Cancer gene therapy最新文献

{"title":"Integration of humanized ROBO1 CAR in PD-1 locus in natural killer cells delivers synergistic tumor-killing effect against non-small cell lung cancer.","authors":"Jia-Hao Tao, Jun Zhang, Chun-Yan Tang, Jia-Xi Duan, Wen-Jing Zhong, Chen-Yu Zhang, Yu-Biao Liu, Jin Ling, Hua-Shun Li, Yong Zhou, Cha-Xiang Guan","doi":"10.1038/s41417-025-00957-x","DOIUrl":"https://doi.org/10.1038/s41417-025-00957-x","url":null,"abstract":"<p><p>Lung cancer is the most common cancer and one of the leading causes of cancer-related deaths in the world, however, the treatment of non-small cell lung cancer (NSCLC) is still limited, and it is a clinically urgent problem. ROBO1 is an important surface receptor on tumor cells, but the role of humanized chimeric antigen receptor (CAR) modified natural killer (NK) cells targeting ROBO1 in NSCLC is rarely explored. Furthermore, the role of PD-1 in NK cell killing tumor cells remains controversial. In this study, we identified the expression pattern of ROBO1 in lung squamous cell carcinoma (LUSC) by searching biological information databases. We constructed hROBO1-CAR-NK-92 cells and performed functional identification.We inserted the hROBO1-CAR at the PD-1 locus and performed functional detection in vitro and in vivo. The results showed that ROBO1 expression was significantly increased in LUSC. After inserting the hROBO1-CAR sequence at the PD-1 locus, the PD-1-KO-hROBO1-CAR-NK-92 cells had the best long-term killing ability and cytokine secretion ability, and had a significant inhibitory effect on tumor growth in the mouse xenograft model. We also observed that the long-term killing ability of PD-1-KO-hROBO1-CAR-NK-92 cells was achieved by inhibiting cell senescence via knocking out PD-1. These studies proposed ROBO1 as a key target for CAR-NK therapy in NSCLC and integrated hROBO1 CAR in PD-1 locus in NK cells, resulting in synergistic tumor killing effects in NSCLC, presenting a new treatment strategy for solid tumor treatment.</p>","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145005929","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 MTPN sensitizes pancreatic cancer of wild-type BRCA1/2 to Cisplatin-based chemotherapy.","authors":"Zhuoxin Wang, Xinyang Huang, Tingting Bai, Yixun Jin, Tingting Gong, Wei Wu, Berik Kouken, Qi Wang, Lifu Wang","doi":"10.1038/s41417-025-00925-5","DOIUrl":"https://doi.org/10.1038/s41417-025-00925-5","url":null,"abstract":"<p><p>The clinical application of combination chemotherapy with cisplatin is unsatisfactory for most pancreatic cancer patients with wild-type BRCA1/2 or PALB2 due to resistance. Genes associated with cisplatin resistance in patients without BRCA1/2 or PALB2 mutations should be pursued. Through bioinformatics analysis, we found that Myotrophin (MTPN) expression was correlated with that of nuclear factor kappa B (NF-κB), a protein involved in the regulation of cisplatin sensitivity. Immunohistochemistry revealed that MTPN was more highly expressed in human pancreatic cancer tissues than in normal tissues. MTPN promoted the malignant biological behaviors of pancreatic cancer (PC) cells and activated the epithelial-mesenchymal transition process. Furthermore, MTPN was found to induce cisplatin resistance in PC cells and upregulate BRCA1/2 while promoting DNA repair. The enhancing effects of MTPN on cisplatin resistance and BRCA1/2 up-regulation were abolished by an inhibitor of IκBα phosphorylation. These studies suggested that MTPN may increase cisplatin resistance by activating IκBα to regulate BRCA1/2 expression. In summary, targeting MTPN could be a potential therapeutic strategy, as MTPN knockdown increased the sensitivity to cisplatin-based chemotherapy in pancreatic cancer with wild-type BRCA1/2.</p>","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144991776","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":"Predicting colorectal cancer risk in FAP patients using patient-specific organoids.","authors":"Aline Habib, Rose Mamistvalov, Mira Malcov, Dalit Ben-Yosef","doi":"10.1038/s41417-025-00923-7","DOIUrl":"10.1038/s41417-025-00923-7","url":null,"abstract":"<p><p>Colorectal cancer (CRC), a prevalent global cancer, is mostly sporadic. Familial adenomatous polyposis (FAP), arises from APC germline mutations. We established FAP-human embryonic stem cell lines (FAP1,2,3) with distinct APC mutations and differentiated them into colon organoids to study cancer development. While normal expressing APC lines and FAP3 formed complex organoids, FAP1,2 failed to differentiate. By utilizing CRISPR editing to correct APC mutations in FAP1,2, we succeeded in restoring their ability to form complex organoids expressing colon gene (CDX2). To elucidate the truncated APC proteins' mechanism of action, we used AlphaFold2 algorithm to model their secondary structures. Structural analysis of the normal phenotype organoids (normal and FAP3) revealed 5-6 salt bridges only at the N-terminal oligomerization domain. In contrast, analysis of disease organoids-phenotype (FAP1,2) revealed a production of novel salt bridges, likely act in a dominant-negative manner on full-length APC, disrupting APC function and promoting tumorigenesis. Our study underscores the critical role of germline APC mutations in colon cancer initiation, revealing how specific mutations influence disease severity. By deciphering APC structure-function relationships, we illuminate potential therapies and the molecular underpinnings of APC mutations that precede clinical presentation.</p>","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":"997-1007"},"PeriodicalIF":5.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12396958/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144688941","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":"<p><p>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.</p>","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":"1018-1029"},"PeriodicalIF":5.0,"publicationDate":"2025-09-01","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}

{"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":"<p><p>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.</p>","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":"913-922"},"PeriodicalIF":5.0,"publicationDate":"2025-09-01","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":"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":"<p><p>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.</p>","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":"923-934"},"PeriodicalIF":5.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cell-intrinsic platinum response and associated genetic and gene expression signatures in ovarian cancer.","authors":"Kristin M Adams, Jae-Rim Wendt, Josie Wood, Sydney Olson, Ryan Moreno, Zhongmou Jin, Srihari Gopalan, Jessica D Lang","doi":"10.1038/s41417-025-00941-5","DOIUrl":"10.1038/s41417-025-00941-5","url":null,"abstract":"<p><p>Ovarian cancers are still largely treated with platinum-based chemotherapy as the standard of care, yet few biomarkers of clinical response have had an impact on clinical decision making. Previous work has relied on poor models of the most common subtypes of epithelial ovarian cancers and necessitates a careful examination of the most suitable in vitro models. We performed extensive drug dose response assays and gene expression profiling on 36 ovarian cancer cell lines across over seven subtypes. This is the largest quantitative database of quantitative cisplatin and carboplatin response in ovarian cancer cell lines. Our results demonstrate that cell lines largely fall either well above or below the clinical maximally achievable dose (C_max) of each compound. We performed differential expression analysis for high-grade serous ovarian carcinoma cell lines. Further, we generated two platinum-resistant derivatives each for OVCAR3 and OVCAR4. Combined with clinically resistant PEO1/PEO4/PEO6 and PEA1/PEA2 isogenic models, we performed differential expression analysis for seven platinum-resistant isogenic pairs. Common themes in differential expression were innate immunity/STAT activation, epithelial-to-mesenchymal transition (EMT) and stemness, and platinum influx/efflux regulators. We also performed copy number signature analysis and orthogonal measures of homologous recombination deficiency (HRD) scar scores and copy number burden, which is the first report to our knowledge applying field-standard copy number signatures to ovarian cancer cell lines. We also examined markers and functional readouts of stemness that revealed that cell lines are poor models for examination of stemness contributions to platinum resistance, suggesting that this is a transient state. Overall, this study serves as a resource to determine the best cell lines to utilize for ovarian cancer research on certain subtypes and platinum response studies, as well as sparks new hypotheses for future study in ovarian cancer.</p>","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":"985-996"},"PeriodicalIF":5.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12396967/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144667263","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":"Integrated multidimensional bioinformatics analysis of the molecular mechanisms of ulcerative colitis-associated colorectal cancer and MMP1 as a potential therapeutic target.","authors":"Xiaopeng Yu, Yutian Tang, Junjie Niu, Jinyang Hu","doi":"10.1038/s41417-025-00917-5","DOIUrl":"10.1038/s41417-025-00917-5","url":null,"abstract":"<p><p>This study aimed to investigate the molecular mechanisms underlying ulcerative colitis (UC)-associated colorectal cancer (CRC) development and identify potential therapeutic targets through integrated multi-omics analysis. Mendelian randomization (MR) analysis, combined with bioinformatics approaches including differential gene expression analysis, protein-protein interaction network construction, gene set enrichment analysis, and single-cell RNA sequencing, was employed. Data were obtained from GEO, TCGA, and genome-wide association study (GWAS) databases. Drug prediction and molecular docking were performed using DSigDB and AutoDockTools. A total of 48 shared genes were identified between UC and CRC, with MMP1 emerging as a significant protective factor (OR = 0.766; 95% CI = 0.593-0.989, P = 0.041). MMP1 demonstrated strong diagnostic potential (AUC = 0.927, 95% CI = 0.895-0.959) and was functionally associated with immune regulation and metabolic pathways. Single-cell analysis revealed predominant MMP1 expression in fibroblasts and immune cells, while immune infiltration analysis showed significant correlations with CD8⁺ T cells and NK cells. Mediation MR analysis indicated that 63.33% of MMP1's protective effect was mediated through naive-mature B cells. Drug prediction identified ilomastat as a potential MMP1 inhibitor with strong binding affinity (binding energy = -7.17 kcal/mol). These findings provide evidence for MMP1's protective role in UC-associated CRC through immune microenvironment modulation, highlighting its potential as a diagnostic biomarker and therapeutic target. The identification of ilomastat as a potential MMP1 inhibitor offers new avenues for targeted therapy in inflammation-associated cancers.</p>","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":"973-984"},"PeriodicalIF":5.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144667264","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":"Pentagamavunone-1 targets excessive MYCN/NCYM expression mediated by mitotic arrest to suppress hepatocellular carcinoma proliferation.","authors":"Dhania Novitasari, Ikuko Nakamae, Noriko Yoneda-Kato, Edy Meiyanto, Jun-Ya Kato","doi":"10.1038/s41417-025-00956-y","DOIUrl":"10.1038/s41417-025-00956-y","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) is a common liver cancer often diagnosed at an advanced stage. While chemotherapies such as sorafenib is effective for some patients, others show poor responses, necessitating new treatments. Overexpression of MYCN/NCYM was recently shown to contribute to the development of HCC. This study investigated the effects of Pentagamavunone-1 (PGV-1), a curcumin analog with strong antiproliferative properties, on HCC cells expressing MYCN/NCYM. PGV-1 was more effective than curcumin and sorafenib in inhibiting HCC cell proliferation by inducing mitotic arrest, oxidative stress, and senescence. In MYCN-positive JHH-7 cells, PGV-1 treatment increased phosphorylation of aurora A, cyclin B1, and PLK1. PGV-1 also suppressed MYCN/NCYM transcription and destabilized MYCN protein by inducing phosphorylation at Ser54 and Thr58. In a xenograft model, PGV-1 significantly reduced tumor formation and growth. These findings highlight PGV-1's potential as a targeted therapy for MYCN-overexpressing HCC, warranting further development.</p>","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144943425","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":"APOE deficiency triggers anti-tumour activity of macrophages in liver cancer.","authors":"Xintong Xia, Zijun Zhou, Xiaoxiao Zheng, Chaoyong Tu, Hao Liu, Zhiming Hu, Tao Ma, Yuexiao Tang, Wei Chen","doi":"10.1038/s41417-025-00936-2","DOIUrl":"10.1038/s41417-025-00936-2","url":null,"abstract":"<p><p>Macrophage infiltration correlates with poor prognosis in patients with liver cancer and resistance to immunotherapy. However, it is difficult to target tumour-associated macrophages (TAMs) because of their inherent heterogeneity. Specific TAM subsets may exhibit distinct functions in tumorigenesis. Herein, we identify a TAM subset characterised by elevated APOE expression, which is correlated with poor overall survival of patients with HCC. The APOE⁺ TAM intensity is highly elevated in ICB non-responder tumours and negatively correlated with CD8⁺ T cell infiltration. Pathway analysis and cell interaction reveal that APOE⁺ TAMs suppress CD8⁺ T cells through signal integration and cholesterol efflux. Furthermore, APOE deficiency in macrophages delays tumour growth and promotes the infiltration of CD8⁺ T cells. Using an immunotherapy-resistant mouse model, we showed that APOE blockade synergises with anti-PD-1 therapy and inhibits tumour growth. Our results elucidate the crucial role of APOE⁺ TAMs in the formation of immunosuppressive microenvironments and offer a potential therapeutic target for ICB combined therapy.</p>","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":"949-962"},"PeriodicalIF":5.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144636191","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}