Oncogene最新文献

{"title":"KPNA2 silencing sensitizes triple-negative breast cancer to chemotherapy by promoting multipolar division and suppressing DNA damage repair.","authors":"Yufan Cai, Junxian Du, Haiyu Wang, Lei Shen, Zujing Xu, Yizhou Zhaoxiong, Zheng Gong, You Zhu, Chuxun Wu, Jialiang Cai, Peiling Zhang, Shiping Chen, Zhi Dai, Run Huang, Wei Zhu","doi":"10.1038/s41388-025-03503-z","DOIUrl":"https://doi.org/10.1038/s41388-025-03503-z","url":null,"abstract":"<p><p>Breast cancer is one of the most common malignancies among women. Triple-negative breast cancer (TNBC) is a distinct subtype of breast cancer characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Consequently, patients with TNBC do not benefit from endocrine therapy or HER2-targeted therapy, leaving conventional chemotherapy as the primary treatment option. Unfortunately, less than 30% of patients with TNBC achieve a complete response to chemotherapy, and many develop resistance, highlighting the urgent need to identify novel therapeutic targets to overcome chemoresistance. In this study, we analyzed breast cancer data from The Cancer Genome Atlas (TCGA) and discovered that KPNA2 was significantly overexpressed in the basal subtype of the PAM50 classification. Furthermore, KPNA2 expression is strongly associated with the prognosis of TNBC patients undergoing chemotherapy. Through in vitro and in vivo experiments, we demonstrated that silencing of KPNA2 enhances TNBC sensitivity to chemotherapy by promoting multipolar division and suppressing homologous recombination repair (HR), a critical DNA damage repair mechanism. Mechanistically, immunoprecipitation mass spectrometry (IP-MS) identified KIFC1 as a downstream effector of KPNA2. KPNA2 not only binds to the nuclear localization signal (NLS) of KIFC1 to regulate its nuclear translocation but also influences the ubiquitination levels of the KIFC1 protein. Additionally, RNA-seq analysis revealed that KPNA2 and KIFC1 are involved in the NF-κB signaling pathway. The KPNA2/KIFC1/NF-κB pathway/HR-related genes axis provides a comprehensive explanation of how KPNA2 influences DNA damage repair. Overall, our findings shed light on the molecular mechanisms underlying chemoresistance in TNBC. This study provides compelling evidence supporting KPNA2 as a promising therapeutic target for overcoming chemoresistance in TNBC.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145086674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"USP10-mediated Ku70/80 stabilization inhibits PANoptosis and promotes chemoresistance in colorectal cancer.","authors":"Penghang Lin, Chunlin Lin, Zuhong Teng, Songyi Liu, Xiang Lin, Ruofan He, Hengxin Yao, Jianxin Ye, Guangwei Zhu","doi":"10.1038/s41388-025-03570-2","DOIUrl":"https://doi.org/10.1038/s41388-025-03570-2","url":null,"abstract":"<p><p>Chemotherapy is a widely used treatment for advanced colorectal cancer; however, its efficacy is often limited by chemotherapy resistance, the complex mechanisms of which remain poorly understood. Interestingly, we discovered that the expression levels of USP10 increase in tumor cells in response to chemotherapy, contributing to chemotherapy resistance. Under chemotherapy-induced stress, USP10 stabilizes the Ku70/80 complex in colorectal cancer cells, promoting DNA repair, reducing intracellular ROS levels, and mitigating PANoptosis, which leads to chemotherapy resistance. Additionally, the promoter activity of USP10 is regulated by the non-coding RNA Linc01106. This study also confirmed that the absence of USP10 enhances chemotherapy sensitivity in colorectal cancer cells, providing a potential strategy for overcoming chemotherapy resistance and improving therapeutic outcomes.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145086642","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NMRK2 leads to the depletion of CD8⁺T cells by mediating the enhancement of NAD⁺-SIRT1-CD38 axis in PRCC-TFE3 rRCC.","authors":"Yi Chen, Xuwentai Liu, Mengmeng Wu, Xiang Dong, Wenliang Ma, Fan Feng, Yibing Ding, Ping Dong, Weidong Ding, Luqing Zhang, Ning Liu, Weidong Gan, Dongmei Li","doi":"10.1038/s41388-025-03577-9","DOIUrl":"https://doi.org/10.1038/s41388-025-03577-9","url":null,"abstract":"<p><p>PRCC-TFE3 rearrangement renal cell carcinoma (rRCC) is an independent subtype of rRCC caused by chromosomal translocation and rearrangement. Previous studies have revealed that nicotinamide riboside kinase 2 (NMRK2), which is transcriptionally upregulated by PRCC-TFE3 fusion protein, as a pivotal molecule in the energy metabolism remodeling of PRCC-TFE3 rRCC. However, the molecular mechanism by which NMRK2-mediated enhancement of nicotinamide adenine dinucleotide (NAD⁺) synthesis contributes to tumor progression in PRCC-TFE3 rRCC remains unclear. In this study, utilizing immune system-humanized mice model and in vitro cell models, we demonstrated that elevated expression of NMRK2 impaired the cytotoxic functions of CD8⁺T cells, leading to the emergence of immune-ignorant phenotypes in PRCC-TFE3 rRCC. Furthermore, it was shown that the increased NAD⁺ metabolism driven by NMRK2 enhanced the stability of CD38 protein through SIRT1-mediated deacetylation, which underlines impairment of CD8⁺T cells and the development of an immunosuppressive state in PRCC-TFE3 rRCC. Our findings not only elucidated a mechanism underlying immunological ignorance in PRCC-TFE3 rRCC but also propose potential therapeutic targets.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145081284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: M6A-mediated-upregulation of lncRNA BLACAT3 promotes bladder cancer angiogenesis and hematogenous metastasis through YBX3 nuclear shuttling and enhancing NCF2 transcription","authors":"Jinbo Xie,&nbsp;Hui Zhang,&nbsp;Keyi Wang,&nbsp;Jinliang Ni,&nbsp;Xiaoying Ma,&nbsp;Christopher J. Khoury,&nbsp;Viktor Prifti,&nbsp;Brock Hoard,&nbsp;Eric G. Cerenzia,&nbsp;Lei Yin,&nbsp;Houliang Zhang,&nbsp;Ruiliang Wang,&nbsp;Dong Zhuo,&nbsp;Weipu Mao,&nbsp;Bo Peng","doi":"10.1038/s41388-025-03575-x","DOIUrl":"10.1038/s41388-025-03575-x","url":null,"abstract":"","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 40","pages":"3879-3882"},"PeriodicalIF":7.3,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-025-03575-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145081359","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RAB22A triggers intercellular chemoresistance transmission in colorectal cancer by promoting exosome release via the PKM2-pSNAP23 axis.","authors":"Yuan Yin, Liang Ming, Yan Qin, Junhui Tang, Bingxin Liu, Yuhang Liu, Guoying Jin, Lingzhen Jiang, Surui Yao, Xiaowei Qi, Zhaohui Huang","doi":"10.1038/s41388-025-03566-y","DOIUrl":"https://doi.org/10.1038/s41388-025-03566-y","url":null,"abstract":"<p><p>Chemoresistance is not only related to tumor cells themselves, but also regulated by the interaction between cells in the tumor microenvironment (TME). However, the underlying mechanisms are not well understood. RAB22A, a member of the RAB family of small GTPases that was identified by our group previously as an oncogene in colorectal cancer (CRC). In this study, we demonstrated that elevated expression of RAB22A in CRC cells, particularly in chemoresistant CRC cells, is associated with increased exosome secretion and enhanced chemoresistance. Mechanistically, RAB22A augments exosome secretion by inhibiting the ubiquitination and degradation of pyruvate kinase type M2 (PKM2), then promoting the phosphorylation of synaptosome-associated protein 23 (SNAP-23). Furthermore, RAB22A not only directly promotes chemoresistance in CRC cells but also indirectly induces acquired drug resistance of other CRC cells in the TME by promoting the secretion of RAB22A-PKM2-rich exosomes, thereby triggering intercellular chemoresistance transmission. Together, we reveal an essential role of RAB22A-PKM2-SNAP-23 signaling cascade in exosome induction in chemoresistant CRC cells and intercellular chemoresistance transmission, highlighting that targeting the RAB22A/PKM2/pSNAP axis is a potential novel strategy to reverse chemoresistance, and suggest circulating exosomal RAB22A and PKM2 as markers to predict the efficacy of chemotherapy in CRC.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145075853","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PLK1-mediated PDHA1 phosphorylation drives metabolic reprogramming in lung cancer.","authors":"Jia Peng, Qiongsi Zhang, Xiongjian Rao, Derek B Allison, Yifan Kong, Ruixin Wang, Jinghui Liu, Yanquan Zhang, Wendy Katz, Zhiguo Li, Xiaoqi Liu","doi":"10.1038/s41388-025-03571-1","DOIUrl":"10.1038/s41388-025-03571-1","url":null,"abstract":"<p><p>Although the involvement of polo-like kinase 1 (PLK1) in metabolic reprogramming from oxidative phosphorylation (OXPHOS) to glycolysis has been previously described, the underlying molecular mechanism remains unclear. Pyruvate dehydrogenase (PDH) catalyzes the conversion of pyruvate into acetyl-CoA, the starting material for the tricarboxylic acid (TCA) cycle. In a companion study by Zhang et al., we demonstrated that PLK1 phosphorylation of PDHA1 at threonine 57 (PDHA1-T57) drives its protein degradation via mitophagy activation. Using a stable-isotope resolved metabolomics (SIRM) approach, we now show that PLK1 phosphorylation of PDHA1-T57 results in metabolic reprogramming from OXPHOS to glycolysis. Notably, cells mimicking PDHA1-T57 phosphorylation rely more on the aspartate-malate shuttle than on glucose-derived pyruvate to sustain the TCA cycle. This metabolic shift was also observed in mouse embryonic fibroblasts (MEFs) and transgenic mice conditionally expressing the PDHA1-T57D variant, highlighting the role of PLK1 in metabolic reprogramming in vivo. It is well-established that pyruvate dehydrogenase kinase (PDK)-mediated phosphorylation of PDH leads to its inactivation and that dichloroacetic acid (DCA), a PDK inhibitor, has been investigated in preclinical and early clinical studies as a potential therapeutic agent for lung cancer. We demonstrated that DCA combined with Onvansertib, a PLK1 inhibitor, synergistically inhibits lung tumor growth by enhancing mitochondrial ROS, inhibiting glycolysis, and inducing apoptosis. This study aims to elucidate how PLK1-associated activity drives the metabolic reprogramming from OXPHOS to glycolysis during cellular transformation, thereby contributing to lung carcinogenesis. Our results provide support for a clinical trial to evaluate the efficacy of Onvansertib plus DCA in treating lung cancer.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12503065/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145075843","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TRIM21-mediated ubiquitination of SIX2 attenuates breast cancer stemness via LGSN suppression.","authors":"Haitao Chen, Yi Zhou, Yunnan Zhang, Yannan Fan, Lufeng Zheng, Qianqian Guo","doi":"10.1038/s41388-025-03572-0","DOIUrl":"https://doi.org/10.1038/s41388-025-03572-0","url":null,"abstract":"<p><p>Breast cancer stem cells (BCSCs) are pivotal drivers of breast tumor initiation, metastasis, and therapy resistance. Our previous studies identified the transcription factor SIX2 as a key regulator in maintaining breast cancer stemness. Here, we demonstrate that TRIM21, as an E3 ubiquitin ligase downregulated in breast cancer tissues, binds to SIX2 via its PRY-SPRY domain and catalyzes K48-type ubiquitination at lysine residues K82, K89, and K97. This modification promotes the degradation of SIX2 via the ubiquitin-proteasome pathway, consequently attenuating the stemness and metastatic potential of breast cancer cells. Furthermore, SIX2 transcriptionally activates LGSN expression through direct binding to its promoter region, thereby promoting the stemness and metastatic capabilities of breast cancer cells. Clinically, elevated expression of both SIX2 and LGSN correlates with poor prognosis in breast cancer patients. These results establish that TRIM21-mediated degradation of SIX2 suppresses LGSN expression, ultimately inhibiting the stemness and metastatic abilities of breast cancer cells, underscoring the critical regulatory role of the TRIM21-SIX2-LGSN axis in breast cancer progression.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145069969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The novel protein SEMA3C-319aa triggers glutathione metabolism-dependent ferroptosis in gastric cancer","authors":"Siyu Xiao,&nbsp;Yin Peng,&nbsp;Lehua Peng,&nbsp;Xiaoya Xie,&nbsp;Jiequan Qin,&nbsp;Huizhen Ma,&nbsp;Xinyi Kang,&nbsp;Chuhan Bing,&nbsp;Bingyan Huang,&nbsp;Ke Liang,&nbsp;Yidan Zhao,&nbsp;Xueying Rong,&nbsp;Xianling Feng,&nbsp;Xinmin Fan,&nbsp;Hassan Ashktorab,&nbsp;Zhong Zhang,&nbsp;Zhe Jin,&nbsp;Xiaojing Zhang","doi":"10.1038/s41388-025-03542-6","DOIUrl":"10.1038/s41388-025-03542-6","url":null,"abstract":"The lack of effective, targeted therapies for gastric cancer (GC) continues to limit patient survival. Circular RNAs (circRNAs), known to act as epigenetic regulators, may also encode functional proteins. In this study, RNA-seq combined with ribosome profiling (Ribo-seq) of human GC cells identified a non-canonically translated circRNA, circSEMA3C, which encodes a novel 319-amino-acid (aa) protein, SEMA3C-319aa. Functionally, both circSEMA3C and SEMA3C-319aa suppressed GC cell viability and tumor growth in vitro and in vivo. Using proteomics and metabolomics, we found that SEMA3C-319aa targets ferroptosis-associated metabolites and metabolic pathways in GC. Notably, SEMA3C-319aa upregulated the production of polyunsaturated fatty acid chains and inhibited glutathione metabolism-particularly the GSH cycle-thereby suppressing GPX4 activity. Mechanistically, SEMA3C-319aa binds to LDHA and, via its non-canonical nuclear localization signal (NLS), sequence shuttles LDHA into the nucleus, where it enhances transcription of the E3 ligase PARK2, promoting GPX4 degradation. Furthermore, combination treatment with SEMA3C-319aa and the GPX4 inhibitor RSL3 was more effective than monotherapy in vivo. Taken together, our findings reveal a novel NLS-dependent nuclear translocation mechanism mediated by SEMA3C-319aa and identify a new ferroptosis pathway in GC. SEMA3C-319aa may offer a promising adjuvant therapeutic strategy for GC.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 39","pages":"3679-3693"},"PeriodicalIF":7.3,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145069960","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"METTL16-mediated inhibition of MXD4 promotes leukemia through activation of the MYC-MAX axis.","authors":"Guglielmo Bove, Mehrad Babaei, Alberto Bueno-Costa, Sajid Amin, Nicla Simonelli, Rosaria Benedetti, Carmela Dell'Aversana, Mariarosaria Conte, Liliana Montella, Vincenzo Summa, Margherita Brindisi, Maria Rosaria Del Sorbo, Marco Crepaldi, Gregorio Favale, Nuria Profitos-Peleja, Vincenzo Carafa, Gaël Roué, Fortunato Ciardiello, Annalisa Capuano, Hendrik G Stunnenberg, Wouter L Megchelenbrink, Angela Nebbioso, Manel Esteller, Lucia Altucci, Nunzio Del Gaudio","doi":"10.1038/s41388-025-03563-1","DOIUrl":"https://doi.org/10.1038/s41388-025-03563-1","url":null,"abstract":"<p><p>N6-methyladenosine (m⁶A) is an RNA modification that governs multiple aspects of RNA metabolism, including splicing, translation, stability, decay, and the processing of marked transcripts. Although accumulating evidence suggests that the m⁶A writer METTL16 is involved in leukemia, the molecular pathway(s) by which it contributes to leukemogenesis remain unexplored. In this study, we shed light on a novel molecular mechanism whereby METTL16 plays a role in acute myeloid leukemia (AML) progression through an m⁶A-dependent manner. Our investigations revealed that METTL16 is overexpressed in primary AML cells. Genetic depletion of METTL16 or its pharmacological inhibition strongly affected the proliferation of AML cells, eventually triggering apoptosis. Transcriptome-wide analysis identified mRNA of MAX Dimerization Protein 4 (MXD4), a MYC pathway regulator, as a downstream target of METTL16. Mechanistically, we showed that METTL16 controls the stability of MXD4 mRNA, resulting in a reduction in MXD4 protein levels that indirectly activates the MYC-MAX axis, essential for leukemogenesis. Strikingly, the suppression of MXD4 rescued the expression levels of MYC target genes, restoring AML cell survival. Our findings unveil a novel METTL16-MXD4 oncogenic axis crucial for AML progression, establishing small-molecule inhibition of METTL16 as a potential therapeutic approach in leukemia and providing a new strategy to target MYC activity in cancer. Molecular model of METTL16-MXD4 axis controlling AML progression by regulating MYC activity. (A) METTL16 installs m⁶A on MXD4 mRNA, decreasing its stability and resulting in decreased MXD4 protein levels. (B) MXD4 reduction ensures MYC-MAX complex formation, MYC target gene expression, and AML cell growth. (C) Silencing or chemical inhibition of METTL16 stabilizes MXD4 mRNA and increases its protein levels. (D) (1) Increased MXD4 proteins may counteract MYC binding with its partner MAX, thus repressing expression of MYC target genes (early event); (2) MXD4 binds to MYC regulatory regions, decreasing MYC expression (late event) and affecting AML proliferation.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058574","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NRF2 immunobiology in cancer: implications for immunotherapy and therapeutic targeting","authors":"Harit Panda,&nbsp;Natalie G. Rowland,&nbsp;Caroline M. Krall,&nbsp;Brittany M. Bowman,&nbsp;Michael B. Major,&nbsp;Paul Zolkind","doi":"10.1038/s41388-025-03560-4","DOIUrl":"10.1038/s41388-025-03560-4","url":null,"abstract":"Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that acts as a key regulator in cellular defense mechanisms against oxidative stress and xenobiotics. NRF2 modulates the expression of over 200 genes involved in antioxidant response, drug metabolism, and cellular resilience. Constitutive activation of NRF2 is a common event in cancer and recent advances provide remarkable insights into the role of NRF2 in oncogenesis, immune evasion, and treatment resistance. This review aims to provide a comprehensive overview of the role of NRF2 in shaping the tumor immune microenvironment and the impact this has on clinical outcomes and treatment opportunities. Across multiple tumor subtypes, the activation of NRF2 is associated with impaired responses to anti-PD1 immunotherapy. Mechanistic insights from genetically engineered mouse models, in vitro studies, and clinical trial samples demonstrate how NRF2 activity supports cell resiliency, diminishes cytotoxic immune responses, and promotes metabolic reprogramming. This also provides a vulnerability which can be targeted through novel drug therapy and future directions will include development of optimal combination strategies to target tumor dependencies while minimizing toxicity and systemic off-target immune related effects.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 39","pages":"3641-3651"},"PeriodicalIF":7.3,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-025-03560-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058577","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}