Cancer gene therapy最新文献

{"title":"Correction to: Methylation of SFRP5 is related to multidrug resistance in leukemia cells.","authors":"H Wang, X Wang, R Hu, W Yang, A Liao, C Zhao, J Zhang, Z Liu","doi":"10.1038/s41417-026-01030-x","DOIUrl":"https://doi.org/10.1038/s41417-026-01030-x","url":null,"abstract":"","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147670507","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":"Blood-brain barrier breakdown in traumatic brain injury: current insights and future directions.","authors":"Haijian Wu, Jingwei Zheng, Weilin Xu, Fengqi Zhou, Cameron Lenahan, Georgios Giamas, Chun Wang, Jianmin Zhang, Jianxiong Ji","doi":"10.1038/s41417-026-01027-6","DOIUrl":"https://doi.org/10.1038/s41417-026-01027-6","url":null,"abstract":"<p><p>Traumatic brain injury (TBI) is among the most devastating condition and involves primary and secondary injury cascades. The blood-brain barrier (BBB) is a selective, semipermeable membrane that tightly controls the brain's microenvironment for proper neuronal function. Existing evidence demonstrates that TBI impairs the integrity and function of the BBB, leading to not only acute pathological changes but also long-term neuropathological consequences. Multiple BBB-related signaling molecules (e.g., Tie-2, EphB3, and Cav-1) are involved in the pathophysiological processes post-injury. These can result in microcirculatory insufficiency, neurotoxin accumulation, and cerebral edema after TBI. Together, such events synergistically cause axonal damage, neuronal cell death, and neuroinflammatory responses, which underlie the pathogenesis of TBI. In this review, we aim to summarize the pathophysiological roles of BBB breakdown in TBI, survey underlying mechanisms, and discuss therapeutic potential for this notorious disease by regulating the BBB.</p>","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147662249","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 ribosomal protein eL21 as a novel externalized protein and a target in triple-negative breast cancer.","authors":"Lucie Arnould, Nina Radosevic-Robin, Laura Duranton, Jérémy Néri, Frédérique Penault-Llorca, Jean-Jacques Diaz, Marie Alexandra Albaret, Frédéric Catez","doi":"10.1038/s41417-026-01026-7","DOIUrl":"https://doi.org/10.1038/s41417-026-01026-7","url":null,"abstract":"<p><p>Proteins normally localized in the intracellular compartments of healthy cells have been observed at the surface of cancer cells, despite lacking a transmembrane domain or secretion signals. This unexpected localization likely reflects yet-unknown functions and presents a unique opportunity to develop cancer cell-specific antibody- or peptide-based therapeutic strategies. While ribosomal proteins (RPs) are primarily involved in translation, several display moonlighting functions in the cytoplasm and nucleus. In this study, we uncover an extracellular form of the ribosomal protein L21 (eL21) in triple-negative breast cancer (TNBC) cells. Using complementary approaches and a broad set of antibodies, we demonstrate that eL21 localizes to the surface of cancer cells. Remarkably, we show that anti-eL21 antibodies trigger a potent, rapid and dose-dependent anti-proliferative effect, including TNBC cell cycle arrest and apoptosis. These findings identify eL21 as a novel ribosomal protein with extra-ribosomal functions at the cancer cell surface and highlight its potential as a therapeutic target in TNBC.</p>","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147643837","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":"Deciphering the role of SIRT6 in suppressing the AMPK-mTOR-TFEB axis: regulation of autophagy activation in HCC.","authors":"Cong Shan Li, Hua Jin, Ruoyu Meng, Seung-Woo Baek, Seong-Hun Kim, Ok Hee Chai, Byung Hyun Park, Ju-Seog Lee, Na Ri Lee, Soo Mi Kim","doi":"10.1038/s41417-026-01023-w","DOIUrl":"10.1038/s41417-026-01023-w","url":null,"abstract":"<p><p>Sirtuin 6 (SIRT6), belong to the NAD-dependent class III protein deacetylase family, is implicated in cancer development through a multifaceted role. While it has been identified with both tumor-suppressive and tumor-promoting roles in Hepatocellular carcinoma (HCC), there remains considerable debate regarding its exact function. The specific molecular mechanisms driving its tumor-suppressive effects in HCC remains poorly understood. In this study, we mechanistically identified a novel pathway involving AMP-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), and transcription factor EB (TFEB): upregulation of SIRT6 enhances AMPK activity and suppresses mTOR activation, leading to TFEB nuclear translocation and the subsequent induction of autophagy. Importantly, our study provides the first evidence that SIRT6 induces the translocation of TFEB into the nucleus, facilitating autophagy. Intriguingly, SIRT6 silencing counteracted the effects of mTOR inhibitors on TFEB and autophagy, suggesting that SIRT6 probably activates lysosome function via an AMPK-mTOR-TFEB axis in HCC. Our in vivo experiments bolster our findings, demonstrating that SIRT6 effectively suppressed HCC tumor growth and metastasis. Overall, our research provides compelling evidence that SIRT6 functions as a tumor suppressor in HCC, offering a valuable therapeutic mechanism for treating HCC and paving the way for a promising avenue in future HCC treatment. Schematic illustration of SIRT6's role in hepatocellular carcinoma. Proposing a model to elucidate the regulatory mechanism of SIRT6-AMPK-mTOR-TFEB signaling axis in orchestrating autophagy activation within hepatocellular carcinoma. Phosphorylation of AMPK by SIRT6 leads to the inhibition of mTOR and its downstream targets. This modulation influences TFEB, promoting its translocation into the nucleus and triggering autophagy activation. This intricate cascade is marked by a significant increase in substrate degradation and the formation of autophagic bilayers, ultimately culminating in the suppression of cell proliferation and the augmentation of cell death.</p>","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147643789","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":"Landscape and functional impact of variants of unknown significance of immune response genes in human cancer.","authors":"Cristina A Diaz, Juan M Morillas, Pablo Navajas-Chocarro, Valentina Provenzano, Fernando Setien, Manel Esteller, Montse Sanchez-Cespedes","doi":"10.1038/s41417-026-01024-9","DOIUrl":"https://doi.org/10.1038/s41417-026-01024-9","url":null,"abstract":"<p><p>Immune checkpoint blockade (ICB) is a standard treatment for several types of human cancer, yet we still lack a deep understanding of the mechanisms underlying primary resistance. Tumor-intrinsic defects in immune recognition and interferon-gamma (IFNγ) signaling pathways facilitate immune evasion and may limit the efficacy of ICB. Here, we delineate the mutational landscape and functional consequences of amino acid substitutions in key immune-related genes, B2M, CALR, IFNGR1, IFNGR2, JAK1, and JAK2, across more than 12,000 primary tumors and cancer cell lines. Genomic alterations affecting the coding regions of at least one of these genes were identified in approximately 11% of cancers, with missense variants accounting for 55% of these events. B2M, encoding the invariant light chain of the heavy chain-I (HLA-I) complex, exhibited the highest mutation frequency per base pair, the mutations predominantly involving truncating variants. A curated set of 2156 missense mutations in B2M and in components of the IFNγ-signaling pathway (IFNGR1, IFNGR2, and JAK2) was analyzed using SIFT, PolyPhen-2, and AlphaMissense, yielding predicted pathogenicity rates of 52%, 35%, and 27%, respectively. The functional assays, performed in lung cancer cells, revealed JAK2 and IFNGR1 variants that impaired IFNγ-mediated transcriptional activation and growth suppression, and B2M variants that disrupted HLA class I complex formation. Notably, AlphaMissense predictions showed the highest concordance with experimental data. These findings provide a detailed mutational map of antigen presentation and IFNγ-response components in cancer. Overall, our results provide a resource of specific mutations in genes involved in immune pathways that compromise tumor immunogenicity and will serve for support in patient selection for response to ICB.</p>","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147618295","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":"Zoledronic acid enhances the antitumor efficacy of the PSMA CAR-T cells for bone tumors, but impedes the ability to control metastases of prostate cancer in mice.","authors":"Dan Li, Xinyu Gu, Jing Li, Yong Huang, Wei-Lin Zhou, Jiaqian Li, Fengling Wang, Feiyang Yan, Haozhan Gao, Xue Ying, Yikun Li, Shimao Qi, Yueting Zhu, Jiyan Liu, Wei Wang","doi":"10.1038/s41417-026-01025-8","DOIUrl":"https://doi.org/10.1038/s41417-026-01025-8","url":null,"abstract":"<p><p>The chimeric antigen receptor (CAR)-T cell therapy has shown promise for the treatment of hematological and solid tumors. Although CAR-T cells targeting PSMA showed robust antitumor efficacy for prostate cancer in preclinical studies, the clinical benefits of PSMA CAR-T cells are unsatisfactory. To maximize the efficacy of this immunotherapy, we combined zoledronic acid (ZOL), a first-line prophylactic drug against skeletal-related events (SREs) and for bone pain management in patients with advanced prostate cancer, with PSMA CAR-T cells for the treatment of prostate cancer. In mice with intratibial inoculation of 22Rv1 prostate tumor, ZOL treatment after PSMA CAR-T cells infusion inhibited growth of the primary intratibial tumor, while it increased the extraskeletal metastasis, demonstrating that ZOL impedes the long-term immunosurveillance, albeit it enhances the short-term antitumor capability of the CAR-T cells. Mechanistically, ZOL showed no increase in the frequency of γδT cell phenotype. Finally, we found that ZOL induced hyperactivation and eventually led to exhaustion of the PSMA CAR-T cells, elucidating the impediment clues of ZOL on the T cell therapy. Our study demonstrates the necessity to balance the contribution of ZOL when combined with CAR-T cell therapy for prostate cancer.</p>","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147607963","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 application of nanoparticle-mediated siRNA delivery systems in ovarian cancer.","authors":"Xueqian Qian, Yi Yuan, Yaning Zhang, Zemin Dou, Chengjin Gao, Yangyang Han","doi":"10.1038/s41417-026-01020-z","DOIUrl":"https://doi.org/10.1038/s41417-026-01020-z","url":null,"abstract":"<p><p>Ovarian cancer is one of the most common gynecological malignancies and has the highest mortality rate among gynecological cancers. Its difficulties in diagnosis, high mortality rate, high recurrence rate, and poor prognosis, have always been a major obstacle for researchers. Gene therapy, a revolutionary medical approach, can correct genetic defects to treat intractable diseases, enable personalized medicine, and boost medical research, thus holding great promise for reshaping healthcare. siRNA interference technology has become one of the key directions in drug research field due to its advantages of high efficiency, high specificity, and low toxicity. And the development of new targeted drugs using siRNA interference technology has attracted significant attention. However, siRNA needs to overcome the vascular barrier, achieve intracellular uptake and escape from lysosomes, while also avoiding degradation by nucleases. Fortunately, the emergence of nanomaterials has provided new insights and strategies for siRNA drug delivery. Herein, we review the current advances in nanoparticle-mediated siRNA delivery strategies, as well as the application of siRNA-loaded nanomaterials in the diagnosis and therapy of ovarian cancer.</p>","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147526985","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":"SPINK5 promotes sensitivity to cisplatin by inducing ferroptosis in head and neck carcinoma.","authors":"Hui Yao, Guanghao Zhu, Haopu Li, Jingjie Wang, Caiyun Zhang, Minhui Zhu","doi":"10.1038/s41417-026-01019-6","DOIUrl":"https://doi.org/10.1038/s41417-026-01019-6","url":null,"abstract":"<p><p>Cisplatin resistance remains a major obstacle in treating head and neck squamous cell carcinoma (HNSCC). Understanding its regulatory mechanisms is critical for improving therapeutic outcomes. SPINK5 expression was analyzed using TCGA datasets and tissue microarrays. Functional assays, including CCK-8, Annexin V-FITC/PI, and ferroptosis-specific probes (FerroOrange, DCFH-DA), were performed in SPINK5-overexpressing and FTH1-silenced HNSCC cells. Transcriptomic data were processed using R packages, with GSEA/GSVA for pathway analysis. Xenograft models were used to evaluate in vivo cisplatin responses. SPINK5 was significantly downregulated in HNSCC and correlated with poor prognosis and lymph node metastasis. Overexpression of SPINK5 enhanced cisplatin sensitivity by inducing ferroptosis, characterized by elevated ROS and Fe²⁺ levels, independent of classical apoptosis pathways. Unsupervised clustering and transcriptomic analysis identified FTH1 as a key downstream target of SPINK5. Mechanistically, SPINK5 suppressed FTH1 expression, promoting ferroptotic cell death and improving cisplatin efficacy in vitro and in vivo. SPINK5 functions as a tumor suppressor and sensitizes HNSCC cells to cisplatin by regulating ferroptosis via FTH1 downregulation, highlighting a novel therapeutic axis to overcome chemoresistance.</p>","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147519825","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 TCR in CAR T cell therapy: use it or lose it?","authors":"Olivia Liseth, Richard Vile","doi":"10.1038/s41417-026-01018-7","DOIUrl":"10.1038/s41417-026-01018-7","url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR) T cell therapy has become an indispensable immunotherapy for the treatment of some hematologic cancers, but still faces numerous challenges in the form of antigen escape, variable patient responses, toxicities, limited CAR T cell persistence, and high cost, particularly against solid tumors. This Review discusses the potential role of the endogenous T cell receptor (TCR) as either a hindrance or partner to CAR T cell function. Specifically, we discuss the differences and similarities between CAR and TCR structure and function, findings supporting the value of TCR elimination in CAR T cells, and, in contrast, data in support of retaining and utilizing the endogenous TCR in CAR T cell therapy. We make the case that, while TCR-knockout systems may improve aspects such as the universality, cost, and CAR expression of CAR therapies, the endogenous TCR continues to play a significant role in maintaining CAR T cell persistence and can be used to augment CAR T cell therapeutic phenotypes. Overall, we highlight the uncertainties that persist within the field of CAR T cell therapy and outline emerging evidence and directions regarding the CAR T cell TCR that have the potential to transform patient outcomes.</p>","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13105299/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147503274","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":"Dioscin suppresses tumorigenesis and overcomes radioresistance by promoting ubiquitination-mediated degradation of Mcl-1.","authors":"Qi Liang, Xuecheng Wu, Dongyu Li, Yiwei Liu, Ruirui Wang, Xiaoying Li, Pengfei Guo, Wei Li","doi":"10.1038/s41417-026-01022-x","DOIUrl":"https://doi.org/10.1038/s41417-026-01022-x","url":null,"abstract":"<p><p>Oral squamous cell carcinoma (OSCC) is a prevalent and aggressive malignancy of the oral cavity, with increasing incidence and poor prognosis. Myeloid leukemia 1 (Mcl-1), an anti-apoptotic protein in the BCL-2 family, is critical for tumor development and progression. In this study, we investigated Dioscin, a natural compound, as a potential therapeutic agent for OSCC. Our results demonstrated that Dioscin significantly inhibits cell viability and colony formation in OSCC cell lines. Mechanistically, Dioscin induced intrinsic apoptosis by promoting the ubiquitination and degradation of Mcl-1. Further analysis revealed that Dioscin enhances the interaction between the E3 ligase β-TRCP and Mcl-1 by inhibiting the Akt/GSK3β signaling pathway, resulting in increased phosphorylation of Mcl-1 at Ser159, which drives its destabilization. In vivo, Dioscin notably suppressed OSCC tumor growth, including in sensitive and radioresistant cells, by reducing Mcl-1 levels. These findings highlight the therapeutic potential of Dioscin for OSCC treatment, offering new insights for overcoming radioresistance and improving clinical outcomes in OSCC patients.</p>","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147509611","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}