Oncogene最新文献

{"title":"SPTLC2-driven sphingolipid reprogramming of neutrophils impairs anti-tumour immunity and drives liver cancer progression","authors":"Zhe Yang, Yun Wang, Jianhao Li, Zishuo Wang, Jianan Chen, Ding Zhang, Guorui Zhao, Liwen Liu, Zhibo Liu, Ning Wang, Ranran Sun","doi":"10.1038/s41388-026-03996-2","DOIUrl":"10.1038/s41388-026-03996-2","url":null,"abstract":"Liver cancer exhibits limited and heterogeneous responses to immune checkpoint blockade, underscoring the need to elucidate tumour microenvironmental mechanisms sustaining immune dysfunction. Here, we integrated single-cell transcriptomic annotation with BayesPrism deconvolution across multiple bulk cohorts and combined these analyses with in vivo liver cancer models, functional assays, and mechanistic investigations to define tumour-associated neutrophil (TAN) programmes linked to clinical outcome. We identified a neutrophil subset characterized by elevated sphingolipid metabolism as the predominant poor-prognosis signature, with SPTLC2 serving as the key molecular marker. High SPTLC2 expression defining this sphingolipid metabolism-high neutrophil population correlated significantly with advanced disease stage, inferior overall survival, and increased tumour infiltration. Tumour cell co-culture induced SPTLC2 upregulation and enhanced sphingolipid metabolic activity in neutrophils. Functional assays verified that myriocin, an SPTLC2 inhibitor, suppressed the proliferation and metastasis of Liver cancer cells and remodelled the antitumour immune function of neutrophils. Myriocin attenuated neutrophil sphingolipid metabolism and restored ROS production and neutrophil extracellular trap (NETosis) formation, revealing a critical regulatory role for sphingolipid metabolism in neutrophil-mediated innate immunity, as corroborated by single-cell analyses showing impaired innate immune function in sphingolipid metabolism-high neutrophils. Mechanistically, we uncovered an SPTLC2-dependent sphingolipid-lipid raft checkpoint that remodels plasma membrane microdomains to constrain neutrophil anti-tumour effector functions. Specifically, myriocin restored NOX2-dependent ROS generation by reducing ceramide accumulation in lipid rafts, thereby facilitating p47phox-p22phox interaction and productive NOX2 complex assembly in tumour-conditioned neutrophils. Collectively, these findings reveal a previously unrecognized immunometabolic axis governing TAN dysfunction in liver cancer, establish SPTLC2 as a rational combinatorial target for cancer immunotherapy, and highlight the therapeutic potential of targeting sphingolipid metabolism to restore neutrophil-mediated antitumour immunity and restrain hepatocellular carcinoma progression.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 44","pages":"4827-4842"},"PeriodicalIF":9.1,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149075523","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":"Metabolites and cancer metastasis","authors":"Suisui Yang, Silin Shi, Junchen Hou, Jian Zhang, Zhenyi Su","doi":"10.1038/s41388-026-03930-6","DOIUrl":"10.1038/s41388-026-03930-6","url":null,"abstract":"Over the past decades, metastasis research has largely emphasized genetic and epigenetic regulators. Emerging evidence indicates that metabolites—including sugars (glucose, fructose), antioxidant vitamins, glutathione, lipids (palmitic acid, cholesterol), and amino acids (glutamine, aspartate, BCAAs)—can critically influence metastasis in a context-dependent manner by driving or restraining progression via metabolic reprogramming and signaling modulation. This review examines how cancer cells re-modulate core metabolic pathways to adapt and metastasize, summarizes how endogenous metabolites, dietary bioactive compounds, metabolic toxins, and pharmacological agents regulate metastasis, and discusses new concepts and perspectives on metabolic regulation of tumor metastasis, and outlines future directions in metabolite-driven tumor metastasis. The metabolic dependencies of metastasis provide a rational basis for intervention through integrated nutritional and therapeutic strategies.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 42","pages":"4471-4497"},"PeriodicalIF":9.1,"publicationDate":"2026-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149069929","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":"A positive feedback loop between YTHDC1 and EP300 drives multiple myeloma tumorigenesis","authors":"Yifan Hou, Qiqi Shen, Jianwei Qu, Enfan Zhang, Ruyi Xu, Huiyao Gu, Wen Cao, Haoguang Chen, Jinna Zhang, Shunnan Yao, Zhenfeng Dai, Hongying Ye, Chunting Zhu, Yunlu Jia, Jingsong He, Pengxu Qian, Zhen Cai","doi":"10.1038/s41388-026-03992-6","DOIUrl":"10.1038/s41388-026-03992-6","url":null,"abstract":"N6-methyladenosine (m6A), the most prevalent internal RNA modification in mammals, regulates key cellular processes through writer, eraser, and reader proteins. Recent studies have emerged that dysregulation of m6A modifiers promotes tumorigenesis by altering RNA metabolism. However, the role of m6A in multiple myeloma (MM) remains enigmatic. Here, we identify YTHDC1, a nuclear m6A reader, as a key oncogenic factor in MM. YTHDC1 is upregulated in MM cells and associated with poor prognosis. Functional studies reveal that YTHDC1 facilitates MM cell growth and survival in an m6A-dependent manner. Mechanistically, YTHDC1 directly binds m6A-modified EP300 mRNA and enhances its stability and expression. In turn, p300 activates YTHDC1 transcription via H3K27ac deposition and IRF3/IRF4 recruitment, establishing a self-reinforcing feedback loop. This interplay between RNA m6A methylation and histone H3K27 acetylation contributes to MM pathogenesis. Our findings highlight the YTHDC1-EP300 axis as a promising target for therapeutic intervention.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 44","pages":"4808-4826"},"PeriodicalIF":9.1,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149063410","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":"KIFC1 engages RUNX2/TGF-β signaling to promote lung cancer bone metastasis via disrupting bone homeostasis","authors":"Jinyan Feng, Qingqian Zhao, Jinwu Wang, Zeyang Li, Houzhi Yang, Yuxiang Shen, Xiaoyu Yang, Yiqin Li, Yao Xu, Xiuxin Han, Chao Zhang, Guowen Wang","doi":"10.1038/s41388-026-03998-0","DOIUrl":"10.1038/s41388-026-03998-0","url":null,"abstract":"Bone metastasis affects 30–40% of lung cancer patients, markedly reducing survival and quality of life, yet the underlying molecular mechanisms remain incompletely understood. Comparative transcriptomic profiling of primary lung tumors and paired bone metastases revealed pronounced KIFC1 enrichment in metastatic lesions, which correlated with poor bone metastasis-free survival. Functionally, KIFC1 enhanced lung cancer cell migration and adhesion toward osteoblast-like cells and upregulated the bone-homing factors CXCR4 and OPN. KIFC1 promoted osteoclast recruitment and differentiation while suppressing osteogenic differentiation, thereby disrupting bone homeostasis. Mechanistically, KIFC1 associated with RUNX2 through its C-terminal motor domain and promoted RUNX2 nuclear accumulation in a motor activity-, microtubule-, and importin-dependent manner. Nuclear RUNX2 directly activated TGFB1 transcription, resulting in preferential activation of the TGF-β/SMAD3 signaling pathway. Genetic silencing of RUNX2 or pharmacological inhibition of SMAD3 largely abrogated KIFC1-mediated pro-metastatic and pro-osteolytic effects. In vivo, KIFC1 knockdown reduced intraosseous tumor burden and alleviated trabecular bone loss, whereas KIFC1 overexpression exacerbated osteolytic lesions, which were mitigated by disrupting RUNX2/TGF-β/SMAD3 signaling. Collectively, our findings identify KIFC1-mediated RUNX2 nuclear transport as a previously unrecognized upstream regulatory mechanism that activates the TGF-β/SMAD3 axis during lung cancer bone metastasis, which provides a conceptual framework for the development of targeted therapeutic strategies.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 44","pages":"1-17"},"PeriodicalIF":9.1,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149063475","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":"KAT5-mediated HSPA1A lactylation drives immunotherapy resistance by inhibiting STAT1 degradation in esophageal squamous cell carcinoma.","authors":"Ziyi Wang, Xinyan Li, Peng Luo, Su Li, Yan Xu, Wenya Li, Quanxing Liu, Yuqiong Chen, Xiangyu Sun","doi":"10.1038/s41388-026-03993-5","DOIUrl":"https://doi.org/10.1038/s41388-026-03993-5","url":null,"abstract":"<p><p>Immunotherapy has shown promising efficacy in esophageal squamous cell carcinoma (ESCC), yet its clinical benefits remain limited due to immune evasion. Lactate accumulation in the tumor microenvironment has been found to facilitate immune evasion through protein lactylation. However, the key lactylated substrates and mechanisms driving immune evasion remain undefined. Here, we show that HSPA1A lactylation at lysine 108 (K108) by KAT5 drives CD8⁺ T cell dysfunction and immunotherapy resistance via the STAT1/PD-L1 axis in ESCC. Mechanistically, K108 lactylation enhances HSPA1A binding to STAT1, protecting STAT1 from TRIM25-mediated ubiquitination and proteasomal degradation. This stabilization promotes STAT1 phosphorylation and nuclear translocation, leading to transcriptional upregulation of PD-L1 and subsequent immune evasion. Collectively, these findings highlight the pivotal role of HSPA1A lactylation in facilitating immune evasion via the STAT1/PD-L1 axis, suggesting a potential target for improving immunotherapy efficacy in ESCC.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":9.1,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149039920","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":"Synonymous codon usage shapes ERα function through specialized translational programs during breast cancer progression.","authors":"Tamara Fernandez-Calero, Raphaël Métivier, Frederic Percevault, Léa Clusan, Mewen Briend, Charly Jehanno, Cyrille Garnier, Coralie Fontaine, Emmanuel Guidice, Reynald Gillet, Hugo Naya, Jean-François Arnal, Monica Marin, Denis Michel, Gilles Flouriot","doi":"10.1038/s41388-026-03991-7","DOIUrl":"https://doi.org/10.1038/s41388-026-03991-7","url":null,"abstract":"<p><p>Long considered neutral, synonymous codon usage is increasingly recognized as a regulatory layer of mRNA translation. Proteins expressed during proliferation are translated from mRNAs with codon compositions distinct from those encoding proteins in differentiated states, suggesting the existence of specialized translational programs. In hormone-receptor-positive breast cancer, estrogen receptor-alpha (ERα/ESR1) acts both as a driver of proliferation and as a maintainer of luminal identity, making its translational regulation particularly relevant. Here, we show that the transition of breast cancer cells from quiescent, differentiated states towards proliferative, less differentiated phenotypes, is accompanied by a systematic shift from G/C3- to A/U3-biased codon usage. ERα coding sequence architecture mirrors these translational programs through both global codon composition and position-dependent codon patterns. These features influence translational efficiency and likely modulate co-translational folding dynamics, thereby adjusting receptor abundance and functional outputs according to the prevailing translational program. Consistent with their functional importance, synonymous codon choices are subject to increased selective constraints within regions encoding structural and functional domains. Using engineer synonymous ERα variants, we demonstrate that codon usage fine-tunes receptor function across distinct cellular states. Together, our findings identify synonymous codon usage as a previously unrecognized mechanism linking translational programs to ERα expression and function.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":9.1,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149040020","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":"Phylogenetic and phylodynamic approaches to understanding the evolution of non-small cell lung cancer using single-cell sequencing","authors":"Teng Li,&nbsp;Xianghan Li,&nbsp;Yiran Zou,&nbsp;Thomas K. F. Wong,&nbsp;Michael J. Campa,&nbsp;Elizabeth B. Gottlin,&nbsp;Edward F. Patz Jr,&nbsp;Allen Rodrigo","doi":"10.1038/s41388-026-03997-1","DOIUrl":"10.1038/s41388-026-03997-1","url":null,"abstract":"Characterizing the genealogy of tumor cells and their population dynamics is central to our understanding of the evolution of cancer. While direct monitoring of the tumor evolutionary process is impractical, we leverage advances in phylogenetics and phylodynamics to explore the evolutionary dynamics of non-small cell lung cancer (NSCLC) using single-cell whole exome sequencing data from 351 tumor cells across 11 NSCLC patients, predominantly focusing on the primary tumors and early stages of NSCLC. Our results reveal distinct phylogenetic tree shapes and evolutionary trajectories across different stages of NSCLC evolution. However, this intricate and multi-phase evolutionary process cannot be fully elucidated by current tumor models. Herein, we hypothesize that tumors progress through the following phases: (1) an initial rapid expansion through Big Bang-like growth, (2) a prolonged plateau period of non-progression with possible accumulation of neutral substitutions, (3) a subsequent phase where adaptive substitutions accumulate gradually, (4) a bottleneck event where selectively advantageous subclones acquire invasive capabilities (characterized by a pattern of punctuated evolution), and, potentially, a rapid expansion leading to metastasis. This work highlights the use of single-cell phylogenetics and phylodynamics for interpreting the evolution of NSCLC, with potential in predicting cancer progression, resistance mechanisms, and treatment response.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 44","pages":"1-14"},"PeriodicalIF":9.1,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-026-03997-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149039891","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":"SETDB1 cooperates with the CRL4B complex to promote colorectal cancer tumorigenesis by disrupting circadian rhythm","authors":"Min Zhang,&nbsp;Dong Yan,&nbsp;Jingyao Zhang,&nbsp;Tianyang Gao,&nbsp;Jingwen Cai,&nbsp;Ting Hu,&nbsp;Tianyu Ma,&nbsp;Yinuo Wang,&nbsp;Miaomiao Huo,&nbsp;Die Zhang,&nbsp;Yu Li,&nbsp;Jingjing Zhang,&nbsp;Chang Guo,&nbsp;Xinhui Hao,&nbsp;Tian Zhu,&nbsp;Jiayi Gao,&nbsp;Zengwei Tang,&nbsp;Baowen Yuan,&nbsp;Yan Wang","doi":"10.1038/s41388-026-03972-w","DOIUrl":"10.1038/s41388-026-03972-w","url":null,"abstract":"The circadian rhythm is an intrinsic, self-regulatory physiological system in organisms that is hierarchically governed by core clock genes. Dysregulation of this rhythm is closely associated with tumor progression. However, the specific molecular mechanisms underlying circadian rhythm disruption–mediated colorectal cancer (CRC) remain largely elusive. The histone methyltransferase SET domain bifurcated 1 (SETDB1) exerts oncogenic functions in multiple solid tumors, prompting this study to investigate the molecular mechanisms through which SETDB1 regulates CRC progression. Our results demonstrate that SETDB1 acts as an oncogene in CRC by interacting with the Cullin 4B-RING E3 ligase (CRL4B) complex to enhance cancer cell proliferation, invasion, and stemness maintenance. Specifically, SETDB1 and the CRL4B complex assemble into a transcriptional repressor complex that binds to the promoters of core clock genes, such as PER3 and CRY1, to repress their transcription, thereby disrupting cellular circadian rhythms and ultimately accelerating CRC cell proliferation and metastasis. Collectively, our findings elucidate the pivotal role of the SETDB1/CRL4B complex in CRC pathogenesis and provide a potential therapeutic strategy targeting SETDB1 for patients with CRC with high CUL4B expression.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 44","pages":"4758-4776"},"PeriodicalIF":9.1,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-026-03972-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149031012","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":"DDR1 sustains ferroptosis resistance in pancreatic ductal adenocarcinoma via SLC40A1-mediated iron homeostasis.","authors":"Chao Song, Luting Zhang, Sheng Xu, Xu-An Wang, Xinyi Zhang, Kai Xuan Cheong, Ganggang Wang, Mengmeng Liu, Yazhou Wang, Yifei Zhang, Taochen He, Kai Ding, Yu Chen, Xin Liang, Bing Zhu, Qianzhi Ni, Wenquan Wang, Jingjing Li, Wenhui Lou, Liang Liu","doi":"10.1038/s41388-026-03980-w","DOIUrl":"https://doi.org/10.1038/s41388-026-03980-w","url":null,"abstract":"<p><p>Integrated single-cell transcriptomics and clinical analyses reveal elevated DDR1 expression in pancreatic ductal adenocarcinoma (PDAC) tissues, which correlates with poor prognosis. Mechanistically, collagen-activated Discoidin Domain Receptor 1 (DDR1) recruits SHC1 to activate the MAPK/ERK pathway, thereby driving transcriptional upregulation of SLC40A1 via the ERK-MYC axis. SLC40A1, encoding an iron exporter, reduces intracellular labile iron pools, thereby suppressing lipid peroxidation and ferroptosis. Consequently, DDR1 overexpression confers resistance to dihydroartemisinin (DHA)-induced ferroptosis in PDAC cells, characterized by diminished ROS accumulation, mitochondrial shrinkage, and cristae loss. Conversely, DDR1 knockdown or pharmacological inhibition (Dasatinib) sensitizes PDAC cells to DHA. Crucially, combining Dasatinib and DHA treatment synergistically inhibits tumor growth in vivo by reactivating ferroptosis, as evidenced by increased 4-HNE accumulation and decreased Ki67 expression. These findings identify DDR1 as a key regulator of iron metabolism and ferroptosis in PDAC, suggesting that dual targeting of DDR1 and ferroptosis represents a promising therapeutic strategy.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":9.1,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149031025","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: Splicing-mediated control of hnRNPD isoform switching by SRSF2 drives PD-L1-dependent immune evasion in gallbladder cancer","authors":"Cheng Zhao,&nbsp;Lin Jiang,&nbsp;Ming-yang Wang,&nbsp;Qiu-yi Tang,&nbsp;Jing-wei Zhao,&nbsp;Zi-yi Yang,&nbsp;Jun Gu,&nbsp;Xiao-ling Song,&nbsp;Ping Dong,&nbsp;Li-jia Pan,&nbsp;Yi-jun Shu,&nbsp;Wei Gong","doi":"10.1038/s41388-026-03999-z","DOIUrl":"10.1038/s41388-026-03999-z","url":null,"abstract":"","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 40","pages":"4345-4345"},"PeriodicalIF":9.1,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-026-03999-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149023274","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}