High-grade serous ovarian cancer (HGSC) accounts for more than 70% of ovarian cancer-related deaths, yet therapeutic progress remains stagnant. Among the four molecular subtypes reported for HGSC, the C5 subtype is distinguished by high proliferation and immune evasion with an unfavorable MHC-I/PD-L1 ratio. However, the molecular drivers of this immune desert state remain largely undefined. Here, we identify RNA-binding proteins (RBPs) as key regulators of immune evasion in C5-HGSC through integrated single-cell and bulk RNA sequencing. We perform a targeted loss-of-function screen in C5-like cell models and find IGF2BP1 as a central mediator of immune evasion in vitro and in vivo. Mechanistically, IGF2BP1 abrogates interferon-gamma signaling by accelerating IRF1 protein degradation, thereby suppressing MHC-I presentation. We also discover that IGF2BP1 decouples PD-L1 expression from IRF1-dependent transcription and reshapes the immune receptor landscape to limit immune cell infiltration and T cell activation. Therapeutically, the small-molecule BTYNB effectively inhibits IGF2BP1 and synergizes with PD-1 blockade to overcome immune evasion in vivo. Multi-spectral imaging confirms these findings in human HGSC tissues and highlights the role of oncofetal RBPs as molecular drivers of the C5-HGSC subtype. This subtype-wide survey uncovers a previously unrecognized RBP-interferon regulatory axis and establishes RBP inhibition as a therapeutic strategy to enhance immune checkpoint therapy in immunologically cold ovarian tumors.
{"title":"Inhibition of RNA-binding proteins enhances immunotherapy in ovarian cancer.","authors":"Nadine Bley,Alexander Rausch,Simon Müller,Theresa Simon,Markus Glaß,Danny Misiak,Laura Schian,Lara Meret Peters,Mohammad Dipto,Ali Hmedat,Bianca Busch,Annekatrin Schott,Marcell Lederer,Alice Wedler,Robin Benedikt Rolnik,Hend Elrewany,Ehab Ghazy,Wolfgang Sippl,Martina Vetter,Markus Wallwiener,Stefan Hüttelmaier","doi":"10.1038/s41392-025-02515-1","DOIUrl":"https://doi.org/10.1038/s41392-025-02515-1","url":null,"abstract":"High-grade serous ovarian cancer (HGSC) accounts for more than 70% of ovarian cancer-related deaths, yet therapeutic progress remains stagnant. Among the four molecular subtypes reported for HGSC, the C5 subtype is distinguished by high proliferation and immune evasion with an unfavorable MHC-I/PD-L1 ratio. However, the molecular drivers of this immune desert state remain largely undefined. Here, we identify RNA-binding proteins (RBPs) as key regulators of immune evasion in C5-HGSC through integrated single-cell and bulk RNA sequencing. We perform a targeted loss-of-function screen in C5-like cell models and find IGF2BP1 as a central mediator of immune evasion in vitro and in vivo. Mechanistically, IGF2BP1 abrogates interferon-gamma signaling by accelerating IRF1 protein degradation, thereby suppressing MHC-I presentation. We also discover that IGF2BP1 decouples PD-L1 expression from IRF1-dependent transcription and reshapes the immune receptor landscape to limit immune cell infiltration and T cell activation. Therapeutically, the small-molecule BTYNB effectively inhibits IGF2BP1 and synergizes with PD-1 blockade to overcome immune evasion in vivo. Multi-spectral imaging confirms these findings in human HGSC tissues and highlights the role of oncofetal RBPs as molecular drivers of the C5-HGSC subtype. This subtype-wide survey uncovers a previously unrecognized RBP-interferon regulatory axis and establishes RBP inhibition as a therapeutic strategy to enhance immune checkpoint therapy in immunologically cold ovarian tumors.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"16 1","pages":"419"},"PeriodicalIF":39.3,"publicationDate":"2025-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145823852","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 : 2025-12-25DOI: 10.1038/s41392-025-02516-0
Mi-Kyung Oh,Hyun Sung Park,Dong-Hoon Chae,Aaron Yu,Jae Han Park,Jiyoung Heo,Keonwoo Cho,Jiho Kim,Byeonghwi Lim,Jun-Mo Kim,Jordan E Axelrad,Kyung Ku Jang,Jong Pil Im,Seong-Joon Koh,Byung-Soo Kim,Kyung-Rok Yu
Current therapies for inflammatory bowel disease (IBD) often fail to achieve complete remission and are associated with systemic toxicity owing to their broad immunosuppressive effects. To overcome these limitations, we developed a bioengineered extracellular vesicle (EV) platform that modulates key immune signaling pathways to efficiently restore the T-cell balance in inflamed intestinal tissues. EVs derived from Wharton's jelly mesenchymal stem cells were engineered to display PD-L1 on their surface and encapsulate miR-27a-3p. Surface PD-L1 engages the PD-1 checkpoint in activated T cells, attenuating T-cell receptor signaling via SHP2-mediated dephosphorylation of ZAP70 and AKT. In parallel, miR-27a-3p suppresses prohibitin 1 (PHB1), a mitochondrial regulator of Th17 cell bioenergetics and inflammatory function, thereby reducing Th17 polarization and increasing the number of FOXP3⁺ regulatory T cells. These dual-targeting EVs preferentially localized to inflamed intestinal tissues via chemokine (CCR2/CXCR4) and PD-1-dependent mechanisms. In humanized mouse models of colitis, these EVs attenuated mucosal inflammation, suppressed effector T-cell responses, and preserved epithelial integrity. In IBD patient-derived colonoid cultures, PD-L1/miR-27a-3p EVs maintained epithelial viability and barrier integrity without inducing cytotoxicity or structural disruption. Transcriptomic and single-cell analyses revealed the downregulation of inflammatory and exhaustion signatures, along with the enrichment of regulatory subsets. Collectively, this study presents a cell-free immunotherapeutic approach that reprograms T cells in inflamed tissues through the PD-1 and mitochondrial signaling pathways while maintaining intestinal epithelial integrity, offering a promising therapeutic strategy for IBD and other T cell-driven inflammatory disorders.
{"title":"Engineered extracellular vesicles reprogram T cells by targeting PD-1 and PHB1 signaling in inflammatory bowel disease.","authors":"Mi-Kyung Oh,Hyun Sung Park,Dong-Hoon Chae,Aaron Yu,Jae Han Park,Jiyoung Heo,Keonwoo Cho,Jiho Kim,Byeonghwi Lim,Jun-Mo Kim,Jordan E Axelrad,Kyung Ku Jang,Jong Pil Im,Seong-Joon Koh,Byung-Soo Kim,Kyung-Rok Yu","doi":"10.1038/s41392-025-02516-0","DOIUrl":"https://doi.org/10.1038/s41392-025-02516-0","url":null,"abstract":"Current therapies for inflammatory bowel disease (IBD) often fail to achieve complete remission and are associated with systemic toxicity owing to their broad immunosuppressive effects. To overcome these limitations, we developed a bioengineered extracellular vesicle (EV) platform that modulates key immune signaling pathways to efficiently restore the T-cell balance in inflamed intestinal tissues. EVs derived from Wharton's jelly mesenchymal stem cells were engineered to display PD-L1 on their surface and encapsulate miR-27a-3p. Surface PD-L1 engages the PD-1 checkpoint in activated T cells, attenuating T-cell receptor signaling via SHP2-mediated dephosphorylation of ZAP70 and AKT. In parallel, miR-27a-3p suppresses prohibitin 1 (PHB1), a mitochondrial regulator of Th17 cell bioenergetics and inflammatory function, thereby reducing Th17 polarization and increasing the number of FOXP3⁺ regulatory T cells. These dual-targeting EVs preferentially localized to inflamed intestinal tissues via chemokine (CCR2/CXCR4) and PD-1-dependent mechanisms. In humanized mouse models of colitis, these EVs attenuated mucosal inflammation, suppressed effector T-cell responses, and preserved epithelial integrity. In IBD patient-derived colonoid cultures, PD-L1/miR-27a-3p EVs maintained epithelial viability and barrier integrity without inducing cytotoxicity or structural disruption. Transcriptomic and single-cell analyses revealed the downregulation of inflammatory and exhaustion signatures, along with the enrichment of regulatory subsets. Collectively, this study presents a cell-free immunotherapeutic approach that reprograms T cells in inflamed tissues through the PD-1 and mitochondrial signaling pathways while maintaining intestinal epithelial integrity, offering a promising therapeutic strategy for IBD and other T cell-driven inflammatory disorders.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"1 1","pages":"418"},"PeriodicalIF":39.3,"publicationDate":"2025-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145823838","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}
Sperm motility and morphology are indispensable for sperm-egg interaction and successful fertilization. However, the RNA splicing mechanisms in an m6A-dependent manner regulating spermiogenesis-related genes remain poorly defined, and targeted therapy strategies to restore impaired sperm motility and morphology are lacking. In this study, we identify heterogeneous nuclear ribonucleoprotein R (hnRNPR) as a critical m6A-dependent splicing mediator. Pathogenic mutations in HNRNPR cause sperm motility decline, morphological abnormality, and male infertility in both humans and mice. Mechanistically, Hnrnpr mutation disrupts m6A-dependent splicing of Skap2 pre-mRNA, thus impairing cytoskeletal structure and mitochondrial organization in sperm. Consistently, specific knockout of Skap2 in male germ cells displays sperm abnormalities, which phenocopy those observed in humans and mice with Hnrnpr mutants, unveiling a functional hnRNPR-SKAP2 axis. Leveraging these insights, we developed a therapeutic strategy to restore sperm motility and morphology, relying on extracellular vesicle-mediated SKAP2 delivery to enter the efferent ductules of the testicles, which could promote sperm cytoskeletal remodeling and mitochondrial organization. Notably, the co-culture of extracellular vesicle SKAP2 with human and mouse sperms also significantly enhanced the sperm motility. Altogether, these findings identify hnRNPR as a pivotal regulator of m6A-mediated Skap2 splicing during spermiogenesis and highlight extracellular vesicle SKAP2 as a promising therapeutic target for poor sperm quality and male infertility.
{"title":"Targeting SKAP2 restores sperm motility and morphology through modulating mitochondrial organization and cytoskeletal remodeling.","authors":"Shiming Gan,Lin Yin,Jiaming Zhou,Sisi Li,Shumin Zhou,Xiaotong Yang,Rui Liu,Xu Fan,Yangyang Li,Zhendong Yao,Jingshou Chen,Peiran Hu,Wenjing Xiong,Yuan Yuan,Yujiao Wen,Youjiang Li,Ge Jin,Jianzhong Sheng,Yuzhen Gao,Hefeng Huang,Chen Zhang","doi":"10.1038/s41392-025-02513-3","DOIUrl":"https://doi.org/10.1038/s41392-025-02513-3","url":null,"abstract":"Sperm motility and morphology are indispensable for sperm-egg interaction and successful fertilization. However, the RNA splicing mechanisms in an m6A-dependent manner regulating spermiogenesis-related genes remain poorly defined, and targeted therapy strategies to restore impaired sperm motility and morphology are lacking. In this study, we identify heterogeneous nuclear ribonucleoprotein R (hnRNPR) as a critical m6A-dependent splicing mediator. Pathogenic mutations in HNRNPR cause sperm motility decline, morphological abnormality, and male infertility in both humans and mice. Mechanistically, Hnrnpr mutation disrupts m6A-dependent splicing of Skap2 pre-mRNA, thus impairing cytoskeletal structure and mitochondrial organization in sperm. Consistently, specific knockout of Skap2 in male germ cells displays sperm abnormalities, which phenocopy those observed in humans and mice with Hnrnpr mutants, unveiling a functional hnRNPR-SKAP2 axis. Leveraging these insights, we developed a therapeutic strategy to restore sperm motility and morphology, relying on extracellular vesicle-mediated SKAP2 delivery to enter the efferent ductules of the testicles, which could promote sperm cytoskeletal remodeling and mitochondrial organization. Notably, the co-culture of extracellular vesicle SKAP2 with human and mouse sperms also significantly enhanced the sperm motility. Altogether, these findings identify hnRNPR as a pivotal regulator of m6A-mediated Skap2 splicing during spermiogenesis and highlight extracellular vesicle SKAP2 as a promising therapeutic target for poor sperm quality and male infertility.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"56 1","pages":"416"},"PeriodicalIF":39.3,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145813412","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 : 2025-12-24DOI: 10.1038/s41392-025-02525-z
Yi Song, Jian Li, Yuzhang Wu
{"title":"Correction: Evolving understanding of autoimmune mechanisms and new therapeutic strategies of autoimmune disorders.","authors":"Yi Song, Jian Li, Yuzhang Wu","doi":"10.1038/s41392-025-02525-z","DOIUrl":"10.1038/s41392-025-02525-z","url":null,"abstract":"","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"10 1","pages":"426"},"PeriodicalIF":52.7,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12738843/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145828142","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Brain metastasis is a major contributor to mortality in patients with lung cancer. The unique microenvironment of the brain plays a critical role in the initiation and progression of brain metastases (BM), yet the molecular mechanisms underlying tumor-microenvironment interactions remain poorly understood. Here, we demonstrate that upregulation of lipocalin-2 (LCN2) in tumor cells promotes brain metastatic progression by orchestrating crosstalk among metastatic tumor cells, astrocytes, and macrophages. Brain metastatic tumor cells secrete LCN2, which binds to SLC22A17 on astrocytes, activating JAK2/STAT3 signaling and inducing astrocyte activation and chemokine secretion, thereby facilitating macrophage recruitment. In turn, macrophages secrete IL-1β, which further upregulates LCN2 expression in tumor cells. Prophylactic administration of the IL-1 receptor antagonist anakinra inhibits BM formation, whereas therapeutic administration alone is ineffective. However, treatment with the STAT3 inhibitor SH4-54, either alone or in combination with anakinra, significantly suppressed tumor growth in the BM. Furthermore, tumor-secreted LCN2 can bind to SLC22A17 on tumor cells, activating JAK2/STAT3 signaling and promoting VEGF-A expression and release, which enhances tumor neovascularization. Inhibition of this axis with SH4-54, bevacizumab, or their combination effectively reduces the tumor burden in BM-bearing mice. These findings underscore the central role of LCN2 in driving brain metastasis and highlight a potential therapeutic strategy for targeting brain metastatic lung cancer.
{"title":"Lipocalin-2 drives brain metastatic progression through reciprocal tumor-microenvironment interactions in lung cancer.","authors":"Yixiang Zhu,Jian Zhang,Danming He,Hongqing Cai,Yan He,Li Yuan,Sini Li,Yucheng Dong,Wei Zhuang,Zhijie Wang,Jianchun Duan,Xue Zhang,Zixiao Ma,Hua Bai,Jie Wang","doi":"10.1038/s41392-025-02514-2","DOIUrl":"https://doi.org/10.1038/s41392-025-02514-2","url":null,"abstract":"Brain metastasis is a major contributor to mortality in patients with lung cancer. The unique microenvironment of the brain plays a critical role in the initiation and progression of brain metastases (BM), yet the molecular mechanisms underlying tumor-microenvironment interactions remain poorly understood. Here, we demonstrate that upregulation of lipocalin-2 (LCN2) in tumor cells promotes brain metastatic progression by orchestrating crosstalk among metastatic tumor cells, astrocytes, and macrophages. Brain metastatic tumor cells secrete LCN2, which binds to SLC22A17 on astrocytes, activating JAK2/STAT3 signaling and inducing astrocyte activation and chemokine secretion, thereby facilitating macrophage recruitment. In turn, macrophages secrete IL-1β, which further upregulates LCN2 expression in tumor cells. Prophylactic administration of the IL-1 receptor antagonist anakinra inhibits BM formation, whereas therapeutic administration alone is ineffective. However, treatment with the STAT3 inhibitor SH4-54, either alone or in combination with anakinra, significantly suppressed tumor growth in the BM. Furthermore, tumor-secreted LCN2 can bind to SLC22A17 on tumor cells, activating JAK2/STAT3 signaling and promoting VEGF-A expression and release, which enhances tumor neovascularization. Inhibition of this axis with SH4-54, bevacizumab, or their combination effectively reduces the tumor burden in BM-bearing mice. These findings underscore the central role of LCN2 in driving brain metastasis and highlight a potential therapeutic strategy for targeting brain metastatic lung cancer.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"23 1","pages":"417"},"PeriodicalIF":39.3,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145813411","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}
Messenger RNA (mRNA)-based transient expression of chimeric antigen receptors (CARs) results in optimal safety profiles and provides promising opportunities to address existing challenges associated with viral vector-based CAR-T-cell therapies and to meet emerging medical needs for noncancerous indications. Conventional linear mRNAs, however, are intrinsically unstable and typically support short-lived protein expression, which can constrain therapeutic activity. Here, we engineered a high-efficiency permuted intron exon (PIE) platform to synthesize scarless circular mRNAs (cmRNAs) that drive robust CAR expression with extended durability. The scarless design avoids extraneous junction sequences, streamlining manufacturability and potentially reducing innate immune sensing. Compared with linear mRNAs, cmRNAs significantly increased both the magnitude and duration of anti-CD19 CAR and anti-GPRC5D CAR expression in primary human T cells. Functionally, cmRNA-based CAR-T cells elicited superior antitumor efficacy over their linear mRNA counterparts, as demonstrated by parallel lines of evidence, including in vitro antigen-specific cytotoxicity, cytokine release, and transcriptomics patterns consistent with sustained activation and absence of exhaustion signatures, as well as in vivo models demonstrating tumor elimination and prolonged survival benefits. Collectively, these findings position cmRNA as a next-generation mRNA modality for potent and controllable CAR expression, thereby providing a robust platform to unleash the full potential of mRNA technologies in cellular immunotherapy and precision medicine.
{"title":"Scarless circular mRNA-based CAR-T cell therapy elicits superior antitumor efficacy.","authors":"Qinchao Hu, Hui Zhao, Kaicheng Zhou, Xuefei Tian, Qian Wang, Xianxin Hua, Xuyao Zhang","doi":"10.1038/s41392-025-02512-4","DOIUrl":"10.1038/s41392-025-02512-4","url":null,"abstract":"<p><p>Messenger RNA (mRNA)-based transient expression of chimeric antigen receptors (CARs) results in optimal safety profiles and provides promising opportunities to address existing challenges associated with viral vector-based CAR-T-cell therapies and to meet emerging medical needs for noncancerous indications. Conventional linear mRNAs, however, are intrinsically unstable and typically support short-lived protein expression, which can constrain therapeutic activity. Here, we engineered a high-efficiency permuted intron exon (PIE) platform to synthesize scarless circular mRNAs (cmRNAs) that drive robust CAR expression with extended durability. The scarless design avoids extraneous junction sequences, streamlining manufacturability and potentially reducing innate immune sensing. Compared with linear mRNAs, cmRNAs significantly increased both the magnitude and duration of anti-CD19 CAR and anti-GPRC5D CAR expression in primary human T cells. Functionally, cmRNA-based CAR-T cells elicited superior antitumor efficacy over their linear mRNA counterparts, as demonstrated by parallel lines of evidence, including in vitro antigen-specific cytotoxicity, cytokine release, and transcriptomics patterns consistent with sustained activation and absence of exhaustion signatures, as well as in vivo models demonstrating tumor elimination and prolonged survival benefits. Collectively, these findings position cmRNA as a next-generation mRNA modality for potent and controllable CAR expression, thereby providing a robust platform to unleash the full potential of mRNA technologies in cellular immunotherapy and precision medicine.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"10 1","pages":"411"},"PeriodicalIF":52.7,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12722250/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145811395","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ubiquitination, a critical posttranslational modification (PTM), involves the enzymatic covalent attachment of ubiquitin to target proteins. This process is fundamental for maintaining cellular homeostasis and regulating key biological functions. The ubiquitination pathway, orchestrated by ubiquitin and its associated enzymes, offers remarkable versatility, acting as a cellular sentinel to ensure precise spatiotemporal control of essential molecular processes. Importantly, the components and mechanisms of ubiquitination can be finely tuned in various ways. Dysregulation of this system can disrupt normal biological processes and contribute to the development of various serious human diseases. These findings underscore the importance of investigating ubiquitination to understand disease mechanisms and develop effective treatment strategies. In this review, we summarize the historical developments and key milestones in ubiquitination research, with a focus on its roles in both health and disease. We explore the components and mechanisms involved, the relevant signaling pathways and their crosstalk, and the multilayered regulatory functions of ubiquitination under physiological and pathological conditions. The pathological contexts discussed include cancer, neurodegenerative disorders, cardiovascular diseases, inflammatory conditions, autoinflammatory disorders and developmental disorders. Enhancing our understanding of ubiquitination could provide novel insights into disease pathogenesis and identify new therapeutic targets. We also highlight emerging strategies for cancer treatment, such as proteolysis-targeting chimeras (PROTACs) and molecular glues. Furthermore, we review therapeutic targets and recent progress in clinical research, including ongoing clinical trials and FDA-approved drugs, aimed at leveraging the ubiquitination pathway for disease treatment.
{"title":"Targeting ubiquitination in disease and therapy.","authors":"Xiaojuan Yang,Tian Lan,Buzhe Zhang,Xue Tao,Weili Qi,Kunlin Xie,Yunshi Cai,Chang Liu,Junhong Han,Hong Wu","doi":"10.1038/s41392-025-02392-8","DOIUrl":"https://doi.org/10.1038/s41392-025-02392-8","url":null,"abstract":"Ubiquitination, a critical posttranslational modification (PTM), involves the enzymatic covalent attachment of ubiquitin to target proteins. This process is fundamental for maintaining cellular homeostasis and regulating key biological functions. The ubiquitination pathway, orchestrated by ubiquitin and its associated enzymes, offers remarkable versatility, acting as a cellular sentinel to ensure precise spatiotemporal control of essential molecular processes. Importantly, the components and mechanisms of ubiquitination can be finely tuned in various ways. Dysregulation of this system can disrupt normal biological processes and contribute to the development of various serious human diseases. These findings underscore the importance of investigating ubiquitination to understand disease mechanisms and develop effective treatment strategies. In this review, we summarize the historical developments and key milestones in ubiquitination research, with a focus on its roles in both health and disease. We explore the components and mechanisms involved, the relevant signaling pathways and their crosstalk, and the multilayered regulatory functions of ubiquitination under physiological and pathological conditions. The pathological contexts discussed include cancer, neurodegenerative disorders, cardiovascular diseases, inflammatory conditions, autoinflammatory disorders and developmental disorders. Enhancing our understanding of ubiquitination could provide novel insights into disease pathogenesis and identify new therapeutic targets. We also highlight emerging strategies for cancer treatment, such as proteolysis-targeting chimeras (PROTACs) and molecular glues. Furthermore, we review therapeutic targets and recent progress in clinical research, including ongoing clinical trials and FDA-approved drugs, aimed at leveraging the ubiquitination pathway for disease treatment.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"154 1","pages":"424"},"PeriodicalIF":39.3,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145813415","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}
Neoantigen vaccines and oncolytic viruses are emerging immunotherapies that can reshape the tumor microenvironment (TME). However, tumors with low mutation burdens often respond poorly to immunotherapies because of their limited immunogenicity. Developing effective immunotherapy strategies for these types of tumors remains a significant challenge. In this study, we engineered oncolytic adenoviruses to accurately amplify neoantigen expression within tumor cells, which demonstrated superior efficacy compared to synthetic long peptide vaccines and showed enhanced effectiveness in a low mutation burden intrahepatic cholangiocarcinoma model. Building on this, we further developed NeoViron, which coexpresses neoantigens and Flt3L, a dendritic cell growth factor, to promote antigen presentation and T-cell infiltration simultaneously. NeoViron significantly inhibited tumor growth and prevented metastasis in intrahepatic cholangiocarcinoma animal models. Mechanistically, NeoViron enhanced the cytotoxicity of CD8+ T cells and promoted the expansion of CD69+ CD8+ tissue-resident memory T cells and TCF1+ CD8+ stem-like T cells to promote anti-tumor immunity and immune memory. When combined with anti-PD-1, it further enhances the cytotoxicity of tissue-resident memory T cells to eradicate solid tumors. These findings demonstrate that NeoViron can effectively sensitize low-mutation tumors to immunotherapy by increasing neoantigen expression and antigen-presentation efficacy, offering a promising strategy for cancer treatment, particularly for tumors with scarce neoantigens.
{"title":"Oncolytic adenovirus delivery of neoantigens sensitizes low-mutation tumors to anti-PD-1 therapy and prevents metastasis.","authors":"Ke-Yu Shen,Shi-Zhe Yu,Ying-Han Su,Sun-Zhe Xie,Chen Zhang,Hao Xu,SamI Yang,Tian-Tian Zou,Yan Fu,Hao Wang,Lin Fang,Yan Zheng,Chang-Qing Su,Lun-Xiu Qin","doi":"10.1038/s41392-025-02511-5","DOIUrl":"https://doi.org/10.1038/s41392-025-02511-5","url":null,"abstract":"Neoantigen vaccines and oncolytic viruses are emerging immunotherapies that can reshape the tumor microenvironment (TME). However, tumors with low mutation burdens often respond poorly to immunotherapies because of their limited immunogenicity. Developing effective immunotherapy strategies for these types of tumors remains a significant challenge. In this study, we engineered oncolytic adenoviruses to accurately amplify neoantigen expression within tumor cells, which demonstrated superior efficacy compared to synthetic long peptide vaccines and showed enhanced effectiveness in a low mutation burden intrahepatic cholangiocarcinoma model. Building on this, we further developed NeoViron, which coexpresses neoantigens and Flt3L, a dendritic cell growth factor, to promote antigen presentation and T-cell infiltration simultaneously. NeoViron significantly inhibited tumor growth and prevented metastasis in intrahepatic cholangiocarcinoma animal models. Mechanistically, NeoViron enhanced the cytotoxicity of CD8+ T cells and promoted the expansion of CD69+ CD8+ tissue-resident memory T cells and TCF1+ CD8+ stem-like T cells to promote anti-tumor immunity and immune memory. When combined with anti-PD-1, it further enhances the cytotoxicity of tissue-resident memory T cells to eradicate solid tumors. These findings demonstrate that NeoViron can effectively sensitize low-mutation tumors to immunotherapy by increasing neoantigen expression and antigen-presentation efficacy, offering a promising strategy for cancer treatment, particularly for tumors with scarce neoantigens.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"45 1","pages":"410"},"PeriodicalIF":39.3,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145807547","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}
Although natural killer (NK) cells are endowed with intrinsic cytotoxicity, their therapeutic application often faces limitations because of their lack of tumor-specific targeting ability and limited ability to infiltrate solid tumors. To overcome these limitations, we developed anti-mesothelin (MSLN) uCAR-like NK cells, which are designed to enhance both the targeting specificity and tumor infiltration capacity, thereby improving the antitumor efficacy of NK cell-based therapies. We constructed, purified, and validated a tetravalent bispecific cell engager (MSLN×CD16A) via the SpyTag/SpyCatcher system. Cytokine-induced memory-like NK cells, induced by IL-12, IL-15, and IL-18, were precomplexed with MSLN×CD16A to generate anti-MSLN CAR-like NK cells. To further enhance tumor penetration, the tumor-penetrating peptide uCendR was integrated into the system to construct anti-MSLN uCAR-like NK cells. In vitro, anti-MSLN CAR-like NK cells demonstrated selective cytotoxicity against MSLN-positive tumor cells through stable binding with MSLN×CD16A while sparing MSLN-negative cells. In xenograft models bearing MSLN-positive tumors, anti-MSLN CAR-like NK cells exhibited significant antitumor activity, with favorable tolerability and no significant body weight loss or toxicity. Notably, anti-MSLN uCAR-like NK cells, which integrate a tumor-penetrating peptide, displayed enhanced intratumor penetration and superior therapeutic efficacy. Overall, this study establishes a modular, nongenetically engineered uCAR-like NK platform that couples targeted recognition with enhanced tissue access. These findings highlight the potential of anti-MSLN CAR-like NK cells, particularly uCAR-like NK cells with enhanced tumor penetration, as promising therapeutic strategies for MSLN-positive solid tumors and lay the foundation for future clinical applications.
虽然自然杀伤细胞（natural killer， NK）具有固有的细胞毒性，但由于其缺乏肿瘤特异性靶向能力和浸润实体瘤的能力有限，其治疗应用往往受到限制。为了克服这些局限性，我们开发了抗间皮素（MSLN） ucar样NK细胞，旨在提高靶向特异性和肿瘤浸润能力，从而提高NK细胞为基础的治疗的抗肿瘤效果。我们通过SpyTag/SpyCatcher系统构建、纯化并验证了四价双特异性细胞接合器（MSLN×CD16A）。细胞因子诱导的记忆样NK细胞，由IL-12、IL-15和IL-18诱导，与MSLN×CD16A预复合生成抗msln car样NK细胞。为了进一步增强肿瘤穿透能力，我们将肿瘤穿透肽uCendR整合到体系中，构建抗msln ucar样NK细胞。在体外，抗msln car -样NK细胞通过与MSLN×CD16A的稳定结合，对msln阳性肿瘤细胞表现出选择性的细胞毒性，同时保留msln阴性细胞。在携带msln阳性肿瘤的异种移植模型中，抗msln car -样NK细胞表现出显著的抗肿瘤活性，具有良好的耐受性，没有明显的体重减轻或毒性。值得注意的是，整合肿瘤穿透肽的抗msln ucar样NK细胞表现出增强的肿瘤内穿透能力和优越的治疗效果。总的来说，本研究建立了一个模块化的、非基因工程的ucar样NK平台，将靶向识别与增强的组织通路结合起来。这些发现突出了抗msln car样NK细胞的潜力，特别是具有增强肿瘤穿透性的ucar样NK细胞，作为msln阳性实体瘤的有希望的治疗策略，并为未来的临床应用奠定了基础。
{"title":"Anti-MSLN chimeric antigen receptor-like NK cell therapy with tumor-penetrating capacity (uCAR-like NK) for solid tumors.","authors":"Mengchao An,Ying Wang,Jie Shao,Siwen Wu,Jiayao Yan,Yuxiang Li,Liqing Zhong,Jingyi Guo,Tianran Chen,Manman Tian,Qin Liu,Rutian Li,Baorui Liu","doi":"10.1038/s41392-025-02524-0","DOIUrl":"https://doi.org/10.1038/s41392-025-02524-0","url":null,"abstract":"Although natural killer (NK) cells are endowed with intrinsic cytotoxicity, their therapeutic application often faces limitations because of their lack of tumor-specific targeting ability and limited ability to infiltrate solid tumors. To overcome these limitations, we developed anti-mesothelin (MSLN) uCAR-like NK cells, which are designed to enhance both the targeting specificity and tumor infiltration capacity, thereby improving the antitumor efficacy of NK cell-based therapies. We constructed, purified, and validated a tetravalent bispecific cell engager (MSLN×CD16A) via the SpyTag/SpyCatcher system. Cytokine-induced memory-like NK cells, induced by IL-12, IL-15, and IL-18, were precomplexed with MSLN×CD16A to generate anti-MSLN CAR-like NK cells. To further enhance tumor penetration, the tumor-penetrating peptide uCendR was integrated into the system to construct anti-MSLN uCAR-like NK cells. In vitro, anti-MSLN CAR-like NK cells demonstrated selective cytotoxicity against MSLN-positive tumor cells through stable binding with MSLN×CD16A while sparing MSLN-negative cells. In xenograft models bearing MSLN-positive tumors, anti-MSLN CAR-like NK cells exhibited significant antitumor activity, with favorable tolerability and no significant body weight loss or toxicity. Notably, anti-MSLN uCAR-like NK cells, which integrate a tumor-penetrating peptide, displayed enhanced intratumor penetration and superior therapeutic efficacy. Overall, this study establishes a modular, nongenetically engineered uCAR-like NK platform that couples targeted recognition with enhanced tissue access. These findings highlight the potential of anti-MSLN CAR-like NK cells, particularly uCAR-like NK cells with enhanced tumor penetration, as promising therapeutic strategies for MSLN-positive solid tumors and lay the foundation for future clinical applications.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"25 1","pages":"425"},"PeriodicalIF":39.3,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145813414","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 : 2025-12-22DOI: 10.1038/s41392-025-02508-0
Jessica A Breznik,Chris P Verschoor
{"title":"Working together: a multi-component intranasal vaccine provides synergistic protection against COVID-19.","authors":"Jessica A Breznik,Chris P Verschoor","doi":"10.1038/s41392-025-02508-0","DOIUrl":"https://doi.org/10.1038/s41392-025-02508-0","url":null,"abstract":"","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"24 1","pages":"408"},"PeriodicalIF":39.3,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145801281","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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