Cancer gene therapy最新文献

{"title":"BCL-xL dependency in chromophobe renal cell carcinoma","authors":"Nadine Mahmoud, Xingping Qin, Wafaa Bzeih, Damir Khabibullin, Michel Alchoueiry, Steven Safi, Joelle Chami, Tiegang Han, Samer Salem, Carmen Priolo, Abhishek A. Chakraborty, Kristopher A. Sarosiek, Elizabeth P. Henske","doi":"10.1038/s41417-025-00953-1","DOIUrl":"10.1038/s41417-025-00953-1","url":null,"abstract":"Chromophobe renal cell carcinoma (ChRCC) is the third most common subtype of kidney cancer, with limited therapeutic options. Using BH3 profiling to screen ChRCC-derived cell lines, we discovered that BH3 peptides targeting BCL-xL promote apoptosis in ChRCC. Downregulation of BCL2L1 is sufficient to induce apoptosis in ChRCC-derived cells, consistent with our screening results. BCL2L1, encoding BCL-xL, is fourfold upregulated in ChRCC compared to normal kidney and has the second highest expression in The Cancer Genome Atlas. BCL2L1 downregulation enhances MCL-1 expression, suggesting a possible compensatory role for MCL-1. Based on these results, we evaluated two BH3 mimetics, A-1331852 (targeting BCL-xL) and S63845 (targeting MCL-1). Their combination resulted in 80% cell death. DT2216, a proteolysis-targeting chimera (PROTAC) that targets BCL-xL for degradation, induced cleaved PARP and caspase 3, indicators of apoptosis. ChRCC cells are known to be highly sensitive to ferroptosis. We combined A-1331852 and S63845 with IKE or RSL3 (ferroptosis-inducing drugs). BCL-xL and MCL-1 inhibition enhanced the susceptibility to ferroptosis, suggesting a link between apoptosis and ferroptosis in ChRCC. These data indicate that BCL-xL maintains ChRCC cell survival by suppressing apoptosis. The BCL-xL-specific PROTAC DT2216, currently in clinical trials, may provide an opportunity for ChRCC therapy.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 10","pages":"1133-1143"},"PeriodicalIF":5.0,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144862111","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":"LncSNHGs: new targets in osteosarcoma","authors":"Yining Zhang, Jinfa Wu, Jiaming Liu","doi":"10.1038/s41417-025-00952-2","DOIUrl":"10.1038/s41417-025-00952-2","url":null,"abstract":"Long non-coding RNAs (lncRNAs) have attracted significant attention for their role in tumor initiation and progression. Specifically, studying lncRNA small nucleolar RNA host genes (lncSNHGs) has opened up new possibilities for the treatment of osteosarcoma (OS). This review aims to give a thorough overview of the state of research on the biological roles, molecular mechanisms, and expression of the lncRNA SNHG family in OS. Through an extensive analysis, it is demonstrated that members of the SNHG family exhibit dysregulated expression patterns in OS. These dysregulations affect multiple oncogenic processes, including tumor proliferation, metastasis, apoptosis, autophagy, and chemotherapy resistance. The lncRNA SNHG family promises to identify novel strategies and targets for diagnosing, treating, and prognosis OS.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 10","pages":"1031-1041"},"PeriodicalIF":5.0,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144862113","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":"Abemaciclib impairs glioblastoma sphere formation by targeting the GSK3β-mediated transcriptional regulation of CD44 and TCF7L2","authors":"Muh-Lii Liang, Chun-Han Chen, Ya-Ching Lin, Yu-Chen Lin, Yun-Ru Liu, Yi-Huei Ding, Cheng-Ying Chu, Tsung-Han Hsieh","doi":"10.1038/s41417-025-00955-z","DOIUrl":"10.1038/s41417-025-00955-z","url":null,"abstract":"Glioblastoma multiforme (GBM) is an aggressive brain tumor partly driven by cancer stem cells (CSCs). Abemaciclib demonstrates the potential for treating GBM, although its mechanisms beyond RB phosphorylation are not fully understood. This study reveals that Abemaciclib diminishes GBM sphere formation by influencing EMT pathways via GSK3β-mediated regulation of CD44 and TCF7L2. Treatment with Abemaciclib significantly hindered sphere formation in GBM cells, and transcriptomic analysis indicated EMT pathways suppression. Mechanistically, Abemaciclib consistently lowered the expression of CD44 and TCF7L2 in both parental and sphere cells by inhibiting GSK3β phosphorylation. A pharmacological GSK3β inhibitor produced similar effects, reinforcing the existence of a GSK3β-CD44/TCF7L2 axis. Moreover, orthotopic xenografts confirmed reduced tumor growth and CD44 expression in vivo. Analyses of TCGA and CGGA datasets revealed that the mesenchymal GBM subtype (MES-GBM), linked with poor outcomes, exhibits elevated EMT gene expression. Treatment of MES-like LN229 cells with Abemaciclib resulted in decreased phosphorylation of GSK3β and reductions in EMT-related gene expression. Our findings highlight a novel EMT-suppressive action of Abemaciclib, illustrating its therapeutic potential for targeting the CSCs and for treating the MES-GBM. This research provides mechanistic insights and justification for repurposing Abemaciclib as targeted therapies for aggressive glioblastoma.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 10","pages":"1120-1132"},"PeriodicalIF":5.0,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144854698","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":"The involvement of lncRNA EMSLR in the disulfidptosis and progression of endometrial carcinoma","authors":"Yixuan Sun, Ruiwen Wang, Xinzhu Li, Wanzhen Zhou, Huixian Huang, Yang Zhou, Xiaolu Zhu, Yifan Yin, Yincheng Teng","doi":"10.1038/s41417-025-00918-4","DOIUrl":"10.1038/s41417-025-00918-4","url":null,"abstract":"The incidence of endometrial cancer (EC) continues to rise. Disulfidptosis, a novel form of cell death, may represent a potential therapeutic target in EC. Through bioinformatic analysis of The Cancer Genome Atlas (TCGA) database, E2F1 mRNA-stabilizing lncRNA (EMSLR) was identified as a lncRNA related to disulfidptosis in EC. Functional assays, including cell proliferation and xenograft assays, demonstrated that knockdown of EMSLR significantly impeded EC cell proliferation, whereas overexpression of EMSLR promoted cell viability. Additionally, EMSLR was found to be associated with glucose uptake and NADPH production in glucose-restricted culture conditions. Moreover, downregulation of EMSLR markedly increased cell death and induced cytoskeletal collapse under glucose deprivation, as evidenced by F-actin and cell death staining. Notably, we observed a strong correlation between EMSLR and the c-MYC-GLUT1 pathway. Mechanistically, EMSLR was found to mediate the expression and nuclear translocation of c-MYC, thereby regulating the progression of EC and its associated disulfidptosis. In conclusion, EMSLR is identified as a disulfidptosis-related gene in endometrial cancer. Elucidating the function and molecular mechanisms of EMSLR in EC presents a promising avenue for therapeutic intervention in patients.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 10","pages":"1107-1119"},"PeriodicalIF":5.0,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41417-025-00918-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144854699","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":"METTL3 facilitates colorectal cancer growth through altering the abundance of intestinal Akkermansia muciniphila","authors":"Ling Wu, Weidong Lian, Rui Bai, Hao Chen, Jianghua Wu, Hanyu Li, Liang Zhao","doi":"10.1038/s41417-025-00949-x","DOIUrl":"10.1038/s41417-025-00949-x","url":null,"abstract":"Colorectal cancer (CRC) is a prevalent malignant tumor that poses a significant threat to human health; however, the precise mechanism underlying its onset remains elusive. In this study, we utilized metagenomic sequencing to reveal the dysregulation of intestinal microbiota caused by CRC. Single-cell sequencing data showed elevated mRNA expression of methyltransferase-like protein 3 (METTL3) in CRC, which was correlated with the abundance of intestinal microbiota. Furthermore, we found that METTL3 promotion of CRC progression is microbiota-dependent. Using induced METTL3fl/fl Vil1-cre+/− mice, we identified the microbiota regulated by METTL3 in CRC. Our research indicates that METTL3 leads to high expression of HIF1α, which promotes the expression of lipocalin 2 (LCN2) in CRC cells, inhibiting the abundance of Akkermansia muciniphila, thereby promoting CRC progression.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 10","pages":"1098-1106"},"PeriodicalIF":5.0,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144820669","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":"NK cells mediate preventive efficacy of intravenous BCG against lung metastasis in mice","authors":"Claudia Guerrero, Marta Casal, Cristina Alierta, Eduardo Moreo, Miguel Araujo-Voces, Santiago Uranga, Ana Belén Gómez, Carlos Martín, Nacho Aguiló","doi":"10.1038/s41417-025-00948-y","DOIUrl":"10.1038/s41417-025-00948-y","url":null,"abstract":"Lung metastases frequently arise from primary tumors, including bladder cancer, and represent a critical negative prognostic factor. Natural Killer (NK) cells have shown to play a vital role in controlling metastasis. Consequently, tumor cells have evolved specific mechanisms to evade NK cell-mediated immune surveillance, promoting metastasis and resistance to immunotherapy. In this study, we investigated the prophylactic and therapeutic potential of intravenous Bacillus Calmette–Guerin (BCG) in preventing lung metastases from bladder cancer cells using a murine model. We demonstrated that prophylactic BCG administration significantly reduced tumor burden and prolonged survival, largely through NK cell activation. However, BCG treatment was ineffective when administered over established tumors, likely due to tumor-driven immune evasion mechanisms. Our results revealed the contribution of interferon-gamma (IFN-γ) to tumor resistance. Tumor cells exposed to IFN-γ were more resistant to BCG in vivo, which correlated with the overexpression of immune checkpoint molecules, whereas disruption of the IFN-γ signaling pathway in tumor cells partially restored the therapeutic efficacy of BCG. Our findings highlight the importance of understanding tumor immune escape mechanisms and suggest that BCG could be a promising treatment for preventing lung metastases in bladder cancer.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 10","pages":"1090-1097"},"PeriodicalIF":5.0,"publicationDate":"2025-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144768393","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":"Targeting MCM10 disrupts cancer stemness and counteracts sorafenib resistance in hepatocellular carcinoma","authors":"Ziyun Zhang, Lu Liang, Yi Li, Ye Fan, Yao Liu, Zhifei He, Xiumin Wu, Li Cong, Yiqun Jiang, Tao Wan","doi":"10.1038/s41417-025-00946-0","DOIUrl":"10.1038/s41417-025-00946-0","url":null,"abstract":"Hepatocellular carcinoma (HCC) is the most prevalent primary malignant tumor, with sorafenib as the main treatment for advanced cases. However, the development of resistance to sorafenib, often driven by cancer stemness, significantly limits its therapeutic efficacy. Minichromosome maintenance complex component 10 (MCM10), a critical regulator of DNA replication and tumor progression, has been implicated in cancer stemness and therapeutic resistance. This study utilized datasets from TCGA and ICGC alongside in vitro and vivo experiments on clinical HCC tissues and sorafenib-resistant cell lines to evaluate MCM10’s role in HCC. The Connectivity Map (CMap) was employed to identify TW-37, a potential gene silencing agent targeting MCM10 transcription. The effects of TW-37 on MCM10 expression, cancer stemness, and sorafenib sensitivity were assessed. Elevated MCM10 expression was observed in sorafenib-resistant HCC cell lines and was associated with poor patient outcomes. MCM10 knockout diminished cancer stemness and restored sorafenib sensitivity in resistant cells. Furthermore, TW-37, identified via CMap, effectively downregulated MCM10, reduced cancer stemness, and enhanced sorafenib efficacy, offering a promising therapeutic approach. MCM10 plays a pivotal role in promoting cancer stemness and sorafenib resistance in HCC. Targeting MCM10 transcription with TW-37 represents a novel strategy to overcome sorafenib resistance and improve therapeutic outcomes in HCC patients.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 10","pages":"1076-1089"},"PeriodicalIF":5.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41417-025-00946-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144764629","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":"Engineered L-asparaginase variants with enhanced therapeutic properties to improve treatment of childhood acute lymphatic leukemia","authors":"Mainak Biswas, Soumika Sengupta, Khushboo A. Gandhi, Saurabh Kumar Gupta, Poonam B. Gera, Bhagyashri Soumya Nayak, Manaswini Jagadeb, Vikram Gota, Avinash Sonawane","doi":"10.1038/s41417-024-00865-6","DOIUrl":"10.1038/s41417-024-00865-6","url":null,"abstract":"Escherichia coli L-asparaginase (EcA), a key component of a multi-drug acute lymphatic leukemia (ALL) treatment regimen, has several limitations that reduce its therapeutic efficacy. The major disadvantages include immunogenicity, serum instability, shorter half-life, and accompanying glutaminase activity that causes neurotoxicity and pancreatitis. Pegylated asparaginase and Erwinase have better therapeutic potential, but they are expensive. Using site-directed mutagenesis, we created several EcA variants by substituting specific amino acid residues at the dimer-dimer interface and B-cell epitope regions. After several rounds of screening and selection, we identified two EcA variants viz. K288S/Y176F (KSY-17) and K288S/Y176F/W66Y (KSYW-17), which showed comparable asparaginase activity to wild-type (WT) and significantly less glutaminase activity (30.36 U/mg for WT vs 1.54 and 0.99 U/mg for KSY-17 and KSYW-17). KSYW-17 was less immunogenic than WT, eliciting 4.8–5.3-fold and 2.4–3.8-fold less IgG and IgM responses, respectively. Compared to WT EcA, we also observed significantly less (~1.5-2-fold) binding of these variants to pre-existing antibodies in ALL patients’ serum. Pharmacokinetic studies showed that KSY-17 (213.3 ± 6.5 min) and KSYW-17 (244.8 ± 35.5 min) had longer plasma half-lives than WT (101.1 ± 5.1 min). Both variants showed no toxicity up to 5000 IU/kg (single dose) and 1600 IU/kg (repeat dose) in mice. ALL xenograft mice studies showed a 90% and 70% reduction in leukemia burden in KSY-17 and KSYW-17 administered mice, respectively, as compared to 30% for WT after repeat dose administration, accompanied by significantly higher mice survival (100% vs. 70% vs. 10% for KSY-17 vs. KSYW-17 vs. WT). Overall, the engineered EcA variants’ showed improved therapeutic efficacy, thus making them promising candidates for primary and relapsed ALL treatment.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 10","pages":"1062-1075"},"PeriodicalIF":5.0,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144752510","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":"Real-world outcomes of Adjuvant De Gramont versus Xelox chemotherapy in reSected gasTric cancER: a propensity score-matched analysis (ASTER study)","authors":"Ina Valeria Zurlo, Fausto Rosa, Diana Giannarelli, Giovanni Trovato, Massimiliano Salati, Andrea Spallanzani, Michele Basso, Carmelo Pozzo, Sergio Alfieri, Giampaolo Tortora, Antonia Strippoli","doi":"10.1038/s41417-025-00945-1","DOIUrl":"10.1038/s41417-025-00945-1","url":null,"abstract":"The role of adjuvant chemotherapy (aCT) in gastric and esophago-gastric junction cancer (GC/EGJC) remains controversial. This study (ASTER study) aimed to compare the clinical outcomes of De Gramont (DG) versus XELOX/FOLFOX (OXA) regimens in a European real-world setting. This retrospective, bicentric study included patients treated with aCT between January 2001 and January 2018. A propensity score-matched (PSM) analysis was performed to compare oncological outcomes between DG and OXA regimens. Primary endpoints were disease-free survival (DFS) and overall survival (OS). Statistical analyses included the chi-square test, Kaplan–Meier method, and Cox proportional hazards modeling. Among 255 patients (127 DG, 128 OXA), 160 were matched (80 per arm) by PSM. Median DFS and OS did not differ significantly between groups (mDFS: 102.3 vs. 85.4 months, p = 0.91; mOS: 119.5 vs. 89.8 months, p = 0.69). In PSM-adjusted analysis, DG showed a trend towards longer DFS (p = 0.052) and significantly improved OS (p = 0.016). Multivariate analysis confirmed age, ECOG PS, resection margins, and stage as major prognostic factors. DG and OXA regimens demonstrated similar efficacy in the adjuvant treatment of resected GC/GEJC in a European cohort. Further prospective studies are warranted to optimize regimen selection and refine patient stratification.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 10","pages":"1054-1061"},"PeriodicalIF":5.0,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41417-025-00945-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717621","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":"Long non-coding RNA PRSS23-AS1 as ceRNA promotes breast cancer progression by regulating EMT via miR-3176 /YBX1 axis","authors":"Yun Huang, Mudan Feng, Yiwei Jiang, Maihuan Wang, Mingkun Wang, Zhen Cao","doi":"10.1038/s41417-025-00943-3","DOIUrl":"10.1038/s41417-025-00943-3","url":null,"abstract":"Breast cancer (BC) remains a leading cause of cancer-related mortality, largely due to its aggressive proliferation and metastatic potential. Long non-coding RNAs (lncRNAs) have emerged as key regulators in tumor development and progression. This study explored the functional role and mechanism of Lnc-PRSS23-AS1 in BC. We assessed Lnc-PRSS23-AS1 expression and localization using fluorescence in situ hybridization, qRT-PCR, and Western blotting in BC tissues and cell lines. Binding interactions between Lnc-PRSS23-AS1, miR-3176, and Y-box binding protein 1 (YBX1) were validated through dual-luciferase reporter assays, RNA pulldown, and RNA immunoprecipitation. Lnc-PRSS23-AS1 was significantly upregulated in BC and predominantly localized in the cytoplasm. Silencing Lnc-PRSS23-AS1 or overexpressing miR-3176 suppressed BC cell proliferation, migration, and invasion in vitro and in vivo. Conversely, miR-3176 inhibition or YBX1 overexpression reversed these effects. Mechanistically, Lnc-PRSS23-AS1 promoted YBX1 protein expression by acting as a molecular sponge for miR-3176. These findings highlight the Lnc-PRSS23-AS1/miR-3176/YBX1 axis as a driver of BC progression and suggest Lnc-PRSS23-AS1 as a potential therapeutic target for breast cancer treatment.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 9","pages":"1018-1029"},"PeriodicalIF":5.0,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144706424","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}