Oncogene最新文献

{"title":"Methylation-driven SOX18 nuclear translocation by IGF2BP1-stabilized METTL21A promotes lymphatic metastasis in gastric cancer","authors":"Ruofan He, Yi Zhang, Songyi Liu, Xiang Lin, Penghang Lin, Xiaoyu Pan, Yan Lin, Guangwei Zhu, Jianxin Ye, Xu Lin, Kunqi Chen","doi":"10.1038/s41388-026-04013-2","DOIUrl":"10.1038/s41388-026-04013-2","url":null,"abstract":"Gastric cancer (GC) is frequently associated with lymph node metastasis, which contributes to a poor prognosis; however, the underlying molecular mechanisms remain incompletely understood. In this study, we identify the N6-methyladenosine (m⁶A) reader IGF2BP1 as a critical driver of lymphatic metastasis in GC. IGF2BP1 is significantly upregulated in GC tissues with lymph node metastasis and is correlated with adverse clinical outcomes. Mechanistically, IGF2BP1 binds to the m⁶A-modified 3′ untranslated region (3′UTR) of METTL21A mRNA, thereby enhancing its mRNA stability and expression levels. METTL21A, a non-histone lysine methyltransferase, interacts with and methylates the transcription factor SOX18, facilitating its nuclear translocation without altering protein stability. Once in the nucleus, SOX18 directly activates the transcription of CXCL12. Secreted CXCL12 promotes lymphangiogenesis and facilitates lymphatic metastasis through CXCR4 signaling. Functionally, both IGF2BP1 and METTL21A enhance tube formation and migration of lymphatic endothelial cells and promote lymphatic metastasis in GC. Notably, METTL21A knockout abolishes IGF2BP1-induced lymphangiogenesis, whereas SOX18 depletion eliminates the pro-lymphangiogenic effects of IGF2BP1. Our findings reveal a previously unrecognized signaling axis—IGF2BP1–METTL21A–SOX18–CXCL12—that links m⁶A-dependent post-transcriptional regulation with methylation-dependent transcriptional activation, offering potential therapeutic targets for the prevention of lymphatic metastasis in gastric cancer.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 45","pages":"4954-4971"},"PeriodicalIF":9.1,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149195882","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}

{"title":"TNFα-driven epigenetic upregulation of TIGIT creates a targetable vulnerability in tumors","authors":"Xuefeng Huang, Chaoyang Xiong, Minghang Yu, Jiyin Wang, Pu Liang, Guohong Li, Xi Wang","doi":"10.1038/s41388-026-04008-z","DOIUrl":"10.1038/s41388-026-04008-z","url":null,"abstract":"T cell immunoreceptor with Ig and ITIM domains (TIGIT) is a key inhibitory receptor on cytotoxic lymphocytes, yet the mechanisms governing its context-dependent upregulation in tumors remain poorly defined. Here, we identify tumor necrosis factor-α (TNFα) signaling as an upstream driver of TIGIT expression. Integrated analyses of patient transcriptomic datasets revealed a consistent positive association between TNFα pathway activity and TIGIT expression across multiple cancer types, with strong concordance in melanoma and prognostic relevance in kidney renal clear cell carcinoma. Mechanistically, TNFα directly induced TIGIT expression in natural killer cells via TNFR2 signaling, increasing chromatin accessibility at distal TIGIT enhancers and promoting NF-κB and AP-1 recruitment together with BRD4 and P300. Functionally, combined anti-TNFα and anti-TIGIT treatment suppressed tumor growth and prolonged survival more effectively than either monotherapy in murine melanoma and colon cancer models. These findings define a TNFα–TNFR2–enhancer axis controlling TIGIT expression and provide a mechanistic rationale for dual TNFα and TIGIT targeting in inflamed tumors. The immune system naturally attacks cancer, but tumors often escape this defense by turning on or exploiting “brakes” on immune cells, known as immune checkpoints. TIGIT is one such checkpoint protein. Although drugs that block TIGIT have shown promising effects in laboratory studies and animal models, they have not yet provided consistent benefit for patients in clinical trials. Our study investigated the specific mechanisms responsible for elevated TIGIT expression on immune cells within the tumor microenvironment. By analyzing patient tumor datasets and performing experiments with human immune cells and mouse tumor models, we found that the inflammatory molecule TNFα, which is often elevated in tumors, directly increases TIGIT expression by changing how the TIGIT gene is regulated. In mouse models, blocking both TNFα and TIGIT suppressed tumor growth more effectively than either treatment alone. These findings suggest that combined targeting of TNFα and TIGIT may improve the effectiveness of cancer immunotherapy, especially for patients with highly inflamed tumors. These findings suggest that combined targeting of TNFα and TIGIT may improve, especially for patients with highly inflamed tumors.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 45","pages":"4940-4953"},"PeriodicalIF":9.1,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149165079","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}

{"title":"Correction: Targeting surface nucleolin induces autophagy-dependent cell death in pancreatic cancer via AMPK activation","authors":"Cheng Xu, Yunfei Wang, Qiu Tu, Zhiye Zhang, Mengrou Chen, James Mwangi, Yaxiong Li, Yang Jin, Xudong Zhao, Ren Lai","doi":"10.1038/s41388-026-04005-2","DOIUrl":"10.1038/s41388-026-04005-2","url":null,"abstract":"","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 45","pages":"4972-4973"},"PeriodicalIF":9.1,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-026-04005-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149167567","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}

{"title":"PTK7 scaffolds DNA-PKcs to promote DNA damage response and immune evasion in triple-negative breast cancer","authors":"Xueying Liu, Kejing Zhang, Yu Zhang, Yuejun Wang, Yuanjie Jiang, Qiao Duan, Liyan Fei, Juan Wei, Sheyu Zhang, Zhonglan Wang, Gaoyang Wang, Jianmin Wu, Yuzhi Luo, Yong Wei, Feng Ge, Lu Guo, Qin Wu","doi":"10.1038/s41388-026-04011-4","DOIUrl":"10.1038/s41388-026-04011-4","url":null,"abstract":"Membrane proteins with nuclear localization often exert non-canonical functions. PTK7, an evolutionarily conserved pseudokinase and a prominent therapeutic target, is primarily recognized for its cell-surface signaling; however, its intracellular role in tumor biology remains unclear. Here, we identify a previously unrecognized role of PTK7 in coordinating DNA damage response and tumor immune response in triple-negative breast cancer (TNBC). Mechanistically, PTK7 translocates to the nucleus where it associates with DNA-dependent protein kinase (DNA-PKcs), acting as a molecular scaffold to enhance its kinase activation and facilitate non-homologous end-joining (NHEJ) repair. Loss of PTK7 impaired DNA-PKcs-associated non-homologous end-joining (NHEJ) repair, increased double-strand breaks, and subsequent activation of the STING-IFN axis. Furthermore, PTK7 deficiency significantly sensitizes TNBC tumors to anti-PD-1 therapy in vivo. Clinically, high PTK7 expression correlates with suppressed immune signatures and poor immunotherapy response in TNBC patients. Together, our findings uncover a PTK7-associated DNA repair and immune-evasion program in TNBC and nominate PTK7 as a potential biomarker and therapeutic target for improving immunotherapy response.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 45","pages":"4927-4939"},"PeriodicalIF":9.1,"publicationDate":"2026-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149170167","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}

{"title":"Adrenomedullin 2 drives intratumoral cancer cell invasion, intravasation and metastasis","authors":"Konstantin Stoletov, Seyedeh Sara Karimian, Douglas Brown, Alice Amitrano, Bishwa Ranjan Si, Varinder Madhav Verma, Somnath Gupta, Amirali B. Bukhari, Suellen Lamb, Konstantinos Konstantopoulos, Gane Ka-Shu Wong, John D. Lewis","doi":"10.1038/s41388-026-04012-3","DOIUrl":"10.1038/s41388-026-04012-3","url":null,"abstract":"Cancer cell intravasation requires both directed invasion toward the vasculature and access to functional blood vessels that act as intravasation sites. Using intravital video microscopy, we identified the peptide hormone adrenomedullin 2 (ADM2) as a critical regulator of this process. ADM2 was selectively upregulated in a highly invasive subpopulation of cancer cells that localize near blood vessels and actively drive intravasation. Knockdown of ADM2 significantly impaired intratumoral cancer cell invasion and intravasation in a chicken embryo metastasis model and in vitro. ADM2-deficient tumors exhibited reduced vascularization, limiting the availability of competent intravasation sites. Moreover, loss of ADM2 suppressed the formation of invasive metastatic lesions, indicating a requirement for ADM2 at multiple stages of the metastatic cascade. Consistently, targeting ADM2 in a mouse metastasis model inhibited the development of large intratumoral blood vessels and reduced metastasis. Collectively, these findings establish ADM2 as a previously unrecognized regulator of tumor–vascular interactions and highlight its potential as a therapeutic target to simultaneously disrupt invasion, vascular support, and metastatic dissemination.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 45","pages":"4916-4926"},"PeriodicalIF":9.1,"publicationDate":"2026-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-026-04012-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149170904","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}

{"title":"Correction: Nuclear amphiregulin and lamin A contribute to genomic stability and the response to replication stress via regulation of heterochromatin","authors":"Tianqi Jiang, Aiman Zein, M. A. Christine Pratt","doi":"10.1038/s41388-026-04009-y","DOIUrl":"10.1038/s41388-026-04009-y","url":null,"abstract":"","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 43","pages":"4715-4717"},"PeriodicalIF":9.1,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-026-04009-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149137828","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}

{"title":"Correction: Novel exosomal circEGFR facilitates triple negative breast cancer autophagy via promoting TFEB nuclear trafficking and modulating miR-224-5p/ATG13/ULK1 feedback loop","authors":"Huachen Song, Zitong Zhao, Liying Ma, Weihong Zhao, Yi Hu, Yongmei Song","doi":"10.1038/s41388-026-04010-5","DOIUrl":"10.1038/s41388-026-04010-5","url":null,"abstract":"","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 43","pages":"4718-4721"},"PeriodicalIF":9.1,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-026-04010-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149137781","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}

{"title":"Correction: Hypomethylation reduced the aggressive potential of human malignant mesothelioma cells","authors":"N-Y Kim, M-C Kim, Y. Kim","doi":"10.1038/s41388-026-04004-3","DOIUrl":"10.1038/s41388-026-04004-3","url":null,"abstract":"","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 44","pages":"4859-4859"},"PeriodicalIF":9.1,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-026-04004-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149137793","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}

{"title":"SMCO2 inhibits ferroptosis through the VDAC1–STAT3 axis by modulating MAM homeostasis in ovarian cancer","authors":"Shan Jiang, Ruqi Jiang, Yuping Du, Bingfeng Lu, Shuo Chen, Fan Shen, Jianjun Zhang, Xin Zhang, Yue Chen, Lingfeng Zhou, Yang Zhao","doi":"10.1038/s41388-026-03983-7","DOIUrl":"10.1038/s41388-026-03983-7","url":null,"abstract":"This study identifies the previously uncharacterised transmembrane protein SMCO2 as a broadly upregulated factor in multi-organ adenocarcinomas and defines it as a novel mitochondria-associated endoplasmic reticulum membrane (MAM) structural and signalling integrator. Adenocarcinoma cells maintain metabolic adaptability and resist cell death through enhanced mitochondrial-endoplasmic reticulum communication; however, the core transmembrane regulation node that regulates this process is still unclear. Our article proves that SMCO2 interacts with VDAC1, enhances its association with STAT3, and promotes mitochondrial localisation and S727 phosphorylation of STAT3. The SMCO2-driven VDAC1–STAT3 axis modulates mitochondrial Ca²+ signalling, oxidative stress homoeostasis, and pivotal ferroptosis-associated networks, ultimately conferring ferroptosis resistance on tumour cells. Targeting SMCO2 or the VDAC1/STAT3 pathway can effectively restore ferroptosis sensitivity. Overall, our study confirms that SMCO2 is a transmembrane regulatory factor and reveals that the MAM-STAT3 axis, as a new mechanism, links metabolic adaptation to adenocarcinoma cell death resistance and has potential therapeutic significance.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 45","pages":"4902-4915"},"PeriodicalIF":9.1,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-026-03983-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149112718","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}

{"title":"Correction: C/EBPδ-Slug-Lox1 axis promotes metastasis of lung adenocarcinoma via oxLDL uptake","authors":"Dongmei Wang, Xinghua Cheng, Yu Li, Mingwei Guo, Wenjun Zhao, Jin Qiu, Ying Zheng, Meiyao Meng, Xiaodan Ping, Xin Chen, Shu Wang, Jian Luo, Qingquan Luo, Xinran Ma, Lingyan Xu","doi":"10.1038/s41388-026-04000-7","DOIUrl":"10.1038/s41388-026-04000-7","url":null,"abstract":"","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 43","pages":"4722-4722"},"PeriodicalIF":9.1,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-026-04000-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149112741","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}