Cancer gene therapy最新文献_第3页

Osteosarcoma cells promote intracellular iron detoxification to mitigate GPX4-mediated ferroptosis. 骨肉瘤细胞促进细胞内铁解毒以减轻gpx4介导的铁下垂。

IF 5 3区医学

Cancer gene therapy Pub Date : 2026-03-23 DOI: 10.1038/s41417-026-01021-y

Md Abdullah, Donghee Lee, Eslenur Nipa, Jessy Castellanos-Gell, Ann M Chan, Oscar Hernandez Maldonado, Marc E Salute, Rebecca Nance-Richey, Rowan J Milner, Jong Hyuk Kim

{"title":"Osteosarcoma cells promote intracellular iron detoxification to mitigate GPX4-mediated ferroptosis.","authors":"Md Abdullah, Donghee Lee, Eslenur Nipa, Jessy Castellanos-Gell, Ann M Chan, Oscar Hernandez Maldonado, Marc E Salute, Rebecca Nance-Richey, Rowan J Milner, Jong Hyuk Kim","doi":"10.1038/s41417-026-01021-y","DOIUrl":"https://doi.org/10.1038/s41417-026-01021-y","url":null,"abstract":"Osteosarcoma is an aggressive and highly metastatic cancer that arises in bones. Ferroptosis, an iron-dependent form of cell death, is critically controlled by glutathione peroxidase 4 (GPX4). In this study, we characterized GPX4 and its upstream regulator xCT across five osteosarcoma cell lines (U2OS, MG-63, HOS, Saos2, and 143B). We also demonstrated that chemical inhibition of these proteins using RSL3 (GPX4 inhibitor) and erastin (xCT inhibitor) significantly suppressed osteosarcoma cell growth. In U2OS and MG-63 cells, GPX4 inhibition triggered lipid peroxidation, NRF2 activation, and upregulated antioxidant genes including, AKR1C1, HO-1, and NQO1, indicating a compensatory response to oxidative stress. Furthermore, GPX4 inhibition, through RSL3 treatment or transient GPX4 knockdown, increased ferritin heavy chain 1 and ferroportin expression, promoting intracellular iron depletion and conferring resistance to ferroptosis. RSL3 exposure also elevated post-translational regulators such as HIF-1α, c-MET and MSPR/RON, associated with cell survival pathways. Pharmacological inhibition of these signaling molecules synergistically enhanced RSL3-induced cytotoxicity. Collectively, our findings reveal that GPX4 inhibition initiates ferroptosis while simultaneously activating NRF2-driven antioxidant defenses, iron homeostasis mechanisms, and adaptive cell survival signaling. The results highlight potential therapeutic strategies that combine GPX4 inhibition with targeted disruption of compensatory pathways to overcome ferroptosis resistance in osteosarcoma.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147503281","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}

引用次数: 0

Gracillin overcomes osimertinib resistance in NSCLC via dual inhibition of EGFR and Mcl-1. 格拉西林通过双重抑制EGFR和Mcl-1克服非小细胞肺癌的奥西替尼耐药。

IF 5 3区医学

Cancer gene therapy Pub Date : 2026-03-19 DOI: 10.1038/s41417-026-01016-9

Jinzhuang Liao, Qi Liang, Xuecheng Wu, Dongyu Li, Yiwei Liu, Shuangze Han, Ruirui Wang, Pengfei Guo, Ming Yi, Wei Li

{"title":"Gracillin overcomes osimertinib resistance in NSCLC via dual inhibition of EGFR and Mcl-1.","authors":"Jinzhuang Liao, Qi Liang, Xuecheng Wu, Dongyu Li, Yiwei Liu, Shuangze Han, Ruirui Wang, Pengfei Guo, Ming Yi, Wei Li","doi":"10.1038/s41417-026-01016-9","DOIUrl":"https://doi.org/10.1038/s41417-026-01016-9","url":null,"abstract":"The advent of molecularly targeted therapies has revolutionized the clinical management of non-small cell lung cancer (NSCLC), substantially expanding therapeutic options. Nevertheless, significant clinical challenges persist, including acquired resistance, treatment-related toxicities, and economic burdens, underscoring the need for novel therapeutic strategies. In this study, we identified a promising epidermal growth factor receptor (EGFR)-targeting natural product, Gracillin. Unlike osimertinib's selective profile, Gracillin possesses broad-spectrum efficacy against both EGFR-mutant (including Ex19del, L858R, and T790M variants) and wild-type (WT) NSCLC. Mechanistically, Gracillin-mediated EGFR inhibition suppresses Akt signaling, leading to GSK3β-dependent phosphorylation of Mcl-1 at Ser159. This post-translational modification promotes β-TRCP-mediated K48-linked polyubiquitination and degradation of Mcl-1, thereby reducing its protein levels and subsequently inducing apoptosis. In vitro, Gracillin reduced cell viability by up to 90% (IC₅₀ ≈ 1.4-2.78 µM) in both EGFR-mutant and WT NSCLC cell lines. Notably, in vivo studies corroborated these findings, with Gracillin demonstrating significant tumor growth inhibition of up to 60% in both osimertinib-sensitive and -resistant NSCLC models. The compound's unique ability to target diverse EGFR genotypes while overcoming TKI resistance suggests its potential as a therapeutic agent with a strong rationale for further clinical development.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147484887","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}

引用次数: 0

Memory programming and new manufacturing paradigms in CAR-T cell therapy. 记忆编程和CAR-T细胞治疗中的新制造范式。

IF 5 3区医学

Cancer gene therapy Pub Date : 2026-03-15 DOI: 10.1038/s41417-026-01015-w

Niloufar Mohammadkhani, Saber Ebrahimi, Marzieh Hesam Mohammadi, Tanja Nicole Hartmann, Mansour Poorebrahim

引用次数: 0

HAUS1-mediated activation of CDK4 transcription enhances proliferation, invasion and migration in hepatocellular carcinoma. haus1介导的CDK4转录激活促进肝细胞癌的增殖、侵袭和迁移。

IF 5 3区医学

Cancer gene therapy Pub Date : 2026-03-06 DOI: 10.1038/s41417-026-01014-x

Lei Tang, Jun Zhao, Rongyuan Liang, Jiale Yang, Caiwei Chen, Zhonghuo Chen, Xiaofei Tao, Jianwei Yi, Taozhi Yu, Kai Wang

{"title":"HAUS1-mediated activation of CDK4 transcription enhances proliferation, invasion and migration in hepatocellular carcinoma.","authors":"Lei Tang, Jun Zhao, Rongyuan Liang, Jiale Yang, Caiwei Chen, Zhonghuo Chen, Xiaofei Tao, Jianwei Yi, Taozhi Yu, Kai Wang","doi":"10.1038/s41417-026-01014-x","DOIUrl":"https://doi.org/10.1038/s41417-026-01014-x","url":null,"abstract":"Hepatocellular carcinoma (HCC) is distinguished by aggressive proliferation, invasion, and migration, with its underlying molecular mechanisms remaining largely elusive.This study delves into the molecular mechanisms underlying HAUS1's role in HCC progression, focusing on its regulatory relationship with Cyclin-Dependent Kinase 4 (CDK4). We analyzed 34 HCC tissue specimens and conducted in vitro assays to evaluate HAUS1's impact on cell proliferation, invasion, migration, cycle and apoptosis. Potential molecules regulated by HAUS1 that could influence HCC function were further screened. Notably, HAUS1 was shown to activate CDK4 (Cyclin-Dependent Kinase 4) transcription, establishing a regulatory nexus where HAUS1-induced CDK4 expression exacerbates HCC malignancy. In vivo studies reinforced these findings, evidencing that HAUS1 influences tumor growth in xenograft models. Collectively, our research elucidates HAUS1's oncogenic role in HCC, mediated through CDK4 activation, and highlights its potential as a therapeutic target in HCC therapy. Mechanistic diagram illustrating how HAUS1 activates CDK4 transcription to promote proliferation, invasion and migration in HCC.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147369182","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}

引用次数: 0

COL3A1 promotes gastric cancer progression by activating PI3K/AKT signaling. COL3A1通过激活PI3K/AKT信号通路促进胃癌进展。

IF 5 3区医学

Cancer gene therapy Pub Date : 2026-02-21 DOI: 10.1038/s41417-026-01011-0

Xiaqiong Mao, Wei Li, Yue Guan, Xiaoyi Kuai, Jie Yuan

引用次数: 0

Perspective of smart nanocapsule swallowable laser-guided for integrated sensing and crispr-mediated cancer gene editing 激光引导下可吞咽的智能纳米胶囊集成传感和crispr介导的癌症基因编辑的前景。

IF 5 3区医学

Cancer gene therapy Pub Date : 2026-02-19 DOI: 10.1038/s41417-026-01004-z

Bakr Ahmed Taha, Ali J. Addie, Adawiya J. Haider, Ahmed Jamal Jasim, Naser M. Ahmed, Norhana Arsad

{"title":"Perspective of smart nanocapsule swallowable laser-guided for integrated sensing and crispr-mediated cancer gene editing","authors":"Bakr Ahmed Taha, Ali J. Addie, Adawiya J. Haider, Ahmed Jamal Jasim, Naser M. Ahmed, Norhana Arsad","doi":"10.1038/s41417-026-01004-z","DOIUrl":"10.1038/s41417-026-01004-z","url":null,"abstract":"Current therapeutic techniques for cancer often lack specificity. They also cause systemic toxicity and lack genetic control. Thus, cancer ranks among the most complex and crucial global health issues. The novel concept of smart nanocapsules is discussed in this Perspective. These oral medications modify genes using CRISPR technology and integrate biosensing and laser-guided activation to enable more personalized cancer therapies. The creation of these versatile nanocapsules is driven by three objectives. First, they aim to enable controlled gene editing in the gastrointestinal tract. Second, they deliver treatments to specific target areas. Third, they detect tumors in real time. Nanocapsules equipped with biosensing components provide microenvironmental input. An external laser can trigger the release of light-absorbing agents. Moreover, these features reduce off-target effects and allow spatiotemporal precision, thhe enteric-coated architecture ensures oral stability. Surface functionalization enhances selective tumor accumulation. AI-guided control algorithms can manage diagnostic interpretation and activation. The CRISPR-based cancer medicines offer the potential for improved safety, specificity, and translational use in the future. Combining advanced nanotechnology, gene editing, and AI-guided control could create innovative solutions.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"33 3","pages":"351-365"},"PeriodicalIF":5.0,"publicationDate":"2026-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41417-026-01004-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146225440","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}

引用次数: 0

The FOSB-IGFBP5-IGF-1 axis: a novel regulatory pathway that suppresses prostate cancer growth. FOSB-IGFBP5-IGF-1轴：抑制前列腺癌生长的新调控途径

IF 5 3区医学

Cancer gene therapy Pub Date : 2026-02-17 DOI: 10.1038/s41417-026-01012-z

Jun Huang, Sheng-Dong Ge, Ling-Lan Zhao, Xian-Lu Song, Qu Li, Xiao-Feng Liu, Wen-Jun Tang, Qing Li, Tao Wang, Shan-Chao Zhao

{"title":"The FOSB-IGFBP5-IGF-1 axis: a novel regulatory pathway that suppresses prostate cancer growth.","authors":"Jun Huang, Sheng-Dong Ge, Ling-Lan Zhao, Xian-Lu Song, Qu Li, Xiao-Feng Liu, Wen-Jun Tang, Qing Li, Tao Wang, Shan-Chao Zhao","doi":"10.1038/s41417-026-01012-z","DOIUrl":"https://doi.org/10.1038/s41417-026-01012-z","url":null,"abstract":"While the functions of activator protein-1 (AP-1) family transcription factors in prostate cancer (PCa) have been well researched, the specific role and mechanisms of FOSB in PCa progression are poorly understood. Here, we aimed to elucidate the precise role of FOSB in PCa and its underlying molecular mechanisms. A comprehensive investigation involving bioinformatics analysis of the TCGA and GEO datasets, validation in clinical PCa samples and cell lines, functional studies in vitro and in vivo, and RNA sequencing coupled with targeted validation (dual-luciferase reporter assays, ChIP‒qPCR, RT‒qPCR, Western blotting, and immunohistochemistry) was performed. FOSB is downregulated in PCa, and its high expression in tumours may reduce the risk of PCa progression by influencing characteristic growth-related cancer pathways. FOSB overexpression significantly inhibited PCa cell proliferation, increased apoptosis in vitro, and attenuated tumour growth in vivo, whereas FOSB knockdown resulted in the opposite effects. Mechanistically, FOSB transcripts were enriched in cell nuclei, where they upregulated the expression of IGFBP5, a gene that modulates the cellular response to IGF-1. This FOSB-mediated upregulation of IGFBP5 expression subsequently weakened the susceptibility of IGF1R to IGF-1 stimulation and suppressed the downstream PI3K/Akt and Ras/Raf/ERK oncogenic pathways. Our findings identify the novel FOSB-IGFBP5-IGF-1 axis upstream of PI3K/Akt and Ras/Raf/ERK signalling as a key regulator of PCa progression.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146212227","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}

引用次数: 0

Clathrin-associated SCYL2 contributes to the activation of PI3K/AKT signaling and tumorigenesis through PTEN phosphorylation in adult T-cell leukemia/lymphoma 在成人t细胞白血病/淋巴瘤中，网格蛋白相关的SCYL2通过PTEN磷酸化参与PI3K/AKT信号的激活和肿瘤发生。

IF 5 3区医学

Cancer gene therapy Pub Date : 2026-02-16 DOI: 10.1038/s41417-026-01008-9

Tomonaga Ichikawa, Shunsuke Shimosaki, Shingo Nakahata, Akira Suekane, Issay Kitabayashi, Hidekatsu Iha, Kazuya Shimoda, Takashi Murakami, Kazuhiro Morishita

{"title":"Clathrin-associated SCYL2 contributes to the activation of PI3K/AKT signaling and tumorigenesis through PTEN phosphorylation in adult T-cell leukemia/lymphoma","authors":"Tomonaga Ichikawa, Shunsuke Shimosaki, Shingo Nakahata, Akira Suekane, Issay Kitabayashi, Hidekatsu Iha, Kazuya Shimoda, Takashi Murakami, Kazuhiro Morishita","doi":"10.1038/s41417-026-01008-9","DOIUrl":"10.1038/s41417-026-01008-9","url":null,"abstract":"Inactivation of PTEN by post-translational modifications causes aberrant amplification of the PI3K/AKT signaling pathway in many tumors. PTEN is a tumor suppressor phosphatase that is frequently phosphorylated at conserved serine/threonine residues (S380, T382, and T383 clusters) in the C-terminal tail of ATL and various solid cancer cells. Here, we identify SCY1-like protein 2 (SCYL2), with a protein kinase-like domain, as a novel PTEN-binding protein; however, the mechanism by which SCYL2 regulates PTEN phosphorylation remains unclear. SCYL2-associated complex phosphorylates PTEN at STT, and SCYL2 downregulation has anti-tumor effects in ATL via inhibition of the PI3K/AKT signaling pathway by dephosphorylating PTEN at STT. SCYL2 reportedly binds to the clathrin heavy chain (CHC), which regulates cytoplasmic vesicle formation, trafficking, and signaling pathways. Our results indicate that SCYL2 expression induces the binding of CHC to PTEN. Furthermore, the inhibition of clathrin-coated vesicles (CCVs) by CHC downregulation or inhibition suppresses cell survival by reducing phosphorylated PTEN at the STT, suggesting that SCYL2 enhances PTEN phosphorylation through CCVs as a signaling platform. Our results indicate that SCYL2/CHC complex plays a pivotal role in regulating the PI3K/AKT signaling pathway through PTEN phosphorylation, thus leading to tumor development and may be a promising novel target for treating tumors.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"33 3","pages":"314-322"},"PeriodicalIF":5.0,"publicationDate":"2026-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41417-026-01008-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146212216","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}

引用次数: 0

MSCs delivering LIGHT prime immune response against CAFs to harness antigen loss variants. 骨髓间充质干细胞提供针对CAFs的LIGHT初级免疫应答，以利用抗原丢失变体。

IF 5 3区医学

Cancer gene therapy Pub Date : 2026-02-16 DOI: 10.1038/s41417-026-01009-8

Weibin Zou, Linbing Zou, Wei Guo

{"title":"MSCs delivering LIGHT prime immune response against CAFs to harness antigen loss variants.","authors":"Weibin Zou, Linbing Zou, Wei Guo","doi":"10.1038/s41417-026-01009-8","DOIUrl":"https://doi.org/10.1038/s41417-026-01009-8","url":null,"abstract":"The tumor niche promotes immune tolerance, enabling malignant cells to evade surveillance. Mesenchymal stem cells (MSCs) have multipotential differentiation capacity and provide a niche for bone marrow homeostasis. MSCs home to tumor tissues, where they can differentiate into Cancer-associated fibroblasts (CAFs). Within the tumor microenvironment, MSCs drive tumor progression by fostering immune suppression, secreting pro-tumorigenic cytokines, and, in some contexts, maintaining dormancy for later relapse. In this study, we engineered MSCs to deliver the immuno-stimulatory TNF superfamily ligand LIGHT (MSC-L). We found that MSC-L simultaneously primed immune responses against both tumor cells and CAFs. This effect relies on the LIGHT-mediated activation of naïve T cells in draining lymph nodes, which subsequently infiltrate the tumor. The recruited T cells eradicate CAFs, thereby remodeling the immunosuppressive niche and harnessing otherwise immune tolerance antigen loss variants. Our findings underscore the critical role of niche reprogramming in tumor control and demonstrate a novel strategy for co-targeting tumor cells and CAFs, even in immune resistant settings. This approach provides a promising foundation for clinical translation.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146206594","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}

引用次数: 0

Pleiotropic mechanisms of cancer-associated fibroblast-mediated resistance in hepatocellular carcinoma: emerging therapeutic vulnerabilities and targeting strategies 肝癌中癌症相关成纤维细胞介导的耐药的多效机制：新出现的治疗脆弱性和靶向策略。

IF 5 3区医学

Cancer gene therapy Pub Date : 2026-02-14 DOI: 10.1038/s41417-026-01007-w

Wei Xie, Jingjing Fang, Zhen Wang, Xia Li, Juan Du, Changquan Ling

引用次数: 0