Oncogene最新文献

{"title":"DDR1 sustains ferroptosis resistance in pancreatic ductal adenocarcinoma via SLC40A1-mediated iron homeostasis.","authors":"Chao Song, Luting Zhang, Sheng Xu, Xu-An Wang, Xinyi Zhang, Kai Xuan Cheong, Ganggang Wang, Mengmeng Liu, Yazhou Wang, Yifei Zhang, Taochen He, Kai Ding, Yu Chen, Xin Liang, Bing Zhu, Qianzhi Ni, Wenquan Wang, Jingjing Li, Wenhui Lou, Liang Liu","doi":"10.1038/s41388-026-03980-w","DOIUrl":"https://doi.org/10.1038/s41388-026-03980-w","url":null,"abstract":"<p><p>Integrated single-cell transcriptomics and clinical analyses reveal elevated DDR1 expression in pancreatic ductal adenocarcinoma (PDAC) tissues, which correlates with poor prognosis. Mechanistically, collagen-activated Discoidin Domain Receptor 1 (DDR1) recruits SHC1 to activate the MAPK/ERK pathway, thereby driving transcriptional upregulation of SLC40A1 via the ERK-MYC axis. SLC40A1, encoding an iron exporter, reduces intracellular labile iron pools, thereby suppressing lipid peroxidation and ferroptosis. Consequently, DDR1 overexpression confers resistance to dihydroartemisinin (DHA)-induced ferroptosis in PDAC cells, characterized by diminished ROS accumulation, mitochondrial shrinkage, and cristae loss. Conversely, DDR1 knockdown or pharmacological inhibition (Dasatinib) sensitizes PDAC cells to DHA. Crucially, combining Dasatinib and DHA treatment synergistically inhibits tumor growth in vivo by reactivating ferroptosis, as evidenced by increased 4-HNE accumulation and decreased Ki67 expression. These findings identify DDR1 as a key regulator of iron metabolism and ferroptosis in PDAC, suggesting that dual targeting of DDR1 and ferroptosis represents a promising therapeutic strategy.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":9.1,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149031025","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: Splicing-mediated control of hnRNPD isoform switching by SRSF2 drives PD-L1-dependent immune evasion in gallbladder cancer","authors":"Cheng Zhao,&nbsp;Lin Jiang,&nbsp;Ming-yang Wang,&nbsp;Qiu-yi Tang,&nbsp;Jing-wei Zhao,&nbsp;Zi-yi Yang,&nbsp;Jun Gu,&nbsp;Xiao-ling Song,&nbsp;Ping Dong,&nbsp;Li-jia Pan,&nbsp;Yi-jun Shu,&nbsp;Wei Gong","doi":"10.1038/s41388-026-03999-z","DOIUrl":"10.1038/s41388-026-03999-z","url":null,"abstract":"","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 40","pages":"4345-4345"},"PeriodicalIF":9.1,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-026-03999-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149023274","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":"Beyond the blood-brain barrier: humanised mice, the missing link in glioblastoma research","authors":"Reza Shirazi Nia,&nbsp;Jian Lu,&nbsp;Daniel De Vega,&nbsp;Niloufar Poudine,&nbsp;Chaoyue Pan,&nbsp;Fengqi Zhou,&nbsp;Jianxiong Ji,&nbsp;Georgios Giamas","doi":"10.1038/s41388-026-03989-1","DOIUrl":"10.1038/s41388-026-03989-1","url":null,"abstract":"Glioblastoma (GBM) remains a major challenge in neuro-oncology, associated with a high rate of mortality despite decades of intensive research and therapeutic advancements, underscoring the urgent need for innovative preclinical platforms that can more accurately recapitulate the biological and pathological features of human disease. While conventional animal models have contributed to our understanding of GBM biology and the evaluation of treatment efficacy, they fail to capture the full complexity and heterogeneity of the tumour microenvironment (TME). Ex vivo models are associated with certain advantages in this context; however, they can not mirror the complex dynamic and multicellular interactions present in living organisms, particularly the critical treatment barriers unique to the central nervous system: the blood-brain barrier (BBB), blood-cerebrospinal fluid barrier (BCSFB) and blood-meningeal barrier (BMB). In response to these limitations, humanised mouse models have emerged as an advanced platform capable of faithfully mimicking the molecular, pathological and immunological features of human GBM. These models enable the replication of complex in vivo crosstalk between the immune system and the TME, while preserving the relevant treatment barriers that govern drug delivery to the brain. Accumulating evidence indicates that humanised mouse models closely reproduce the infiltration of human immune components into the TME, enabling the study of clinically relevant interactions that contribute to therapeutic resistance and treatment failure in GBM. This review aims to provide a comprehensive and systematic overview of the currently employed humanised mouse models in GBM research, highlighting their applications and comparative advantages. Finally, we evaluate the opportunities and challenges associated with each model and discuss future directions to increase the translational relevance and predictive power of preclinical GBM research.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 41","pages":"4347-4361"},"PeriodicalIF":9.1,"publicationDate":"2026-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-026-03989-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149008539","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":"A canonical role of SMAD4 in safeguarding 3D genome architecture to suppress lung tumorigenesis","authors":"Yaping Xu,&nbsp;Xinyan Han,&nbsp;Junming Li,&nbsp;Shirong Zhang,&nbsp;Chen Lian,&nbsp;Chenghang Yu,&nbsp;Zhanyu Xu,&nbsp;Zhenting Zhang,&nbsp;Bo Yang,&nbsp;Ran Ji,&nbsp;Huiran Wang,&nbsp;Manyu Xiao,&nbsp;Zijin Wang,&nbsp;Boyu Wang,&nbsp;Silin Chen,&nbsp;Yunze Wang,&nbsp;Yufei Liu,&nbsp;Songsong Li,&nbsp;Zuolin Shen,&nbsp;Xi Lu,&nbsp;Xueqi Han,&nbsp;Yilu Zhou,&nbsp;Yao Yao,&nbsp;Jiaqi Deng,&nbsp;Yijiang Guo,&nbsp;Lian Wang,&nbsp;Shuifang Chen,&nbsp;Xiaoke Chen,&nbsp;Ying Chi,&nbsp;You Yu,&nbsp;Yong Tang,&nbsp;Martin Kosar,&nbsp;Junqiang Fan,&nbsp;Nuo Yang,&nbsp;Jian Liu","doi":"10.1038/s41388-026-03984-6","DOIUrl":"10.1038/s41388-026-03984-6","url":null,"abstract":"Dysregulation of three-dimensional (3D) genome architecture is a hallmark of cancer, yet the mechanisms by which its disruption drives tumorigenesis remain incompletely understood. Here, we demonstrated that SMAD4 regulated 3D genome organization through its canonical transcription factor activity by directly binding chromatin, thereby suppressing lung tumorigenesis. Hi-C analyses of human lung tumors identify SMAD4 as a potential regulator of 3D genome integrity. Using PTEN-deficient human bronchial epithelial cells and genetically engineered mouse models, we showed that SMAD4 loss induced widespread reorganization of chromatin compartments, topologically associating domain (TAD) boundaries, and chromatin loops, leading to oncogenic transcriptional rewiring during early tumorigenesis. Mechanistically, SMAD4 directly bound chromatin loops and spatially connected gene promoters with active or repressive regulatory elements to control transcription. Upon SMAD4 ablation, enhancer–promoter rewiring dysregulated critical oncogenic drivers, including ELF3. Functional manipulation of an SMAD4-regulated ELF3-associated chromatin loop altered ELF3 expression and cell survival both in vitro and in vivo. Collectively, our findings establish SMAD4 as a direct regulator of 3D genome architecture through classical transcription factor binding to chromatin loops and reveal enhancer–promoter rewiring as a key mechanism driving lung tumorigenesis and a potential therapeutic vulnerability in SMAD4-deficient lung cancer.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 44","pages":"4743-4757"},"PeriodicalIF":9.1,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-026-03984-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149002404","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":"CRISPR/Cas9 screening revealed BIRC6-AS1/BIRC6 mediates abiraterone resistance via NHEJ pathway-dependent A20 degradation in prostate cancer","authors":"Lan Li,&nbsp;Xue-Ni An,&nbsp;Yong-Tong Ruan,&nbsp;Rong Yang,&nbsp;Peng Li,&nbsp;Pei-Tong Shen,&nbsp;Han-Yu Zeng,&nbsp;Xiao-Yu Wu,&nbsp;Xian-Chao Huang,&nbsp;Ming-Yuan Song,&nbsp;Jing-Lan Hao,&nbsp;Ping Gao,&nbsp;Xiao-Ming Dong","doi":"10.1038/s41388-026-03977-5","DOIUrl":"10.1038/s41388-026-03977-5","url":null,"abstract":"Abiraterone acetate is a standard-of-care therapy for prostate cancer (PCa). However, resistance frequently emerges, often characterized by the progression to AR-independent phenotypes. Employing a genome-wide CRISPR/Cas9 library screening strategy, we identified 523 long non-coding RNAs (lncRNAs) and 2,183 protein-coding genes as potential candidates associated with abiraterone resistance. Notably, a pair of sense-antisense genes, BIRC6-AS1/BIRC6, was identified as a significant contributor to abiraterone resistance, serving as a critical survival factor in AR-independent contexts. BIRC6-AS1 depletion led to a reduction in both the mRNA and protein levels of BIRC6. Moreover, depletion of either BIRC6-AS1 or BIRC6 enhanced the sensitivity of PCa cells to abiraterone in both in vitro and in vivo settings. Further investigation revealed that BIRC6-AS1 stabilized the mRNA of BIRC6 through interaction with ILF2. Suppression of either BIRC6-AS1 or BIRC6 attenuated non-homologous end joining (NHEJ) repair activity, resulting in the disassembly of 53BP1 foci at DNA damage sites and an increased accumulation of DNA damage, thereby exposing a vulnerability in AR-independent resistant cells. Mechanistically, BIRC6 interacted with A20 and facilitated the K48-linked ubiquitination and subsequent degradation of A20 at the K337 residue. Additionally, A20 knockdown effectively reversed the abiraterone sensitivity induced by BIRC6-AS1 depletion. Collectively, our study provides a landscape of lncRNAs and protein-coding genes associated with abiraterone resistance and suggests that targeting the BIRC6-AS1/BIRC6 axis represents a potential therapeutic strategy to eradicate AR-independent resistant tumors in prostate cancer.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 44","pages":"4723-4742"},"PeriodicalIF":9.1,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148990920","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":"Epithelial tumor suppressor deletion promotes neuroendocrine differentiation in bladder cancer and reveals homoharringtonine as a candidate vulnerability","authors":"Lei Qian,&nbsp;Bo Liu,&nbsp;Ruiyun Zhang,&nbsp;Weiwei Zhang,&nbsp;Siqi Wang,&nbsp;Yuchen Wu,&nbsp;Tianxiang Zhang,&nbsp;Guanglei Zhuang,&nbsp;Di Jin,&nbsp;Qi Wang,&nbsp;Haige Chen","doi":"10.1038/s41388-026-03975-7","DOIUrl":"10.1038/s41388-026-03975-7","url":null,"abstract":"Neuroendocrine bladder carcinoma (NEBC) is a highly aggressive malignancy with unresolved lineage determinants and limited preclinical models, hindering mechanistic investigation and therapeutic development. Here, we sought to assess whether bladder epithelial-derived models are competent to acquire neuroendocrine lineage programs under defined tumor suppressor alterations and to identify candidate therapeutic vulnerabilities in these systems. We integrated genomic and transcriptomic analyses of human NEBC with genetically engineered mouse models, epithelial-derived bladder organoids, and patient-derived NEBC models. Human NEBC exhibited dominant RB1 and TP53 alterations and an epithelial transcriptional continuum consistent with lineage plasticity. In vivo, intravesical Adeno-Cre-mediated tumor suppressor deletion predominantly generated sarcoma-like tumors, whereas epithelial-restricted organoid models recapitulated the molecular and neuroendocrine features of human NEBC, supporting epithelial lineage competence for neuroendocrine differentiation. Patient-derived models and human NEBC specimens further supported epithelial identity in NEBC. Using these complementary platforms, drug screening identified homoharringtonine (HHT) as a candidate therapeutic vulnerability in the tested NEBC systems. HHT suppressed neuroendocrine marker expression, induced apoptosis, and attenuated IL6–JAK–STAT3 signaling. Together, these findings describe complementary epithelial-derived NEBC models and support further investigation of HHT as a candidate therapeutic vulnerability.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 43","pages":"4703-4714"},"PeriodicalIF":9.1,"publicationDate":"2026-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148983490","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":"JNK acts as a molecular brake of the CDC73 positive feedback loop to modulate osteosarcoma malignant progression via UBR5","authors":"Dingji Li,&nbsp;Xinchen Wang,&nbsp;Huigen Luo,&nbsp;Hua Tu,&nbsp;Lili Hao,&nbsp;IoHong Lei,&nbsp;Renjie Hu,&nbsp;Pengchao Zheng,&nbsp;Yuhan Shi,&nbsp;Jianbo Sun,&nbsp;Minying Zhu,&nbsp;Chengnong Guan,&nbsp;Baoshan Xu","doi":"10.1038/s41388-026-03978-4","DOIUrl":"10.1038/s41388-026-03978-4","url":null,"abstract":"CDC73 is a well-characterized tumor suppressor regulated by stress stimuli, governing progression of diverse human malignancies. Although previous studies have shown that E3 ubiquitin ligase UBR5 drives CDC73 ubiquitination and degradation to modulate tumorigenesis, the mechanisms by which stress-responsive pathways regulate UBR5-mediated CDC73 inactivation and transcriptional reprogramming remain elusive. Here, via integrated analyses of public datasets, multi-omics profiling (assay for transposase-accessible chromatin with sequencing [ATAC-seq], cleavage under targets and tagmentation [CUT&amp;Tag], mRNA sequencing [mRNA-seq]), in vitro/in vivo assays, and molecular approaches including co-immunoprecipitation (Co-IP) and molecular docking, we demonstrate that UBR5 depletion profoundly alters chromatin accessibility and genome-wide transcriptional profiles in a CDC73-dependent manner. UBR5 ablation markedly suppresses osteosarcoma malignant phenotypes in cultured cells and xenograft models, with these effects fully rescued by concurrent CDC73 silencing. Mechanistically, we identify the JNK cascade as the critical upstream regulator: JNK activation sustains CDC73 stability by antagonizing UBR5-mediated CDC73 polyubiquitination, and map Lys257 as the key residue for UBR5-dependent CDC73 ubiquitination and degradation. Collectively, our findings define a novel JNK-dependent UBR5-CDC73 axis that acts as a molecular brake of the CDC73 positive feedback loop to orchestrate transcriptional programs, providing new mechanistic insights into CDC73 post-translational regulation in tumorigenesis and promising therapeutic targets for CDC73-dysregulated diseases.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 43","pages":"4689-4702"},"PeriodicalIF":9.1,"publicationDate":"2026-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148983469","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":"CircLAMA5 traps Sam68 in the cytoplasm to regulate alternative splicing and drive sunitinib resistance in ccRCC","authors":"Zhehao Xu,&nbsp;Haohua Lu,&nbsp;Zeyi Lu,&nbsp;Ruyue Wang,&nbsp;Ziwei Zhu,&nbsp;Yiming Ding,&nbsp;Yang Li,&nbsp;Yi Lu,&nbsp;Fan Li,&nbsp;Wenqin Luo,&nbsp;Yudong Lin,&nbsp;Xudong Mao,&nbsp;Chenshuo Xu,&nbsp;Yi Chen,&nbsp;Zhen Yan,&nbsp;Guanghua Huo,&nbsp;Zhenwei Zhou,&nbsp;Min Xu,&nbsp;Lifeng Ding,&nbsp;Gonghui Li,&nbsp;Liqun Xia","doi":"10.1038/s41388-026-03981-9","DOIUrl":"10.1038/s41388-026-03981-9","url":null,"abstract":"Tyrosine kinase inhibitor (TKI) resistance remains a major challenge in the treatment of clear cell renal cell carcinoma (ccRCC), yet the underlying molecular mechanisms are not fully understood. Here, we identify circular RNA circLAMA5 (hsa_circ_0061093) as a critical driver of sunitinib resistance in ccRCC. CircLAMA5 is significantly upregulated in sunitinib‑resistant cell lines and cell‑derived xenografts (CDX-R). Functional studies demonstrate that circLAMA5 enhances ccRCC cell survival, colony formation, and apoptosis evasion under sunitinib treatment both in vitro and in vivo. Mechanistically, circLAMA5 binds to the C-terminal region of Sam68 and promotes its cytoplasmic retention, at least in part by impairing the interaction between Sam68 and the nuclear import receptor TNPO1. This reduces nuclear Sam68 availability and suppresses its regulatory role in the alternative splicing of Bcl-x pre-mRNA, leading to a decreased pro‑apoptotic Bcl‑x(s)/anti‑apoptotic Bcl‑x(L) ratio and ultimately conferring sunitinib resistance. Importantly, we developed a biomimetic nanoparticle system coated with ccRCC cell membranes (RCCM@NPs) for targeted delivery of sh‑circLAMA5, effectively restoring sunitinib sensitivity in resistant tumors in vivo. Our findings reveal circLAMA5 as a key regulator of sunitinib resistance via the Sam68‑Bcl‑x splicing axis and propose a promising targeted nanotherapeutic strategy for overcoming resistance in advanced ccRCC.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 43","pages":"4673-4688"},"PeriodicalIF":9.1,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-026-03981-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148977392","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":"Targeting the PRMT5-CBX8 axis overcomes dual barriers of CD8⁺ T cell exclusion and tumor stemness for sensitizing TNBC to anti-PD-1 therapy","authors":"Congcong Chen,&nbsp;Yuheng Zhang,&nbsp;Chang Liu,&nbsp;Runkai Zhao,&nbsp;Kaiming Liu,&nbsp;Zhiqi Guo,&nbsp;Yinyin Yang,&nbsp;Cong Wang,&nbsp;Jiaxin Tian,&nbsp;Yanguan Guo,&nbsp;Guo Chen,&nbsp;Liyan Jin,&nbsp;Xun Zhu,&nbsp;Danyang Zhou,&nbsp;Guoqin Jiang","doi":"10.1038/s41388-026-03987-3","DOIUrl":"10.1038/s41388-026-03987-3","url":null,"abstract":"The efficacy of immune checkpoint blockade in triple-negative breast cancer (TNBC) is limited by poor CD8⁺ T cell infiltration. Here, we demonstrate that tumor-derived proprotein convertase subtilisin/kexin type 9 (PCSK9) drives CD8⁺ T cell exclusion, and we identify protein arginine methyltransferase 5 (PRMT5) as an important epigenetic regulator responsible for PCSK9 expression in TNBC. Mechanistically, we elucidate that PRMT5-mediated methylation of the chromobox homolog 8 (CBX8) facilitates its interaction with the deubiquitinase USP7, which removes K33-linked ubiquitination on CBX8. This post-translational modification modulates CBX8 function, enabling it to drive the transcriptional upregulation of key downstream targets PCSK9, which inhibits CD8+ T cell infiltration, and LGR5, which enhances tumor stemness. Crucially, inhibition of PRMT5 profoundly sensitizes TNBC tumors to anti-PD-1 therapy in vivo. Our work unveils a novel epigenetic pathway orchestrated by PRMT5 that converges on the functional modulation of CBX8 to synchronously governs CD8⁺ T cell exclusion and tumor stemness, nominating PRMT5 inhibition as a compelling therapeutic strategy for combination immunotherapy in TNBC.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 43","pages":"4659-4672"},"PeriodicalIF":9.1,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148970457","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":"Development and preclinical evaluation of a decoy DLL4-encoding oncolytic HSV-1 for high-grade glioma","authors":"Kimberly A. Rivera-Caraballo,&nbsp;Karina Vázquez-Arreguín,&nbsp;Harmanpreet Singh,&nbsp;Upasana Sahu,&nbsp;Manika Kaur,&nbsp;Esrat Jahan,&nbsp;Bangxing Hong,&nbsp;Ashok Sharma,&nbsp;Balveen Kaur","doi":"10.1038/s41388-026-03985-5","DOIUrl":"10.1038/s41388-026-03985-5","url":null,"abstract":"Preclinical and clinical investigation of oncolytic HSV-1 (oHSV) treatment for cancer has indicated increased Notch signaling in tumors after treatment. Since Notch activation often heralds cancer cell stemness, angiogenesis, and invasion, the induction of this pathway after oHSV virotherapy can support tumor growth and limit response to virotherapy. Here, we evaluated the impact of blocking DLL4, a Notch ligand, on virotherapy. Matched tumor biopsies pre- and post-oHSV (CAN-3110, NCT03152318) treatment revealed an induction of DLL4 post-therapy. We observed that expression of a recombinant soluble decoy DLL4 (sDLL4) could block Notch activation in tumor cells. Thus, we engineered an oHSV vector designed to encode soluble DLL4 (OVsDLL4) to block ligand-mediated Notch signaling. RNA sequencing and gene set enrichment analysis revealed that, relative to control oHSV, OVsDLL4 blocked Notch and sprouting angiogenesis pathways after treatment. Despite slower virus replication in vitro, OVsDLL4 cytotoxicity remained effective against tumor cells. Transcriptome profiling also indicated a significant dysregulation of metabolic pathways related to oxidative phosphorylation and glutathione metabolism, in accordance with increased oxygen consumption observed by Seahorse analysis in cells expressing sDLL4. OVsDLL4-treated cells further showed increased reactive oxygen species relative to control oHSV-treated cells. Co-culture of infected tumor cells with immune cells revealed that OVsDLL4 treatment polarized them toward an inflammatory phenotype. In vivo, the therapeutic efficacy of OVsDLL4 was underscored, as treatment of glioma-bearing mice resulted in reduced tumor burden and prolonged survival.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 43","pages":"4647-4658"},"PeriodicalIF":9.1,"publicationDate":"2026-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-026-03985-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148955973","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}