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}
N6-methyladenosine (m6A) modification of mRNAs is a predominant epigenetic regulatory mechanism in tumor initiation and progression. Cancer stem cells (CSCs) are the key drivers of colorectal cancer (CRC) initiation and chemotherapy resistance. Here, we found that the m6A reader YT521-B homologous domain family, member 1 (YTHDF1), promotes CRC stemness, tumorigenesis, and chemotherapy resistance. YTHDF1 protein expression was positively correlated with CD133 and LGR5 expression in human CRC tissues (N = 184, P < 0.001 for both markers). YTHDF1 promoted m6A-dependent self-renewal in CSCs and patient-derived organoids and increased the tumor-initiating potential in vivo. Lgr5-specific Ythdf1-KI mice presented accelerated ApcMin/+ (P < 0.05) and AOM/DSS (P < 0.05)-induced colorectal tumorigenesis, whereas Lgr5-specific Ythdf1 knockout in ApcMin/+ mice inhibited tumorigenesis (P < 0.01). Integrative multiomic profiling revealed NOTCH1 as a downstream target. YTHDF1 binds m6A-modified NOTCH1, promoting its translation and enhancing NOTCH signaling. NOTCH1 knockdown or blockade by the γ-secretase inhibitor DAPT abolished YTHDF1-mediated tumorigenesis in Ythdf1 knock-in mice (P < 0.01). YTHDF1 promoted resistance to oxaliplatin and 5-fluorouracil in CSCs by inhibiting apoptosis and DNA damage. AOM/DSS-treated Ythdf1 knock-in mice presented increased resistance to oxaliplatin (P < 0.001) and 5-fluorouracil (P < 0.05). Translationally, in vivo targeting of YTHDF1 via VNP-encapsulated siYTHDF1 or salvianolic acid C inhibited tumor growth (P < 0.05 for both treatments) and increased treatment efficacy when VNP was combined with oxaliplatin (P < 0.05, SAC: P < 0.01) or 5-fluorouracil (P < 0.05 for both treatments). In conclusion, YTHDF1 promotes stemness and chemoresistance in CRC via NOTCH1 activation. Targeting YTHDF1 is a promising strategy to improve the outcome of chemotherapy in CRC.
{"title":"YTHDF1 targets the chemotherapy response by suppressing NOTCH1-induced stemness in colorectal cancer.","authors":"Henley Cheung,Huarong Chen,Danyu Chen,Heming Zhou,Cong Liang,Weixin Liu,Alvin Ho-Kwan Cheung,Yanqiang Ding,Kai Yuan,Xiaoxing Li,Yongxin Zhang,Shiyan Wang,Wei Kang,Ka-Fai To,Housheng He,Chi Chun Wong,Jun Yu","doi":"10.1038/s41392-025-02507-1","DOIUrl":"https://doi.org/10.1038/s41392-025-02507-1","url":null,"abstract":"N6-methyladenosine (m6A) modification of mRNAs is a predominant epigenetic regulatory mechanism in tumor initiation and progression. Cancer stem cells (CSCs) are the key drivers of colorectal cancer (CRC) initiation and chemotherapy resistance. Here, we found that the m6A reader YT521-B homologous domain family, member 1 (YTHDF1), promotes CRC stemness, tumorigenesis, and chemotherapy resistance. YTHDF1 protein expression was positively correlated with CD133 and LGR5 expression in human CRC tissues (N = 184, P < 0.001 for both markers). YTHDF1 promoted m6A-dependent self-renewal in CSCs and patient-derived organoids and increased the tumor-initiating potential in vivo. Lgr5-specific Ythdf1-KI mice presented accelerated ApcMin/+ (P < 0.05) and AOM/DSS (P < 0.05)-induced colorectal tumorigenesis, whereas Lgr5-specific Ythdf1 knockout in ApcMin/+ mice inhibited tumorigenesis (P < 0.01). Integrative multiomic profiling revealed NOTCH1 as a downstream target. YTHDF1 binds m6A-modified NOTCH1, promoting its translation and enhancing NOTCH signaling. NOTCH1 knockdown or blockade by the γ-secretase inhibitor DAPT abolished YTHDF1-mediated tumorigenesis in Ythdf1 knock-in mice (P < 0.01). YTHDF1 promoted resistance to oxaliplatin and 5-fluorouracil in CSCs by inhibiting apoptosis and DNA damage. AOM/DSS-treated Ythdf1 knock-in mice presented increased resistance to oxaliplatin (P < 0.001) and 5-fluorouracil (P < 0.05). Translationally, in vivo targeting of YTHDF1 via VNP-encapsulated siYTHDF1 or salvianolic acid C inhibited tumor growth (P < 0.05 for both treatments) and increased treatment efficacy when VNP was combined with oxaliplatin (P < 0.05, SAC: P < 0.01) or 5-fluorouracil (P < 0.05 for both treatments). In conclusion, YTHDF1 promotes stemness and chemoresistance in CRC via NOTCH1 activation. Targeting YTHDF1 is a promising strategy to improve the outcome of chemotherapy in CRC.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"16 1","pages":"409"},"PeriodicalIF":39.3,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145801284","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}
Nab-paclitaxel plus gemcitabine (AG) is the standard first-line chemotherapy for advanced or metastatic pancreatic ductal adenocarcinoma and has limited efficacy. This phase 1b/2 study aimed to evaluate SHR-1701 (an anti-PD-L1/TGF-βRII fusion protein) plus AG in this population (NCT04624217). In phase 1b part, the recommended dose of SHR-1701 was identified as 30 mg/kg every 3 weeks, when combined with AG. In phase 2 part, the primary endpoint was objective response rate (ORR). As of Mar 31, 2023, 56 patients were enrolled. Median follow-up was 10.3 months (range, 0.2-24.7). ORR was 32.1% (95% CI, 20.3-46.0). Median progressive-free survival (PFS) was 5.6 months (95% CI, 4.3-6.6), and median overall survival (OS) was 10.3 months (95% CI, 8.8-12.3). Treatment-related adverse events of grade ≥3 were reported in 27 (48.2%) patients, with the most common being decreased neutrophil count. Patients with PD-L1 TPS ≥ 1% showed a higher ORR (66.7% vs. 25.0%), as well as extended median PFS (6.3 vs. 5.3 months) and median OS (18.8 vs. 9.9 months). Additionally, reduction of CA19-9 by at least 80% during treatment and pSMAD2/3 staining intensity of 1+ at baseline were potential monitoring tools and predictive biomarkers for better clinical outcomes, respectively. Tumor-specific T-cell infiltration and pancreatic cancer tumor subtypes were associated with anti-tumor response. The interactions within tumor microenvironment were involved disease progression. Overall, first-line SHR-1701 plus AG showed promising anti-tumor activity and controllable safety in advanced or metastatic pancreatic ductal adenocarcinoma, and features of patients more likely to benefit from the combination were drawn.
nab -紫杉醇加吉西他滨（AG）是晚期或转移性胰腺导管腺癌的标准一线化疗方案，但疗效有限。这项1b/2期研究旨在评估SHR-1701（一种抗pd - l1 /TGF-βRII融合蛋白）加AG在该人群中的作用（NCT04624217）。在1b期研究中，SHR-1701的推荐剂量确定为每3周30 mg/kg，与AG联合使用。在第二阶段，主要终点是客观缓解率（ORR）。截至2023年3月31日，共有56名患者入组。中位随访时间为10.3个月（范围0.2-24.7）。ORR为32.1% （95% CI, 20.3-46.0）。中位无进展生存期（PFS）为5.6个月（95% CI, 4.3-6.6），中位总生存期（OS）为10.3个月（95% CI, 8.8-12.3）。27例（48.2%）患者报告了≥3级的治疗相关不良事件，最常见的是中性粒细胞计数减少。PD-L1 TPS≥1%的患者表现出更高的ORR (66.7% vs. 25.0%)，中位PFS （6.3 vs. 5.3个月）和中位OS （18.8 vs. 9.9个月）延长。此外，治疗期间CA19-9减少至少80%，基线时pSMAD2/3染色强度为1+，分别是更好临床结果的潜在监测工具和预测性生物标志物。肿瘤特异性t细胞浸润和胰腺癌肿瘤亚型与抗肿瘤反应相关。肿瘤微环境内的相互作用与疾病进展有关。总体而言，一线SHR-1701联合AG在晚期或转移性胰腺导管腺癌中显示出良好的抗肿瘤活性和可控的安全性，并且更有可能从联合治疗中获益的患者的特征被描绘出来。
{"title":"A phase 1b/2 study of first-line anti-PD-L1/ TGF-βRII fusion protein SHR-1701 combined with nab-paclitaxel and gemcitabine for advanced pancreatic ductal adenocarcinoma.","authors":"Ran Xue,Miaoyan Wei,Jiajia Yuan,Zhihua Li,Yuhong Zhou,Zeyun Xue,Yiwen Wu,Hongxia Han,Jun Zhou,Xianjun Yu,Lin Shen","doi":"10.1038/s41392-025-02530-2","DOIUrl":"https://doi.org/10.1038/s41392-025-02530-2","url":null,"abstract":"Nab-paclitaxel plus gemcitabine (AG) is the standard first-line chemotherapy for advanced or metastatic pancreatic ductal adenocarcinoma and has limited efficacy. This phase 1b/2 study aimed to evaluate SHR-1701 (an anti-PD-L1/TGF-βRII fusion protein) plus AG in this population (NCT04624217). In phase 1b part, the recommended dose of SHR-1701 was identified as 30 mg/kg every 3 weeks, when combined with AG. In phase 2 part, the primary endpoint was objective response rate (ORR). As of Mar 31, 2023, 56 patients were enrolled. Median follow-up was 10.3 months (range, 0.2-24.7). ORR was 32.1% (95% CI, 20.3-46.0). Median progressive-free survival (PFS) was 5.6 months (95% CI, 4.3-6.6), and median overall survival (OS) was 10.3 months (95% CI, 8.8-12.3). Treatment-related adverse events of grade ≥3 were reported in 27 (48.2%) patients, with the most common being decreased neutrophil count. Patients with PD-L1 TPS ≥ 1% showed a higher ORR (66.7% vs. 25.0%), as well as extended median PFS (6.3 vs. 5.3 months) and median OS (18.8 vs. 9.9 months). Additionally, reduction of CA19-9 by at least 80% during treatment and pSMAD2/3 staining intensity of 1+ at baseline were potential monitoring tools and predictive biomarkers for better clinical outcomes, respectively. Tumor-specific T-cell infiltration and pancreatic cancer tumor subtypes were associated with anti-tumor response. The interactions within tumor microenvironment were involved disease progression. Overall, first-line SHR-1701 plus AG showed promising anti-tumor activity and controllable safety in advanced or metastatic pancreatic ductal adenocarcinoma, and features of patients more likely to benefit from the combination were drawn.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"181 1","pages":"415"},"PeriodicalIF":39.3,"publicationDate":"2025-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145796241","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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