Cancer gene therapy最新文献

{"title":"Correction: Targeted suppression of tumor growth by CREPT promoter-driven diphtheria toxin fragment A.","authors":"Jingya Li, Mengdi Li, Wenchen Wang, Guancheng Jiang, Yinyin Wang, Jianqiu Sheng, Zhijie Chang, Jian Sheng, Mingyang Li, Fangli Ren","doi":"10.1038/s41417-026-01006-x","DOIUrl":"https://doi.org/10.1038/s41417-026-01006-x","url":null,"abstract":"","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146177813","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":"Therapeutic advances with KRASG12C inhibitors and combination strategies in non-small cell lung cancer brain metastases","authors":"Debanjan Bhattacharya, Benjamin Roman, Sanjana Reddy","doi":"10.1038/s41417-026-01003-0","DOIUrl":"10.1038/s41417-026-01003-0","url":null,"abstract":"Non-small cell lung cancer (NSCLC) frequently metastasizes to the brain in approximately 20–40% of cases. Mutations in the Kirsten rat sarcoma viral oncogene homologue (KRAS) are common in NSCLC, with the KRASG12C variant accounting for approximately 40% of KRAS-mutant cases. Up to 40% of NSCLC patients harboring the KRASG12C mutation develop brain metastases during follow-up, and a substantial proportion present with brain metastases at diagnosis. While KRASG12C inhibitors such as sotorasib and adagrasib are approved therapies, most patients with KRASG12C mutant NSCLC experience disease progression within 5 to 6 months. Emerging KRASG12Cinhibitors, such as adagrasib, RMC-6236, and olomorasib, show intracranial activity in KRASG12C mutant NSCLC brain metastases, but adaptive resistance limits their effectiveness as monotherapies. This article examines the clinical and translational application of specific next-generation blood-brain barrier penetrant KRASG12C inhibitors, such as sotorasib, adagrasib, olomorasib, RMC-6236, and D3S-001, and their rational integration with radiation therapy, targeted therapies, and immunotherapies to overcome therapeutic resistance in patients with NSCLC brain metastases. This review summarizes recent advances aimed at enhancing intracranial tumor control and overall survival in patients with NSCLC brain metastases through the use of next-generation KRASG12C inhibitors and multimodal therapies.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"33 3","pages":"323-337"},"PeriodicalIF":5.0,"publicationDate":"2026-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41417-026-01003-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146149254","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":"Ataxia-telangiectasia mutated kinase inhibition overcomes gemcitabine resistance in intrahepatic cholangiocarcinoma via DNA ligase I-dependent repair vulnerability","authors":"Sheng-Hsuan Lin, Yi-Ru Pan, Tsai-Hsien Hung, Wen-Kuan Huang, Chun-Nan Yeh","doi":"10.1038/s41417-026-01005-y","DOIUrl":"10.1038/s41417-026-01005-y","url":null,"abstract":"Gemcitabine-based chemotherapy remains the standard first-line treatment for cholangiocarcinoma (CCA), but acquired resistance presents a significant clinical challenge. Synthetic lethality approaches targeting double-strand break repair (DSBR) pathways offer promising therapeutic opportunities. Ataxia-telangiectasia mutated (ATM) kinase, a central regulator of homologous recombination (HR) and non-homologous end joining (NHEJ), is critical for maintaining genomic integrity following DNA damage. Here, we demonstrate that combining the ATM inhibitor AZD0156 with DNA-damaging agents (cisplatin or photon irradiation) significantly enhances cytotoxicity in gemcitabine-resistant intrahepatic CCA sublines (GR-iCCAs) while sparing gemcitabine-sensitive parental cells. This selective sensitization manifests in impaired colony formation, increased apoptosis, and persistent γ-H2AX nuclear accumulation. The magnitude of AZD0156 sensitization in GR cells substantially exceeds additive expectations, strongly suggesting synergistic interaction. Genetic ATM depletion in GR-iCCAs under genotoxic stress recapitulated these effects, confirming on-target specificity. Mechanistically, GR-iCCAs exhibit significantly reduced DNA ligase I (LIG1) expression, a critical component of the alternative NHEJ (alt-NHEJ) repair pathway, particularly under DNA damage conditions. Genetic restoration of LIG1 expression reversed AZD0156 sensitivity, establishing LIG1 deficiency as a key determinant modulating DNA repair pathway dependency. In xenograft models, AZD0156 combined with cisplatin substantially suppressed tumor growth compared to monotherapy, with acceptable tolerability profiles. These findings identify ATM inhibition as a promising strategy to overcome gemcitabine resistance in CCA, particularly in tumors with compromised alt-NHEJ repair capacity, providing a mechanistic rationale for clinical development of this combination therapy.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"33 3","pages":"289-300"},"PeriodicalIF":5.0,"publicationDate":"2026-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41417-026-01005-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146137435","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":"C1orf35 contributes to high anabolic metabolism by simultaneously promoting aerobic glycolysis and oxidative phosphorylation in multiple myeloma cells.","authors":"Rui He, Wei Xiong, Saiqun Luo, Ruoyan Dang, Xiang Zhou, Yan Wu, Wei-Xin Hu, Jingping Hu","doi":"10.1038/s41417-026-01002-1","DOIUrl":"https://doi.org/10.1038/s41417-026-01002-1","url":null,"abstract":"<p><p>Similar to other malignancies, multiple myeloma (MM) has acquired several functional capabilities known as \"Hallmarks of cancer\", and one of them is the deregulation of cell metabolism, especially glucose metabolism. Our current study focuses on the role of Chromosome 1 Open Reading Frame 35(C1orf35) in the glucose metabolism of MM cells. We found that the expression of C1orf35 was negative correlated with the overall survival of MM patients, MM cell lines with high C1orf35 expression not only had a faster proliferation rate but also higher levels of both aerobic glycolysis and oxidative phosphorylation (OXPHOS). Mechanistic studies revealed that C1orf35 promoted aerobic glycolysis through the c-MYC/PKM2 pathway and interacted with Leucine-Rich PPR Motif-Containing Protein (LRPPRC) to enhance OXPHOS. Moreover, treating MM cells with Gossypol Acetic Acid (GAA), a small molecule inhibitor specifically targeting LRPPRC, unexpectedly led to the degradation of C1orf35 protein and an \"energy crisis\" in these cells. Finally, we confirmed C1orf35 is on the upstream of PI3K/AKT/mTOR pathway, thus C1orf35 may play a pivotal role in anabolic metabolism. Our study uncovers a \"C1orf35-driven\" energy metabolism model in MM cells, providing new insights into the pathogenesis of MM and a potential novel target for the treatment of cancer cells with a high\"C1orf35-driven\" anabolic metabolism. Schematic diagram of C1orf35 simultaneously promotes glycolysis and OXPHOS.</p>","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146096806","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":"Effective delivery of genome editor to cervical cancer targeting Mcl1 for cancer therapy.","authors":"Yue Wan, Yiming He, Xun Chen, Shengwu Wang, Guannan Zhou, Xiaoyan Ying, Haiyan Zhang","doi":"10.1038/s41417-025-00958-w","DOIUrl":"https://doi.org/10.1038/s41417-025-00958-w","url":null,"abstract":"<p><p>CRISPR/Cas9 represents a transformative advancement in precision therapies, offering the promise of more effective and targeted treatment options. However, there are still limitations (including off-target editing as well as unsatisfied delivery tool) which obstruct the wide application of CRISPR/Cas9. Here, an endogenic artificial extracellular vesicles (EVs) system is engineered for effective delivery of Cas9 ribonucleoprotein (RNP). We demonstrated that the endogenic Cas9 RNP were sorted by the Lamp2b and delivered by the artificial EVs, which could markedly inhibit the growth of cervical cancer cells by inducing cell apoptosis. Moreover, artificial endogenic EVs^RNP (Cas9-Mcl1) could result in remarkable antitumor effects in animal models of cervical cancer through suppressing Mcl1 expression. Our findings indicate that the artificial EVs delivery strategy could deliver Cas9 RNP effectively to inhibit cancer progression, which might be a promising treatment.</p>","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146060092","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":"LMTK3 regulates breast cancer angiogenesis via a context-dependent mesenchymal-epithelial transition program.","authors":"Jian Lu, Xiaoyan Huang, Hang Yao, Chrysa Filippopoulou, Reza Shirazi Nia, Xidong Gu, Xiaohong Xie, Qijin Shu, Georgios Giamas","doi":"10.1038/s41417-026-01001-2","DOIUrl":"https://doi.org/10.1038/s41417-026-01001-2","url":null,"abstract":"<p><p>Angiogenesis constitutes a critical rate-limiting determinant of tumor progression in breast cancer (BC). Resistance to conventional anti-angiogenic therapies in BC highlights an unmet need to identify upstream molecular regulators coordinating malignant cell plasticity and vascular remodeling. Lemur tail kinase 3 (LMTK3) is a well-established oncogenic kinase; however, its specific role within the tumor angiogenic microenvironment remains undefined. Here, we identify LMTK3 as a context-dependent driver of angiogenesis through a mesenchymal-epithelial transition (MET) program. By integrating single-cell RNA sequencing with functional validation, we uncover a 'Simpson's paradox' (where a correlation present in different groups disappears or reverses when combined): In mesenchymal-like triple-negative breast cancer (TNBC), LMTK3 promotes a pro-angiogenic, 'partial EMT' (p-EMT) state characterized by sustained ERK signaling and elevated secretion of angiogenic factors, including angiogenin. Conversely, in luminal-like cells, LMTK3 enforces a hyperepithelialized state that suppresses angiogenic phenotypes. Consequently, LMTK3 emerges as a central regulator of angiogenic plasticity, and its targeted inhibition offers a promising strategy to abrogate the pro-angiogenic p-EMT state and promote vascular normalization in TNBC.</p>","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146040460","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":"Exploration of the mechanism of anlotinib in reversing PD-1 immunotherapy resistance: insights from single-cell sequencing","authors":"Wanjin Shi,&nbsp;Yidong Zhang,&nbsp;Qiyi Yu,&nbsp;Huilong Li,&nbsp;Miaomiao Niu,&nbsp;Shengtao Xu,&nbsp;Jun Yin,&nbsp;Xiaoman Li,&nbsp;Lufeng Zheng","doi":"10.1038/s41417-026-01000-3","DOIUrl":"10.1038/s41417-026-01000-3","url":null,"abstract":"Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis have revolutionized cancer therapy, yet primary and acquired resistance remain major clinical obstacles. Dysregulated angiogenesis fuels the development of an immunosuppressive tumor microenvironment, while crosstalk between immunity and angiogenesis further propels tumor immune evasion and treatment resistance. The present study aimed to establish a penpulimab-resistant model, delineate anti-PD-1 resistance traits via single-cell RNA sequencing, and unravel the precise mechanisms through which anlotinib—an anti-angiogenic agent—mitigates penpulimab resistance. These findings offer insights to guide clinical management of immune-pretreated patients. Single-cell sequencing analyses demonstrated that anlotinib reverses penpulimab resistance by reprogramming the tumor immune microenvironment, thereby boosting PD-1 blockade efficacy via modulation of immune infiltration and tumor signaling pathways. Identifying Apoe⁺ M2 macrophages, Srgn⁺ M1 macrophages, and Cxcl2⁺ T cells provides key cellular and molecular targets for developing clinically actionable immunotherapies. Taken together, this work validates the preclinical potential of anlotinib combined with immunotherapy for immunotherapy-resistant tumors.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"33 2","pages":"248-260"},"PeriodicalIF":5.0,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146028371","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":"Correction: Pan-cancer oncogenic properties and therapeutic potential of SF3B4.","authors":"Yanmei Shi, Qimei Pan, Wenli Chen, Limin Xie, Shiru Tang, Zhizhi Yang, Man Zhang, Dong Yin, Lehang Lin, Jian-You Liao","doi":"10.1038/s41417-026-00999-9","DOIUrl":"https://doi.org/10.1038/s41417-026-00999-9","url":null,"abstract":"","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146017103","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":"Characteristics and developmental trajectory of clinical trials focused on tumor-infiltrating lymphocytes for cancer treatment","authors":"Jinyi Liu,&nbsp;Chun Xiao,&nbsp;Wei Zhang,&nbsp;Xinhong Li,&nbsp;Xuebin Wang","doi":"10.1038/s41417-026-00998-w","DOIUrl":"10.1038/s41417-026-00998-w","url":null,"abstract":"Tumor-infiltrating lymphocytes (TIL) have shown promise in cancer immunotherapy, yet their clinical application and developmental trajectory remain insufficiently characterized. In this study, we conducted a cross-sectional, descriptive analysis of interventional clinical trials investigating TIL therapies for cancer treatment registered on ClinicalTrials.gov up to December 31, 2024. Trial characteristics, temporal trends, and treatment strategies were systematically assessed. Among 177 eligible trials, the vast majority were early-phase studies enrolling small patient cohorts. Malignant melanoma was the most frequently studied tumor type. North America conducted the largest number of trials overall, while recent years have seen rapid growth in trial activity and industry sponsorship, particularly in Asia. Cytokine support and immune checkpoint inhibitors (ICIs) were the most common combination strategies. Since 2017, increasing interest has been observed in TIL monotherapy and in TIL–ICI combinations. Genetically engineered TIL trials were less likely to incorporate cytokine support or non-myeloablative chemotherapy, whereas selectively expanded TIL trials more frequently evaluated radiotherapy as a combination strategy. Overall, clinical trials of TIL therapy have primarily focused on early-phase exploration. Cytokines and ICIs remain the predominant combination approaches, while the use of TIL monotherapy has emerged as a growing trend. Continued research efforts and clinical investigation are essential to support the broader and more standardized application of TIL-based therapies in cancer treatment.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"33 2","pages":"236-247"},"PeriodicalIF":5.0,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145970497","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":"m6A epitranscriptomic regulation of KRAS by METTL3 promotes EMT and stromal remodeling through TGF-β/SMAD signaling in cervical cancer","authors":"Yangmei Gong,&nbsp;Jie Wu,&nbsp;Yi Hu","doi":"10.1038/s41417-025-00993-7","DOIUrl":"10.1038/s41417-025-00993-7","url":null,"abstract":"KRAS N6-methyladenosine (m6A) modification has emerged as a crucial epigenetic regulator in cancer progression, but its role in cervical cancer epithelial-mesenchymal transition (EMT) and stromal remodeling remains unclear. This study explored how METTL3-dependent m6A methylation of KRAS influences metastasis through the TGF-β/SMAD/SNAIL pathway. RNA sequencing (RNA-seq) and MeRIP-seq revealed that METTL3 knockdown significantly reduces KRAS m6A levels and suppresses TGF-β/SMAD pathway activation. Functional assays, including Western blot, immunofluorescence, Transwell, and scratch tests, demonstrated that METTL3 depletion inhibits cell migration, invasion, and EMT marker expression. Co-immunoprecipitation confirmed that m6A modification facilitates interactions between KRAS, SMAD2/3, and SNAIL. In vivo models showed reduced tumor growth and pulmonary metastasis upon METTL3 silencing. These findings define a novel METTL3-KRAS-TGF-β/SMAD/SNAIL axis in cervical cancer, offering new insights into m6A-mediated metastasis and potential therapeutic targets.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"33 2","pages":"198-211"},"PeriodicalIF":5.0,"publicationDate":"2026-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145896418","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}