-term survival remains poor, underscoring the need to identify novel molecular drivers of disease aggressiveness. Hypertranscription is a genome-wide increase in total RNA output that has emerged as a hallmark of oncogenic transformation. However, the role of mRNA-specific hypertranscription in HNSCC and its underlying molecular drivers remain undefined. In the present study, we investigated the association between mRNA hypertranscription and malignant phenotypes in HNSCC. Single-cell transcriptomics data revealed that elevated mRNA hypertranscription was significantly associated with the activation of oncogenic pathways and poor clinical outcomes. Through transcription factor activity analysis, we identified the transcription factor Spi-1 Proto-Oncogene (SPI1) as a potential regulator of mRNA hypertranscription in HNSCC malignant cells. Loss- and gain-of-function experiments in HNSCC cell lines and xenograft models established that SPI1 drives cell proliferation, invasion, migration, and tumor growth in vitro and in vivo. Mechanistically, inducible SPI1 overexpression elevated nascent RNA synthesis as measured by EU incorporation, and integrative ChIP-seq/RNA-seq profiling identified direct genomic targets of SPI1 enriched in oncogenic transcriptional programs. Collectively, our findings show that SPI1-driven mRNA hypertranscription is important in HNSCC progression and provide novel insights into the transcriptional dysregulation underlying aggressive malignancies.
{"title":"Spi-1 proto-oncogene regulates mRNA hypertranscription and malignant progression in head and neck cancer.","authors":"Zheran Liu,Zijian Qin,Huilin Li,Lili Zhu,Ling He,Na Chen,Dan Zhu,Qinghong Liu,Lei Dai,Xingchen Peng","doi":"10.1038/s41392-026-02669-6","DOIUrl":"https://doi.org/10.1038/s41392-026-02669-6","url":null,"abstract":"Head and neck squamous cell carcinoma (HNSCC) is one of the most prevalent and lethal cancers worldwide. Despite multimodal therapeutic advances, long-term survival remains poor, underscoring the need to identify novel molecular drivers of disease aggressiveness. Hypertranscription is a genome-wide increase in total RNA output that has emerged as a hallmark of oncogenic transformation. However, the role of mRNA-specific hypertranscription in HNSCC and its underlying molecular drivers remain undefined. In the present study, we investigated the association between mRNA hypertranscription and malignant phenotypes in HNSCC. Single-cell transcriptomics data revealed that elevated mRNA hypertranscription was significantly associated with the activation of oncogenic pathways and poor clinical outcomes. Through transcription factor activity analysis, we identified the transcription factor Spi-1 Proto-Oncogene (SPI1) as a potential regulator of mRNA hypertranscription in HNSCC malignant cells. Loss- and gain-of-function experiments in HNSCC cell lines and xenograft models established that SPI1 drives cell proliferation, invasion, migration, and tumor growth in vitro and in vivo. Mechanistically, inducible SPI1 overexpression elevated nascent RNA synthesis as measured by EU incorporation, and integrative ChIP-seq/RNA-seq profiling identified direct genomic targets of SPI1 enriched in oncogenic transcriptional programs. Collectively, our findings show that SPI1-driven mRNA hypertranscription is important in HNSCC progression and provide novel insights into the transcriptional dysregulation underlying aggressive malignancies.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"79 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147478879","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 : 2026-03-17DOI: 10.1038/s41392-026-02609-4
Ming-yu Zhang, Dong-ni Ji, Wen-yi Qi, Shuo Wang, Cai-yu Dai, Fei-yong Xu, Zheng Dong, Chao Xiong, Bo-wen Zhang, Yan Wang, Xiao-fei Guo, Bo Zhang, Wen-zheng Cheng, Xin-yue Zhang, Sai-di Jin, Xiao-xiang Guan, Hong Hong, Tong Zhou, Shu-feng Li, Rong Zhang, Li-hua Sun, Li-na Xuan, Yuan Jiang, Bao-feng Yang, Chao-qian Xu
Cardiac ischemia‒reperfusion (I/R) injury is a leading cause of disability and mortality worldwide, but the underlying mechanism remains largely unknown. Despite the emerging recognition of circular RNAs (circRNAs) as pivotal regulators of cardiac development and disease, their roles in cardiac I/R injury have yet to be thoroughly investigated. In this study, we identified a circRNA named circArhgap26, which is regulated by m6A modification. The expression of circArhgap26 was significantly decreased in the I/R myocardium. Cardiac-specific overexpression of circArhgap26 ameliorated cardiac dysfunction and reduced the infarct area and cardiomyocyte apoptosis in I/R model mice. Mechanistically, circArhgap26 directly bound to PKP1, thereby inhibiting the interaction between PKP1 and the palmitoyltransferase ZDHHC1. The subsequent palmitoylation of PKP1 and its protein stability are subsequently diminished, leading to a reduction in APAF1 protein synthesis and the inhibition of the Caspase-9/Caspase-3 signaling pathway, thereby mitigating cardiomyocyte apoptosis. Most importantly, the expression of circArhgap26 in the plasma of patients undergoing percutaneous coronary intervention (PCI) was decreased. This study not only elucidates the dual regulatory mechanisms of circArhgap26, m6A modification and posttranslational modification (palmitoylation), in combating I/R injury but also provides a theoretical foundation for circRNA-based therapies. Its dual value as a prognostic biomarker and therapeutic target holds promise for advancing precision cardiovascular medicine and improving outcomes in globally prevalent I/R-related diseases.
{"title":"M6A-modified circArhgap26 attenuates cardiac ischemia‒reperfusion injury by suppressing plakophilin-1 palmitoylation","authors":"Ming-yu Zhang, Dong-ni Ji, Wen-yi Qi, Shuo Wang, Cai-yu Dai, Fei-yong Xu, Zheng Dong, Chao Xiong, Bo-wen Zhang, Yan Wang, Xiao-fei Guo, Bo Zhang, Wen-zheng Cheng, Xin-yue Zhang, Sai-di Jin, Xiao-xiang Guan, Hong Hong, Tong Zhou, Shu-feng Li, Rong Zhang, Li-hua Sun, Li-na Xuan, Yuan Jiang, Bao-feng Yang, Chao-qian Xu","doi":"10.1038/s41392-026-02609-4","DOIUrl":"https://doi.org/10.1038/s41392-026-02609-4","url":null,"abstract":"Cardiac ischemia‒reperfusion (I/R) injury is a leading cause of disability and mortality worldwide, but the underlying mechanism remains largely unknown. Despite the emerging recognition of circular RNAs (circRNAs) as pivotal regulators of cardiac development and disease, their roles in cardiac I/R injury have yet to be thoroughly investigated. In this study, we identified a circRNA named circArhgap26, which is regulated by m6A modification. The expression of circArhgap26 was significantly decreased in the I/R myocardium. Cardiac-specific overexpression of circArhgap26 ameliorated cardiac dysfunction and reduced the infarct area and cardiomyocyte apoptosis in I/R model mice. Mechanistically, circArhgap26 directly bound to PKP1, thereby inhibiting the interaction between PKP1 and the palmitoyltransferase ZDHHC1. The subsequent palmitoylation of PKP1 and its protein stability are subsequently diminished, leading to a reduction in APAF1 protein synthesis and the inhibition of the Caspase-9/Caspase-3 signaling pathway, thereby mitigating cardiomyocyte apoptosis. Most importantly, the expression of circArhgap26 in the plasma of patients undergoing percutaneous coronary intervention (PCI) was decreased. This study not only elucidates the dual regulatory mechanisms of circArhgap26, m6A modification and posttranslational modification (palmitoylation), in combating I/R injury but also provides a theoretical foundation for circRNA-based therapies. Its dual value as a prognostic biomarker and therapeutic target holds promise for advancing precision cardiovascular medicine and improving outcomes in globally prevalent I/R-related diseases.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"52 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2026-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147465215","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 : 2026-03-17DOI: 10.1038/s41392-026-02597-5
Xinran Ma, Yang Zhang, Yao Wang, Fuxin Han, Yuting Lu, Chuan Tong, Yelei Guo, Jianshu Wei, Qi Zhu, Liang Dong, Zhi Cao, Zhenzhen Meng, Jinhong Shi, Zhiqiang Wu, Weidong Han
Primary resistance to chimeric antigen receptor (CAR) T-cell therapies has limited their widespread application. Our prior genome-wide CRISPR/Cas9 screening revealed that the loss of CD58, a crucial intrinsic resistance factor in tumors, resulted in insufficient immune synapse formation and impaired CAR T-cell activation and cytotoxicity. However, the specific signaling pathway and transcriptional changes associated with CAR T-cell dysfunction have not been addressed. Here, we revealed that AP-1-mediated activation was attenuated in CAR T cells impaired by tumor CD58 loss, driving a decrease in mitochondrial biogenesis, metabolic kinetic impairment, mitochondrial membrane potential loss and ROS accumulation. Moreover, this AP-1 attenuation triggered death receptor-independent apoptosis through the intrinsic mitochondrial pathway. In seeking therapeutic strategies, we pharmacologically and genetically blocked three distinct inhibitory phosphatases positioned upstream of AP-1 signaling. Multifaceted validation has demonstrated that dual specificity phosphatase 6 (DUSP6) blockade is an effective approach to supplement AP-1 signaling while notably reducing CAR T-apoptosis and enhancing mitochondrial fitness, proliferation and long-term cytotoxicity. The transcriptomic profiles of DUSP6-ablated CAR T cells revealed markedly upregulated T-cell activation signatures and enriched metabolic pathways. Clinically, bulk and single-cell RNA-seq analyses revealed that DUSP6 was downregulated in patients who responded to T-cell-based immunotherapy, implying its relevance to patient outcomes. Our findings repositioned CD58 not merely as an immune synapse component but also a metabolic checkpoint in CAR T-cell biology, the loss of which triggers AP-1-dependent mitochondrial derangement and creates a permissive landscape for intrinsic apoptosis, which can be ameliorated by ablation of the inhibitory phosphatase DUSP6. Crucially, DUSP6 ablation represents a promising engineering target to potentiate CAR T-cell efficacy in broader applications.
{"title":"DUSP6 ablation restores CAR T-cell fitness impaired by tumor CD58 loss through invigoration of AP-1 signaling","authors":"Xinran Ma, Yang Zhang, Yao Wang, Fuxin Han, Yuting Lu, Chuan Tong, Yelei Guo, Jianshu Wei, Qi Zhu, Liang Dong, Zhi Cao, Zhenzhen Meng, Jinhong Shi, Zhiqiang Wu, Weidong Han","doi":"10.1038/s41392-026-02597-5","DOIUrl":"https://doi.org/10.1038/s41392-026-02597-5","url":null,"abstract":"Primary resistance to chimeric antigen receptor (CAR) T-cell therapies has limited their widespread application. Our prior genome-wide CRISPR/Cas9 screening revealed that the loss of CD58, a crucial intrinsic resistance factor in tumors, resulted in insufficient immune synapse formation and impaired CAR T-cell activation and cytotoxicity. However, the specific signaling pathway and transcriptional changes associated with CAR T-cell dysfunction have not been addressed. Here, we revealed that AP-1-mediated activation was attenuated in CAR T cells impaired by tumor CD58 loss, driving a decrease in mitochondrial biogenesis, metabolic kinetic impairment, mitochondrial membrane potential loss and ROS accumulation. Moreover, this AP-1 attenuation triggered death receptor-independent apoptosis through the intrinsic mitochondrial pathway. In seeking therapeutic strategies, we pharmacologically and genetically blocked three distinct inhibitory phosphatases positioned upstream of AP-1 signaling. Multifaceted validation has demonstrated that dual specificity phosphatase 6 (DUSP6) blockade is an effective approach to supplement AP-1 signaling while notably reducing CAR T-apoptosis and enhancing mitochondrial fitness, proliferation and long-term cytotoxicity. The transcriptomic profiles of DUSP6-ablated CAR T cells revealed markedly upregulated T-cell activation signatures and enriched metabolic pathways. Clinically, bulk and single-cell RNA-seq analyses revealed that DUSP6 was downregulated in patients who responded to T-cell-based immunotherapy, implying its relevance to patient outcomes. Our findings repositioned CD58 not merely as an immune synapse component but also a metabolic checkpoint in CAR T-cell biology, the loss of which triggers AP-1-dependent mitochondrial derangement and creates a permissive landscape for intrinsic apoptosis, which can be ameliorated by ablation of the inhibitory phosphatase DUSP6. Crucially, DUSP6 ablation represents a promising engineering target to potentiate CAR T-cell efficacy in broader applications.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"4 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2026-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147465160","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}
Docetaxel (Doc), a widely used chemotherapeutic agent, was limited by suboptimal therapeutic efficacy and dose-limiting systemic toxicity due to the insufficiency of hydrophilicity and tumor-targeting specificity. To address this limitation, we developed an amphiphilic ferrocene-based polymer, PPEGMA-b-PFMMA (PF), to co-encapsulate Doc and the photosensitizer IR808, forming photothermally responsive nanoparticles (NPs) termed P8D NPs. P8D NPs significantly improved the aqueous stability and tumor-specific accumulation of both agents by leveraging a hydrogen peroxide (H₂O₂)-triggered drug release mechanism within the tumor microenvironment. Under near‑infrared (NIR) irradiation, P8D NPs generated substantial heat and a burst of reactive oxygen species (ROS), promoting NPs disintegration and drug release. Mechanistically, Doc induced nuclear to cytoplasmic translocation of HMGB1, while photothermal/photodynamic therapy (PTT/PDT) facilitated the extracellular release of damage-associated molecular patterns (DAMPs) and tumor-associated antigens via ferroptosis and cell membrane rupture. Together, these actions enhanced dendritic cells (DCs) maturation, antigen presentation and cytotoxic CD8⁺ T cell infiltration in tumor, thereby effectively reversing the immunosuppressive tumor microenvironment. Remarkably, this combination strategy not only inhibited the growth of distant tumors but also established long-term anti-tumor immunological memory to prevent recurrence. This study demonstrates that ferrocene-based nanocarrier-mediated PTT/PDT synergizes with Doc to reactivate antitumor immunity through ferroptosis-induced immunogenic cell death (ICD).
{"title":"Chemo-photothermal synergy ignites antitumor immunity via ferroptosis","authors":"Jundong Lin, Huikang Yang, Zhihao Zou, Lizhi Deng, Xiaoxia Cai, Muqi Chen, Jiaquan Xu, Wenjun Yin, Biyan Wen, Wenjie Xie, Qianfeng Xu, Guowei Zhong, Zhenjie Wu, Yanfei Chen, Rihong Zhang, Weicheng Tian, Yixun Zhang, Yusen Long, Yize Li, Zhaodong Han, Yuxiang Liang, Jianheng Ye, Jianming Lu, Yingke Liang, Qishan Dai, Fen Zou, Huichan He, Weide Zhong, Yangjia Zhuo","doi":"10.1038/s41392-026-02608-5","DOIUrl":"https://doi.org/10.1038/s41392-026-02608-5","url":null,"abstract":"Docetaxel (Doc), a widely used chemotherapeutic agent, was limited by suboptimal therapeutic efficacy and dose-limiting systemic toxicity due to the insufficiency of hydrophilicity and tumor-targeting specificity. To address this limitation, we developed an amphiphilic ferrocene-based polymer, PPEGMA-b-PFMMA (PF), to co-encapsulate Doc and the photosensitizer IR808, forming photothermally responsive nanoparticles (NPs) termed P8D NPs. P8D NPs significantly improved the aqueous stability and tumor-specific accumulation of both agents by leveraging a hydrogen peroxide (H₂O₂)-triggered drug release mechanism within the tumor microenvironment. Under near‑infrared (NIR) irradiation, P8D NPs generated substantial heat and a burst of reactive oxygen species (ROS), promoting NPs disintegration and drug release. Mechanistically, Doc induced nuclear to cytoplasmic translocation of HMGB1, while photothermal/photodynamic therapy (PTT/PDT) facilitated the extracellular release of damage-associated molecular patterns (DAMPs) and tumor-associated antigens via ferroptosis and cell membrane rupture. Together, these actions enhanced dendritic cells (DCs) maturation, antigen presentation and cytotoxic CD8⁺ T cell infiltration in tumor, thereby effectively reversing the immunosuppressive tumor microenvironment. Remarkably, this combination strategy not only inhibited the growth of distant tumors but also established long-term anti-tumor immunological memory to prevent recurrence. This study demonstrates that ferrocene-based nanocarrier-mediated PTT/PDT synergizes with Doc to reactivate antitumor immunity through ferroptosis-induced immunogenic cell death (ICD).","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"11 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2026-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147465161","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}
COVID-19 resulting from SARS-CoV-2 infection has presented significant challenges to global health over the past several years. Animal models are essential for studying the pathogenic mechanisms of SARS-CoV-2 and facilitating the development of therapeutic strategies. Transgenic hACE2 mouse models are widely used to explore the mechanisms responsible for severe and lethal COVID-19. However, current lethal transgenic mouse models are reported to die primarily from central nervous system infection, whereas in human patients, respiratory system infection is the primary cause of death. Moreover, earlier mouse models require the use of high-containment biosafety laboratories, which significantly limits SARS-CoV-2 studies and restricts broader experimental applications. Here, we established mouse models with systemic or lung-specific expression of the SARS-CoV-2 nucleocapsid (N) protein based on the K18-hACE2 KI mice. Both strains of mice are susceptible to SARS-CoV-2 ΔN/GFP-HBiT replicon delivery particles (RDPs), allowing efficient viral replication without producing infectious virions. Notably, lung-specific N-expressing mice exhibit only pulmonary infection, with lethality and pathological features closer to the clinical presentations of COVID-19. This RDP-infected mouse model enables the evaluation of anti-SARS-CoV-2 drugs, with infection phenotypes closely resembling those of wild-type SARS-CoV-2. Overall, this model offers a safer, increasingly convenient, and more universally applicable tool for SARS-CoV-2 research and antiviral therapy development.
{"title":"A biosafe mouse model for SARS-CoV-2 infection that more realistically simulates COVID-19 symptoms","authors":"Xiaoya Huang, Yingjian Li, Jikai Deng, Xue Tan, Shimin Yang, Jintao Liu, Zhengzhong Wu, Peiliang Shi, Li Zhou, Yu Chen","doi":"10.1038/s41392-026-02640-5","DOIUrl":"https://doi.org/10.1038/s41392-026-02640-5","url":null,"abstract":"COVID-19 resulting from SARS-CoV-2 infection has presented significant challenges to global health over the past several years. Animal models are essential for studying the pathogenic mechanisms of SARS-CoV-2 and facilitating the development of therapeutic strategies. Transgenic hACE2 mouse models are widely used to explore the mechanisms responsible for severe and lethal COVID-19. However, current lethal transgenic mouse models are reported to die primarily from central nervous system infection, whereas in human patients, respiratory system infection is the primary cause of death. Moreover, earlier mouse models require the use of high-containment biosafety laboratories, which significantly limits SARS-CoV-2 studies and restricts broader experimental applications. Here, we established mouse models with systemic or lung-specific expression of the SARS-CoV-2 nucleocapsid (N) protein based on the K18-hACE2 KI mice. Both strains of mice are susceptible to SARS-CoV-2 ΔN/GFP-HBiT replicon delivery particles (RDPs), allowing efficient viral replication without producing infectious virions. Notably, lung-specific N-expressing mice exhibit only pulmonary infection, with lethality and pathological features closer to the clinical presentations of COVID-19. This RDP-infected mouse model enables the evaluation of anti-SARS-CoV-2 drugs, with infection phenotypes closely resembling those of wild-type SARS-CoV-2. Overall, this model offers a safer, increasingly convenient, and more universally applicable tool for SARS-CoV-2 research and antiviral therapy development.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"11 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147465225","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 : 2026-03-16DOI: 10.1038/s41392-026-02607-6
Yuqiao Wang, Hao Zhao, Ke Sun, Dan Deng, Guanyu Liu, Lan Li, Tao Liu, Lin Bao, Wei Xu, Chunying Chen
Pyroptosis, which rapidly releases cellular contents through pyroptotic pores, is an ideal method for inducing in situ cancer vaccines, evoking systemic antitumor immunity, and suppressing primary and metastatic tumors. However, the clinical translation of pyroptosis-based therapy is hindered by the inability to spatially control the activation of inert precursors and the inefficient catalytic activity of nanozymes, which often fail to generate sufficient reactive oxygen species for effective treatment. To address this, we designed a conductive coordination nanozyme prodrug, Cu–DHN. Its π-conjugated polyphenol backbone functions as an intrinsic “electron highway,” enabling rapid electron shuttling to utilize the entire nanoparticle volume for catalysis, thereby achieving exceptional peroxidase-like activity. Upon systemic administration, Cu–DHN remains inert in circulation but is precisely activated within the tumor microenvironment by a tandem GSH-depletion and H2O2-responsive logic gate. This triggers a self-cascade reaction that locally transforms the coordinated prodrug into juglone, which concurrently reverses gasdermin D epigenetic silencing and activates the NLRP3 inflammasome for caspase-1-mediated cleavage. This single-agent, tumor-specific initiation of pyroptosis, augmented by concomitant cuproptosis, elicits potent immunogenic cell death and robust systemic antitumor immunity, effectively suppressing primary and metastatic tumors while exhibiting a pristine safety profile. Our work establishes electron-shuttling coordination polymers as a versatile platform for developing safe and potent catalytic immunotherapies.
{"title":"Conductive coordination nanozyme prodrugs precisely trigger pyroptosis, cuproptosis and ferroptosis for in situ cancer vaccination","authors":"Yuqiao Wang, Hao Zhao, Ke Sun, Dan Deng, Guanyu Liu, Lan Li, Tao Liu, Lin Bao, Wei Xu, Chunying Chen","doi":"10.1038/s41392-026-02607-6","DOIUrl":"https://doi.org/10.1038/s41392-026-02607-6","url":null,"abstract":"Pyroptosis, which rapidly releases cellular contents through pyroptotic pores, is an ideal method for inducing in situ cancer vaccines, evoking systemic antitumor immunity, and suppressing primary and metastatic tumors. However, the clinical translation of pyroptosis-based therapy is hindered by the inability to spatially control the activation of inert precursors and the inefficient catalytic activity of nanozymes, which often fail to generate sufficient reactive oxygen species for effective treatment. To address this, we designed a conductive coordination nanozyme prodrug, Cu–DHN. Its π-conjugated polyphenol backbone functions as an intrinsic “electron highway,” enabling rapid electron shuttling to utilize the entire nanoparticle volume for catalysis, thereby achieving exceptional peroxidase-like activity. Upon systemic administration, Cu–DHN remains inert in circulation but is precisely activated within the tumor microenvironment by a tandem GSH-depletion and H2O2-responsive logic gate. This triggers a self-cascade reaction that locally transforms the coordinated prodrug into juglone, which concurrently reverses gasdermin D epigenetic silencing and activates the NLRP3 inflammasome for caspase-1-mediated cleavage. This single-agent, tumor-specific initiation of pyroptosis, augmented by concomitant cuproptosis, elicits potent immunogenic cell death and robust systemic antitumor immunity, effectively suppressing primary and metastatic tumors while exhibiting a pristine safety profile. Our work establishes electron-shuttling coordination polymers as a versatile platform for developing safe and potent catalytic immunotherapies.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"5 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147465229","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}
Nanoparticle-based phototherapy represents a paradigm shift in precision medicine, harnessing light-activated mechanisms to modulate cellular pathways across a spectrum of diseases. By integrating nanoparticles, phototherapeutic modalities achieve enhanced light absorption and improved targeting and amplification effects, such as reactive oxygen species generation in photodynamic therapy and localized heating in photothermal therapy. Gold nanoparticles and hybrid constructs have attracted considerable attention in both photothermal and photodynamic therapies, while delivery platforms, such as liposomes and dendrimers, fine-tune biodistribution and release kinetics. At the molecular level, phototherapy induces oxidative stress, triggers apoptotic and autophagic cascades and modulates immune responses by altering cytokine profiles and T-cell activity processes, which are critical not only in cancer therapy but also in managing various chronic conditions, including cardiovascular, neurodegenerative, metabolic and autoimmune disorders. In this review, we chart the evolution of nanoparticle-based phototherapy systems by examining their core components, classification schemes and delivery platforms that drive treatment specificity. We then dissect the underlying signaling pathways, highlighting how light-triggered interventions intersect with key molecular networks in chronic disease contexts. Additionally, we critically evaluate FDA-approved agents and insights from recent clinical trials, outlining the major challenges to clinical translation, including nanoparticle optimization, efficient light delivery and regulatory hurdles. By integrating molecular insights with clinical advancements, nanoparticle-based phototherapy has emerged as a transformative, noninvasive strategy poised to revolutionize therapeutic approaches for a wide range of diseases.
{"title":"Nanoparticles-based phototherapy systems: molecular mechanisms and clinical applications.","authors":"Deepak S Chauhan,Rajendra Prasad,Mukesh Dhanka,Navneet Kaur,Hitasha Vithalani,Kaveesha Liyanapathirana,Roopa Hebbandi Nanjundappa,Huile Gao,Channakeshava Sokke Umeshappa","doi":"10.1038/s41392-025-02536-w","DOIUrl":"https://doi.org/10.1038/s41392-025-02536-w","url":null,"abstract":"Nanoparticle-based phototherapy represents a paradigm shift in precision medicine, harnessing light-activated mechanisms to modulate cellular pathways across a spectrum of diseases. By integrating nanoparticles, phototherapeutic modalities achieve enhanced light absorption and improved targeting and amplification effects, such as reactive oxygen species generation in photodynamic therapy and localized heating in photothermal therapy. Gold nanoparticles and hybrid constructs have attracted considerable attention in both photothermal and photodynamic therapies, while delivery platforms, such as liposomes and dendrimers, fine-tune biodistribution and release kinetics. At the molecular level, phototherapy induces oxidative stress, triggers apoptotic and autophagic cascades and modulates immune responses by altering cytokine profiles and T-cell activity processes, which are critical not only in cancer therapy but also in managing various chronic conditions, including cardiovascular, neurodegenerative, metabolic and autoimmune disorders. In this review, we chart the evolution of nanoparticle-based phototherapy systems by examining their core components, classification schemes and delivery platforms that drive treatment specificity. We then dissect the underlying signaling pathways, highlighting how light-triggered interventions intersect with key molecular networks in chronic disease contexts. Additionally, we critically evaluate FDA-approved agents and insights from recent clinical trials, outlining the major challenges to clinical translation, including nanoparticle optimization, efficient light delivery and regulatory hurdles. By integrating molecular insights with clinical advancements, nanoparticle-based phototherapy has emerged as a transformative, noninvasive strategy poised to revolutionize therapeutic approaches for a wide range of diseases.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"59 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147465226","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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