Cancer gene therapy最新文献

{"title":"Targeting RAB27A-mediated small extracellular vesicle secretion via CRISPR-Cas9 negatively affects proliferation and metastasis in both in vitro and in vivo SCLC models","authors":"Onur Tokgün, Kubilay İnci, Aziz Gültekin, Büşra Çelikkaya, Nesrin İrep, Hakan Akça, Pervin Elvan Tokgün","doi":"10.1038/s41417-026-01063-2","DOIUrl":"10.1038/s41417-026-01063-2","url":null,"abstract":"Small cell lung cancer (SCLC) comprises 15% of lung cancers with a capacity for early and distant metastatic development, high proliferative capacity, and poor survival rates. Ionizing radiation and chemotherapy are effective against early-stage SCLC. This sensitivity wanes over time, however, making treatment difficult. Different types of neoplasms have demonstrated the pivotal role of small extracellular vesicles (sEVs) in disease progression. However, the role of sEVs development in SCLC remains unclear. In this study, the impact of sEVs secretion in SCLC cells was investigated using the CRISPR-Cas9 system to target the RAB27A. The effects of sEVs release inhibition on tumour growth and metastasis were evaluated using micro-PET-CT analysis. A reduction in cellular proliferation as a consequence of sEVs release, along with diminished expression of proteins and RNA (CD9, CD63, and Tsg101) implicated in sEVs secretion in silenced SCLC cells (p < 0.001, p < 0.0001) was detected. The suppression of sEVs release exhibited significant adverse effects on tumor development and metastatic dissemination in the in vivo tumor model. The present study suggests that the targeting of RAB27A could be a viable cancer therapy for SCLC. Targeting the exosomal pathway has the potential to enhance treatment efficacy, and SCLC may depend on sEVs secretion.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"33 8","pages":"1000-1013"},"PeriodicalIF":6.4,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148535291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CagA promotes gastric cancer stemness and metastasis via DNMT1-mediated epigenetic silencing of BEX1","authors":"Yan Wang, Dajun Chen, Shuai Qian, Fengping Wang, Huibin Weng","doi":"10.1038/s41417-026-01057-0","DOIUrl":"10.1038/s41417-026-01057-0","url":null,"abstract":"Helicobacter pylori (H. pylori) cytotoxin-associated gene A (CagA) critically contributes to gastric cancer (GC) pathogenesis, though its epigenetic control of cancer stemness is incompletely characterized. This study establishes that CagA enhances self-renewal capacity and metastatic potential in GC cells by elevating DNA methyltransferase 1 (DNMT1) expression. Upregulated DNMT1 catalyzes hypermethylation of the brain-expressed X-linked gene 1 (BEX1) promoter, resulting in transcriptional silencing of this tumor suppressor. Functional validation through tumorsphere/colony formation assays and transcriptomic profiling confirmed DNMT1-mediated BEX1 suppression as essential for sustaining stemness phenotypes. Crucially, in vivo models demonstrated that BEX1 overexpression reverses CagA-driven tumor growth and pulmonary metastasis, while BEX1 knockdown compromises the anti-tumor efficacy of DNA methyltransferase inhibitor 5-aza-2’-deoxycytidine (DAC). These findings define a novel pathogenic cascade wherein CagA initiates DNMT1-dependent epigenetic silencing of BEX1 to maintain cancer stemness. The mechanistic identification of this CagA-DNMT1-BEX1 axis provides a therapeutic rationale for targeting DNMT1 activity and restoring BEX1 function in metastatic GC.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"33 8","pages":"964-980"},"PeriodicalIF":6.4,"publicationDate":"2026-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148469313","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retraction Note: Downregulation of SBF2-AS1 functions as a tumor suppressor in clear cell renal cell carcinoma by inhibiting miR-338-3p-targeted ETS1","authors":"Xiuqin Yang, Yuanyuan Zhang, Haiying Fan","doi":"10.1038/s41417-026-01061-4","DOIUrl":"10.1038/s41417-026-01061-4","url":null,"abstract":"","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"33 8","pages":"1-1"},"PeriodicalIF":6.4,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41417-026-01061-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148454734","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibiting CXCL12/CXCR4 axis enhances T cell activity in gastric cancer","authors":"Fengyu Ling, Meibiao Zhang, Jia Kuang, Shuai Wu, Zhao Yang","doi":"10.1038/s41417-026-01053-4","DOIUrl":"10.1038/s41417-026-01053-4","url":null,"abstract":"This study aimed to investigate how the CXCL12/CXCR4 axis facilitates immune evasion in gastric cancer (GC) by enhancing cellular communication between cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) using single-cell transcriptome sequencing. Single-cell RNA sequencing of tumor and normal gastric tissues in a murine GC model revealed an increased macrophage population in GC, characterized by predominantly M2-polarized TAMs. The study identified that the CXCL12/CXCR4 axis potentially triggers M2 macrophage polarization through mediating communication between CAFs and TAMs. In vitro experiments confirmed that CAFs induced M2 polarization through CXCL12/CXCR4 signaling. Inhibition of the PD-L1/PD-1 axis disrupted communication between M2 macrophages and T cells, which enhanced T cell activation. In vivo experiments showed that silencing CXCR4 reduced M2 macrophages and PD-L1 expression, leading to improved T cell proliferation, reduced immune evasion, and slower tumor growth. These findings highlight the role of the CXCL12/CXCR4 axis in driving immune evasion in GC by inducing M2 polarization and PD-L1-mediated T cell suppression, and indicate a promising therapeutic target for GC immunotherapy.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"33 8","pages":"981-999"},"PeriodicalIF":6.4,"publicationDate":"2026-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148419123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LD–associated signatures identified by perilipin-based proximity labeling proteomics reveal GNA14 as a therapeutic and prognostic target in renal cell carcinoma","authors":"Yuankang Feng, Xinran Zhang, Shiyue Zhang, Jianqiao Li, Zhihao Bo, Jialu Ma, Xinyu Liu, Yang Liu, Shumin Yu, Rui Wang, Mingjian Lian, Yaqun Zhang, Dan Yue, Yong Wang","doi":"10.1038/s41417-026-01055-2","DOIUrl":"10.1038/s41417-026-01055-2","url":null,"abstract":"Renal cell carcinoma (RCC), especially clear cell RCC (ccRCC), is characterized by metabolic reprogramming, notably disordered lipid metabolism and prominent intracellular lipid droplet accumulation. In addition to abnormal triglyceride and cholesterol ester storage, lipid droplets promote tumor proliferation, survival, and drug resistance by supplying energy, membrane components, and signaling platforms, thereby representing potential therapeutic targets. We integrated TMU-RNAseq and TCGA-KIRC datasets and performed proximity-labeling mass spectrometry targeting PLIN2/3 to identify perilipin-related genes (PRGs). Based on TCGA-KIRC, we established a lipid droplet-related model (LDM), and the LDM score (LDMS) effectively predicted ccRCC prognosis. Validation in TCGA-KIRC and three external cohorts (GSE22541, E-MTAB-1980, and E-MTAB-3267) showed superior prognostic performance over conventional clinical parameters. High LDMS was associated with increased mutation frequency and an immunosuppressive microenvironment. Drug sensitivity analysis suggested differential responses to Sorafenib, Cediranib, and Saracatinib. Functional assays demonstrated that GNA14 inhibits ccRCC progression and enhances lipid accumulation via PLIN2 upregulation. GNA14 overexpression combined with Lovastatin further strengthened antitumor effects. Overall, LDM is a robust prognostic tool, and GNA14 plus Lovastatin may offer a potential therapeutic strategy for ccRCC.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"33 8","pages":"944-963"},"PeriodicalIF":6.4,"publicationDate":"2026-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148419182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PYGO2 is overexpressed in multiple myeloma patients with 1q21 amplification, driving plasma cell proliferation and cell cycle progression","authors":"Nicolas Thomas Iannozzi, Paola Storti, Rosanna Vescovini, Camilla Sitzia, Andrea Poletti, Valentina Franceschi, Giannalisa Todaro, Gabriella Sammarelli, Denise Toscani, Vincenzo Raimondi, Mattia Dessena, Oxana Lungu, Fazel Mohammadi, Matteo Scita, Matia Bernardi, Anna Benedetta Dalla Palma, Stefania Ricci, Bruno Lorusso, Costanza Anna Maria Lagrasta, Federico Quaini, Luca Agnelli, Gaetano Donofrio, Nicola Giuliani","doi":"10.1038/s41417-026-01060-5","DOIUrl":"10.1038/s41417-026-01060-5","url":null,"abstract":"Chromosome 1q21 copy number alterations (1q21+) are among the most frequent secondary events in multiple myeloma (MM), correlating with poor prognosis and therapy resistance. However, the molecular drivers of this lesion remain poorly defined. Here, we identify PYGO2, a Wnt/β-catenin co-activator located on 1q21, as a critical effector of MM progression. Analysis of primary CD138+ plasma cells and public datasets revealed that PYGO2 expression is significantly increased in 1q21+ patients and correlates with chromosome 1q copy number. High PYGO2 levels were associated with adverse cytogenetics and shorter progression-free and overall survival. Functional studies showed that PYGO2 knockdown (KD) in 1q21+ cell lines impaired proliferation, induced cell cycle perturbation coupled with CCND1 downregulation and reduced H3K4me3 enrichment, while increasing Carfilzomib and Bortezomib sensitivity. Conversely, PYGO2 overexpression enhanced cell growth and proteasome inhibitor resistance. RNA-seq profiling of KD cells revealed coordinated suppression of canonical Wnt/TCF target genes involved in proliferation and reshaped the replication stress and DNA damage response transcriptome, suggesting enhanced replication stress. RNA-seq profiling of KD cells also revealed suppression of oncogenic and immunomodulatory pathways, suggesting a broader role in tumor-microenvironment crosstalk. Overall, our data establish PYGO2 as a previously unrecognized effector of 1q21-driven aggressiveness in MM and suggest that it represents a therapeutic vulnerability in high-risk 1q21+ MM patients.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"33 8","pages":"919-930"},"PeriodicalIF":6.4,"publicationDate":"2026-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41417-026-01060-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148419140","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"VPS37A loss creates CASP8-dependent vulnerability via the MAP3K7–NF-κB–CFLAR axis","authors":"Tatsuya Hattori, Longgui Chen, Xinwen Liang, Kouta Hamamoto, Hong-Gang Wang, Yoshinori Takahashi","doi":"10.1038/s41417-026-01054-3","DOIUrl":"10.1038/s41417-026-01054-3","url":null,"abstract":"VPS37A, a subunit of ESCRT-I involved in endosomal sorting and autophagy, is frequently downregulated in diverse human cancers. In this study, we showed that VPS37A downregulation, as part of a large chromosome 8p deletion, arises early during tumorigenesis and persists throughout tumor progression. Integrative analysis of VPS37A gene copy number and CRISPR dependency revealed that VPS37A deficiency creates a synthetic lethal dependency on the MAP3K7–NF-κB–CFLAR axis, and targeting this axis triggered CASP8-mediated apoptosis and suppressed tumor growth. This synthetic vulnerability depends on ATG8ylated membranes, which serve as a platform for CASP8 activation upon inhibition of phagophore closure, and can be triggered without disrupting receptor sorting. Consistently, despite frequent co-deletion of VPS37A and the death receptors TNFRSF10A/B, inhibition of the MAP3K7–NF-κB–CFLAR axis selectively induced apoptosis in spheroid tumors with 8p deletion. These results uncover a selective vulnerability in cancer cells harboring VPS37A/8p loss, providing a mechanistic rationale for targeted therapeutic intervention.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"33 8","pages":"897-908"},"PeriodicalIF":6.4,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41417-026-01054-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148403726","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Transcriptomic profiling of a novel gastric implantation model identifies mechanisms and pathways that drive implantation into explanted human peritoneum","authors":"Deanna Ng, Karineh Kazazian, Kiera Lee, Yi Qing Lu, Aiman Ali, Karina Pacholczyk, Savtaj Brar, James Conner, Igor Jurisica, Christopher Allan McCulloch, Dae-Kyum Kim, Carol Jane Swallow, Marco Magalhaes","doi":"10.1038/s41417-026-01056-1","DOIUrl":"10.1038/s41417-026-01056-1","url":null,"abstract":"","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"33 8","pages":"1024-1024"},"PeriodicalIF":6.4,"publicationDate":"2026-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41417-026-01056-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148396003","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptomic profiling of a novel gastric implantation model identifies mechanisms and pathways that drive implantation into explanted human peritoneum","authors":"Deanna Ng, Karineh Kazazian, Kiera Lee, Yi Qing Lu, Aiman Ali, Karina Pacholczyk, Savtaj Brar, James Conner, Igor Jurisica, Christopher Allan McCulloch, Dae-Kyum Kim, Carol Jane Swallow, Marco Magalhaes","doi":"10.1038/s41417-026-01048-1","DOIUrl":"10.1038/s41417-026-01048-1","url":null,"abstract":"Epithelial cancers such as stomach and ovarian cancer tend to metastasize to the peritoneum, often leading to intractable disease and poor survival. The mechanisms that enable gastric cancer cells to implant, invade, and survive in the peritoneal niche are poorly understood. We developed a novel human peritoneal explant model using freshly harvested peritoneal tissue samples. GFP-labeled human gastric adenocarcinoma cells (AGS) were co-cultured with the peritoneal samples, and 2% of these cells implanted into the peritoneum. The transcriptomic profile of the implanted AGS cells was compared to AGS cells that failed to implant using RNA sequencing. Differentially expressed genes in implanted AGS cells were enriched for cell adhesion and motility. We functionally validated these genes with CRISPR knockout and identified ADAM12 as a regulator of peritoneal metastasis. ADAM12 KO significantly impaired peritoneal metastasis in vivo and ex vivo and marked disruption of the ITGβ1 interactome in GCa cells. Our approach and the new data identify a distinct peritoneal metastasis gene set that facilitates the implantation and invasion of gastric cancer cells within the peritoneum. Disruption of these pathways with peritoneal-directed therapies has the potential to improve survival in patients with high-risk primary gastric cancer.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"33 8","pages":"931-943"},"PeriodicalIF":6.4,"publicationDate":"2026-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148307085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NCBP1 promotes the malignant progression of Wilms’ tumor through stabilization of KPNA2 mRNA","authors":"Yintao Cheng, Wu Wang, Jun Wang, Wei Lei, Yawei Zhang, Hui Guo, Fei Peng, Hang Liu","doi":"10.1038/s41417-026-01050-7","DOIUrl":"10.1038/s41417-026-01050-7","url":null,"abstract":"Nephroblastoma, also known as Wilms’ tumor (WT), is the most common malignant renal tumor in children under 5 years of age. Despite a generally favorable prognosis, approximately 15% of cases experience recurrence. Currently, treatment options for refractory and recurrent WT remain limited, and targeted therapeutic strategies are still under investigation. NCBP1 is a core component of the cap-binding complex and plays a role in mRNA processing, transport, and translational regulation; however, its involvement in the initiation and progression of WT has not yet been elucidated. This study utilized bioinformatics analysis to identify that NCBP1 is highly expressed in WT tissues and is associated with a poor prognosis. Molecular experiments further confirmed that NCBP1 is significantly overexpressed in the WT cell lines 17.94 and HFWT. Functional assays demonstrated that silencing NCBP1 suppresses the proliferation, migration, invasion, and tumorigenic potential of both 17.94 and HFWT cells. Through screening for NCBP1-interacting proteins, KPNA2 was identified, and a positive correlation was observed between the expression levels of KPNA2 and NCBP1 in WT tissues. Through RNA immunoprecipitation experiments, we further validated the interaction between NCBP1 and KPNA2 in WT cells. Silencing of NCBP1 resulted in reduced stability and expression levels of KPNA2 mRNA in 17.94 and HFWT cells. Furthermore, KPNA2 overexpression not only enhanced the proliferation, migration, and invasion capabilities of 17.94 and HFWT cells, but also partially counteracted the inhibitory effects of NCBP1 silencing on these malignant cellular behaviors. In conclusion, the findings of this study elucidate the involvement of NCBP1 in the malignant progression of WT. NCBP1 enhances the stability of KPNA2 mRNA, thereby upregulating KPNA2 expression and subsequently promoting the malignant progression of WT cells.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"33 7","pages":"847-860"},"PeriodicalIF":6.4,"publicationDate":"2026-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148270438","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}