Cancer gene therapy最新文献

{"title":"SLC34A2 inhibits tumorigenesis and progression via upregulating LRRK2/TTF-1/SELENBP1 axis in lung adenocarcinoma","authors":"Ying Zhu, Ning An, Qiongyin Zhang, Yang Liu, Peiling Gu, Jinzhu Zhao, Wuliang Pan, Qiang Pu, Zhu Wen","doi":"10.1038/s41417-025-00928-2","DOIUrl":"10.1038/s41417-025-00928-2","url":null,"abstract":"Alveolar type II epithelial (AT2) cells have the properties of stem cells, abnormal AT2 cells serve as one of the original cells in lung adenocarcinoma (LUAD). However, the abnormal genes expression of AT2 cells during their malignant transformation into LUAD cells remain poorly understood. Importantly, SLC34A2 is a specific gene in AT2 cells of the lung. Our previous researches have reported that overexpression of SLC34A2 significantly inhibited proliferation, migration and invasion of LUAD cells. But, the underlying mechanisms of SLC34A2 in LUAD are largely unknown until now. Here, the present study discovered that the protein expression of Napi2b (SLC34A2), SELENBP1, TTF-1 and LRRK2 were all located in human AT2 cells of adjacent non-tumor tissues. However, the expression level of SLC34A2, SELENBP1, TTF-1 and LRRK2 were significantly decreased in LUAD tissues, and the expression of SLC34A2 was obviously positive correlation with the expression of SELENBP1, TTF-1 and LRRK2, respectively. Mechanistically, our study elucidated that overexpression of SLC34A2 could inhibit the activation of MEK/ERK signaling pathway through up-regulating the expression of LRRK2, and subsequently suppressed the expression of p-TTF-1(Ser327), which upregulated the expression of SELENBP1 by enhancing TTF-1 transcriptional activity. Ultimately, overexpression of SLC34A2 depressed the activation of PI3K/AKT/mTOR signaling pathway via up-regulating the expression of SELENBP1, which significantly inhibited the malignant characteristics of LUAD. In summary, our current research revealed a novel SLC34A2/LRRK2/TTF-1/SELENBP1 axis and its involvement in inhibiting the malignant characteristics of LUAD cells for the first time, which made contribution to further exploring the clinical application of SLC34A2. Furthermore, it also might offer novel insights into understanding how AT2 cells undergo malignant transformation into LUAD cells in the future.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 8","pages":"870-883"},"PeriodicalIF":5.0,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12353814/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144552328","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":"Enhancer hijacking drives FAM20C expression to promote papillary thyroid cancer progression","authors":"Xianhui Ruan, Wei Zhang, Xiukun Hou, Guiming Fu, Weike Ma, Jianfeng Huang, Yuyang Qian, Mengran Tian, Nan Qin, Yupeng Chen, Ming Gao, Dapeng Li, Xiangqian Zheng","doi":"10.1038/s41417-025-00930-8","DOIUrl":"10.1038/s41417-025-00930-8","url":null,"abstract":"Papillary thyroid cancer (PTC) is the most common endocrine cancer, with a good prognosis in most cases. However, aggressive PTC can metastasise or reoccur and become refractory disease. Therefore, it’s urgent to uncover new biomarkers for aggressive PTC. Accumulating evidence suggests that aberrant enhancers and targeted gene transcription drive the progression of PTC. To identify the cancer-specific enhancers and their downstream genes in PTC, we profiled the transcriptomes (RNA-seq) and enhancer-based epigenomic reorganisation (ChIP-seq) of cancer tissues and matched normal tissues from three PTC patients. Importantly, six candidate genes (RHBDF1, FAM20C, PHLDA2, TMPRSS6, LAD1, and BGN) were identified to be consistently upregulated by enhancers in PTC and correlated with prognosis. Further experiments verified the function of enhancers governing FAM20C in regulating PTC tumorigenesis, thereby unveiling a FAM20C-governed oncogenic mechanism for suppressing two cytokines (TNF-α and TGF-β) in PTC. Additionally, we demonstrated that a FAM20C inhibitor (3r) suppressed the proliferation and invasion of thyroid cancer cells in vitro and vivo. Moreover, FAM20C is driven by KLF12 through its enhancer. Collectively, our study uncovers the potential correlations between the aberrant activation of cancer-specific enhancers and PTC tumorigenesis and identifies FAM20C as a novel target for PTC.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 8","pages":"854-869"},"PeriodicalIF":5.0,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144526526","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":"Modified hTERT promoters-driven purine nucleoside phosphorylase-gene therapy in association with chemo- and targeted therapy in the context of ovarian cancer","authors":"Quoc Manh Nguyen, Pierre-François Dupré, Mathieu Berchel, Marylène Lévêque, Sylvie Choblet-Thery, Frédérique d’Arbonneau, Tristan Montier","doi":"10.1038/s41417-025-00932-6","DOIUrl":"10.1038/s41417-025-00932-6","url":null,"abstract":"Ovarian cancer has the highest mortality-to-incidence ratio among gynecologic cancers worldwide. E.coli Purine Nucleoside Phosphorylase-based gene-directed enzyme prodrug therapy (PNP-GDEPT) offers a promising alternative for the treatment of solid tumors. This study proposes an original ovarian cancer treatment through the use of two recently developed modified hTERT promoters: the mutated hTERT (hTERTm) and the chimeric hTERT-CMV. Four plasmids were engineered to investigate the effects of cancer-specific PNP gene expression: pCMV-PNP, phTERT-PNP, phTERTm-PNP, and phTERT-CMV-PNP. The cationic lipid formulation BSV163/DOPE was employed to transfect PNP-coding plasmids into cisplatin-sensitive ovarian cancer cells and their resistant counterparts. hTERT-driven PNP-GDEPT selectively reduced cancer cell viability while sparing primary human fibroblasts. In addition, combining PNP-GDEPT with either cisplatin or olaparib further enhanced anticancer effects on cell viability and apoptosis. However, no combined effects were observed for the concurrent use of cisplatin and olaparib, with or without PNP-GDEPT. Our results demonstrate that targeted PNP-GDEPT has the potential to enhance the efficacy of chemotherapy and targeted therapy against ovarian cancer while minimizing side effects on healthy cells. This treatment is effective irrespective of cisplatin resistance status and warrants further investigation.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 8","pages":"843-853"},"PeriodicalIF":5.0,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144511604","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":"Barriers and solutions for CAR-T therapy in solid tumors","authors":"Zhihao Tu, Yuelin Chen, Zhimi Zhang, Wanrong Meng, Ling Li","doi":"10.1038/s41417-025-00931-7","DOIUrl":"10.1038/s41417-025-00931-7","url":null,"abstract":"Chimeric antigen receptor (CAR)-T cell therapy has emerged as a transformative approach for cancer treatment, particularly in hematologic malignancies. However, barriers in the development of effective CAR-T therapies for solid tumors, including antigenic escape, tumor immunosuppressive microenvironments, severe toxicities, and limitations in preclinical models, hinder its scalability and broader clinical implementation. To overcome these barriers, strategies have been developed in recent years, such as optimizing CAR designs, enhancing CAR-T cell infiltration, neutralizing immunosuppressive cells, remodeling metabolism of CAR-T cells, eliminating antigen escape, mitigating toxicities, advancing preclinical models, and in situ programming CAR-T cells. Here, we discuss current barriers and potential strategies for CAR-T cell therapy in solid tumors. Ultimately, we present perspectives on these advanced strategies for broader clinical adoption of CAR-T cell therapy.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 9","pages":"923-934"},"PeriodicalIF":5.0,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41417-025-00931-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144511603","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":"The dual role of GPX4 in breast cancer: mechanisms of therapeutic resistance and potential for novel targeted therapies","authors":"Tingyu Gu, Kun Wang, Xiao Yuan, Haowen Tang, Shouchao Wang, Zhihong Zhao","doi":"10.1038/s41417-025-00927-3","DOIUrl":"10.1038/s41417-025-00927-3","url":null,"abstract":"Glutathione peroxidase 4 (GPX4) is a key intracellular antioxidant enzyme that maintains oxidative homeostasis by catalyzing the reduction of lipid peroxides and relies on glutathione-specific inhibition of iron death. In recent years, it has been found that GPX4 exhibits significant aberrant expression in breast cancer (BC) and promotes BC development by regulating tumor cell proliferation, invasion, metastasis, and stem cell properties. More importantly, GPX4 overexpression leads to decreased sensitivity of BC to chemotherapy, radiotherapy, endocrine therapy, immune checkpoint inhibitors, and targeted therapies by inhibiting iron death, attenuating oxidative damage, and activating pro-survival signaling pathways. In this paper, we systematically review the molecular characterization of GPX4 and its cancer-promoting mechanism in BC, focusing on resolving its molecular regulatory network in multimodal therapy resistance. Based on the reversal of drug resistance and synergistic anti-tumor effects demonstrated by GPX4 inhibitors in preclinical studies, iron death induction strategies targeting GPX4 or combining with existing therapies are expected to be a new direction to overcome the bottleneck of drug resistance in BC.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 9","pages":"913-922"},"PeriodicalIF":5.0,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144483226","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":"UBE2N inhibition abrogates cancer chemoresistance and metastasis in lung adenocarcinoma","authors":"Zi-Mei Peng, Jin-Yong Xiong, Feng-Yi Deng, Xing Wang, Tao Wang, Chun-Xi Yang, Yan-Ru Chen, Xiao-Jian Han, Zhen Zhang","doi":"10.1038/s41417-025-00929-1","DOIUrl":"10.1038/s41417-025-00929-1","url":null,"abstract":"Chemoresistance and metastasis remain significant challenges in cancer therapy, resulting in treatment failures for cancer patients. Therefore, there is a need to investigate the mechanisms underlying cancer chemoresistance and metastasis, identify novel drug targets, and develop innovative antitumor medications. In this study, we have shown that the ubiquitin conjugating enzyme UBE2N plays a crucial role in promoting chemoresistance and metastasis in lung adenocarcinoma (LUAD) both in vitro and in vivo. Significantly, our study revealed that the natural compound wilforine functions as a potential inhibitor of UBE2N, effectively reversing resistance to cisplatin (CDDP) and inhibiting metastasis of LUAD both in vitro and in vivo. Our findings collectively suggest that UBE2N may have a pivotal role in the development of chemoresistance and metastasis in LUAD, providing a foundation for potential therapeutic strategies in the management of advanced cancer.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 8","pages":"831-842"},"PeriodicalIF":5.0,"publicationDate":"2025-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144339920","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":"AAV for ovarian cancer gene therapy","authors":"Hee Chan Yoo, Sangkil Lee, Joong Yull Park, Eun-Ju Lee","doi":"10.1038/s41417-025-00926-4","DOIUrl":"10.1038/s41417-025-00926-4","url":null,"abstract":"Recent advancements in ovarian cancer treatment, particularly with PARP inhibitors, have markedly enhanced the recurrence-free interval, shifting the treatment paradigm and increasing treatment success in patients with BRCA mutations or HRD (homologous recombination deficiency). However, a significant proportion of cases experience relapse, resulting in poorer long-term survival rates when compared to other female cancers, such as breast cancer. This review explores the potential of adeno-associated virus (AAV) vectors for gene therapy in ovarian cancer and examines rational gene therapy strategies by categorizing them based on target cells and target genes to determine the most effective approach for ovarian cancer treatment. Specifically, it examines strategies such as anti-angiogenesis and immune modulation, highlighting the strategy of gene supplementation to hinder ovarian cancer progression. Innovations in AAV capsid design now allow for targeted delivery, focusing on ovarian cancer stem cells (CSCs) identified by specific markers. Additionally, leveraging DNA sequencing technologies enhances the identification and incorporation of therapeutic genes into AAV vectors, promising new avenues for ovarian cancer gene therapy.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 8","pages":"817-830"},"PeriodicalIF":5.0,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12353829/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144336321","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":"Blocking the functional domain of cancer cell surface TIP1 upregulates Midkine via the β-catenin/Wnt signaling pathway","authors":"Minakshi Saikia, Harendra Kumar Shah, Dennis E. Hallahan, Abhay Kumar Singh, Vaishali Kapoor","doi":"10.1038/s41417-025-00922-8","DOIUrl":"10.1038/s41417-025-00922-8","url":null,"abstract":"Drug resistance exhibited by cancer cells remains one of the primary reasons for the failure of therapeutic approaches to increase the survival of cancer patients. Marginal improvement in therapeutic efficacy with current treatment approaches for non-small cell lung cancer (NSCLC) mandates new treatment strategies. Tax interacting Protein-1 (TIP1) is a radiation-inducible molecular target involved in various cancer pathways. TIP1 expression correlates with poor survival in NSCLC patients. Antibody blocking the functional domain of TIP1 reduced cell proliferation and sensitized cancer cells to radiation. A ten-fold increase in Midkine (MDK) was observed in the proteomic analysis of cells treated with anti-TIP1 antibody. Wnt signaling activation led to MDK upregulation at the mRNA and protein levels following TIP1 blockade. Genetic silencing of β-catenin abrogated the induction of MDK following anti-TIP1 antibody treatment. Inhibiting TIP1 along with MDK showed a reduction in the colony-forming capability of the cells, indicating that MDK upregulation might be a strategy employed by cancer cells to combat the anti-proliferative capabilities of the anti-TIP1 antibody. Co-targeting cell surface TIP1 and MDK may be an effective therapeutic strategy for NSCLC patients.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 7","pages":"785-792"},"PeriodicalIF":5.0,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144324592","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":"Identification of an immunomodulatory lncRNA signature associated with immune cell reprogramming in high-grade glioma","authors":"Alessandro Canella, Prajwal Rajappa","doi":"10.1038/s41417-025-00919-3","DOIUrl":"10.1038/s41417-025-00919-3","url":null,"abstract":"High-grade gliomas (HGGs) are among the most aggressive brain tumors in pediatric, adolescent, and young adult (AYA) cancer patients, with a median survival of 12–15 months post-diagnosis. Their poor prognosis is driven by a highly immunosuppressive tumor immune microenvironment (TIME), which inhibits cytotoxic immune infiltration and anti-tumor response. This study investigated the involvement of long non-coding RNAs (lncRNAs) in shaping the immune phenotype of HGGs using two murine models: RCAS-PDGFb representing an immunosuppressive TME, and RCAS-BRAF V600E characterized by a signature more consistent with a pro-inflammatory TME. Transcriptomic analysis of tumor-infiltrating immune cells identified distinct lncRNA signatures associated with immunosuppressive and pro-inflammatory TMEs. Single-cell RNA sequencing and spatial transcriptomics supported context-dependent expression of these lncRNAs in high-grade glioma-associated immune cells, such as myeloid, T, and NK cells, and revealed their spatial distribution within the glioblastoma (GBM) TME. Several lncRNAs were enriched at the tumor edge and within necrotic regions in GBM patient samples, correlating with immunosuppression reprogramming and immune evasion mechanisms. These findings highlight specific immunomodulatory lncRNAs as potential players in the immunosuppressive glioma TME, and likely candidates for future studies aimed at developing novel therapeutic strategies to overcome immune suppression and improve clinical outcomes.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 7","pages":"778-784"},"PeriodicalIF":5.0,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12277174/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144315929","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":"Retraction Note: HADHA promotes glioma progression by accelerating MDM2-mediated p53 ubiquitination","authors":"Rudong Chen, Hao Chen, Changchen Hu","doi":"10.1038/s41417-025-00924-6","DOIUrl":"10.1038/s41417-025-00924-6","url":null,"abstract":"","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 8","pages":"912-912"},"PeriodicalIF":5.0,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41417-025-00924-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144315930","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}