{"title":"ets1驱动的核仁应激协调OLR1+巨噬细胞串扰维持透明细胞肾细胞癌的免疫抑制微环境","authors":"Lei Xiao, Zicheng Zhang, Tong Li, Yuyin Jiang, Yuanxin Liu, Jia Wang, Wei Tang","doi":"10.1155/humu/8856239","DOIUrl":null,"url":null,"abstract":"<p>While hypoxia-driven nucleolar stress (NS) has been recognized as a critical modulator of the immunosuppressive tumor microenvironment in clear cell renal cell carcinoma (ccRCC), its mechanistic contribution to disease progression remains poorly defined. To address this gap, we systematically mapped NS-associated molecular landscapes through integrated spatial transcriptomics and single-cell RNA sequencing of ccRCC specimens. Our analysis stratified tumors into two distinct NS subtypes, revealing that high-NS tumors exhibit aggressive clinical behavior, elevated expression of immunosuppressive checkpoints, and significantly reduced survival. At single-cell resolution, high-NS malignant cells displayed enhanced proliferative activity, glycolytic metabolic reprograming, and marked chromosomal instability. Mechanistic investigations demonstrated that hypoxia-induced ETS1 activation orchestrates NS via the MYC/NPM1/DDX17 signaling axis, directly promoting tumor proliferation and metabolic adaptation in preclinical models. Spatial multiomics further uncovered coordinated niche formation between high-NS cells and OLR1<sup>+</sup> macrophages, with ligand–receptor profiling identifying the EDN1–EDNRA–OLR1 axis as a central mediator of this immunosuppressive crosstalk. Functional validation in syngeneic mouse models confirmed that ETS1 overexpression accelerates tumor growth while enriching OLR1<sup>+</sup> macrophages with immunosuppressive phenotypes. Clinically, high OLR1<sup>+</sup> macrophage infiltration correlated with shorter survival across independent cohorts. These findings establish a hypoxia–ETS1–NS–macrophage axis as a key mechanism sustaining ccRCC progression and highlight actionable targets for disrupting protumorigenic immune niches through modulation of the NS pathway.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2025 1","pages":""},"PeriodicalIF":3.7000,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/8856239","citationCount":"0","resultStr":"{\"title\":\"ETS1-Driven Nucleolar Stress Orchestrates OLR1+ Macrophage Crosstalk to Sustain Immunosuppressive Microenvironment in Clear Cell Renal Cell Carcinoma\",\"authors\":\"Lei Xiao, Zicheng Zhang, Tong Li, Yuyin Jiang, Yuanxin Liu, Jia Wang, Wei Tang\",\"doi\":\"10.1155/humu/8856239\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>While hypoxia-driven nucleolar stress (NS) has been recognized as a critical modulator of the immunosuppressive tumor microenvironment in clear cell renal cell carcinoma (ccRCC), its mechanistic contribution to disease progression remains poorly defined. To address this gap, we systematically mapped NS-associated molecular landscapes through integrated spatial transcriptomics and single-cell RNA sequencing of ccRCC specimens. Our analysis stratified tumors into two distinct NS subtypes, revealing that high-NS tumors exhibit aggressive clinical behavior, elevated expression of immunosuppressive checkpoints, and significantly reduced survival. At single-cell resolution, high-NS malignant cells displayed enhanced proliferative activity, glycolytic metabolic reprograming, and marked chromosomal instability. Mechanistic investigations demonstrated that hypoxia-induced ETS1 activation orchestrates NS via the MYC/NPM1/DDX17 signaling axis, directly promoting tumor proliferation and metabolic adaptation in preclinical models. Spatial multiomics further uncovered coordinated niche formation between high-NS cells and OLR1<sup>+</sup> macrophages, with ligand–receptor profiling identifying the EDN1–EDNRA–OLR1 axis as a central mediator of this immunosuppressive crosstalk. Functional validation in syngeneic mouse models confirmed that ETS1 overexpression accelerates tumor growth while enriching OLR1<sup>+</sup> macrophages with immunosuppressive phenotypes. Clinically, high OLR1<sup>+</sup> macrophage infiltration correlated with shorter survival across independent cohorts. These findings establish a hypoxia–ETS1–NS–macrophage axis as a key mechanism sustaining ccRCC progression and highlight actionable targets for disrupting protumorigenic immune niches through modulation of the NS pathway.</p>\",\"PeriodicalId\":13061,\"journal\":{\"name\":\"Human Mutation\",\"volume\":\"2025 1\",\"pages\":\"\"},\"PeriodicalIF\":3.7000,\"publicationDate\":\"2025-10-03\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/8856239\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Human Mutation\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1155/humu/8856239\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"GENETICS & HEREDITY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Human Mutation","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1155/humu/8856239","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}
ETS1-Driven Nucleolar Stress Orchestrates OLR1+ Macrophage Crosstalk to Sustain Immunosuppressive Microenvironment in Clear Cell Renal Cell Carcinoma
While hypoxia-driven nucleolar stress (NS) has been recognized as a critical modulator of the immunosuppressive tumor microenvironment in clear cell renal cell carcinoma (ccRCC), its mechanistic contribution to disease progression remains poorly defined. To address this gap, we systematically mapped NS-associated molecular landscapes through integrated spatial transcriptomics and single-cell RNA sequencing of ccRCC specimens. Our analysis stratified tumors into two distinct NS subtypes, revealing that high-NS tumors exhibit aggressive clinical behavior, elevated expression of immunosuppressive checkpoints, and significantly reduced survival. At single-cell resolution, high-NS malignant cells displayed enhanced proliferative activity, glycolytic metabolic reprograming, and marked chromosomal instability. Mechanistic investigations demonstrated that hypoxia-induced ETS1 activation orchestrates NS via the MYC/NPM1/DDX17 signaling axis, directly promoting tumor proliferation and metabolic adaptation in preclinical models. Spatial multiomics further uncovered coordinated niche formation between high-NS cells and OLR1+ macrophages, with ligand–receptor profiling identifying the EDN1–EDNRA–OLR1 axis as a central mediator of this immunosuppressive crosstalk. Functional validation in syngeneic mouse models confirmed that ETS1 overexpression accelerates tumor growth while enriching OLR1+ macrophages with immunosuppressive phenotypes. Clinically, high OLR1+ macrophage infiltration correlated with shorter survival across independent cohorts. These findings establish a hypoxia–ETS1–NS–macrophage axis as a key mechanism sustaining ccRCC progression and highlight actionable targets for disrupting protumorigenic immune niches through modulation of the NS pathway.
期刊介绍:
Human Mutation is a peer-reviewed journal that offers publication of original Research Articles, Methods, Mutation Updates, Reviews, Database Articles, Rapid Communications, and Letters on broad aspects of mutation research in humans. Reports of novel DNA variations and their phenotypic consequences, reports of SNPs demonstrated as valuable for genomic analysis, descriptions of new molecular detection methods, and novel approaches to clinical diagnosis are welcomed. Novel reports of gene organization at the genomic level, reported in the context of mutation investigation, may be considered. The journal provides a unique forum for the exchange of ideas, methods, and applications of interest to molecular, human, and medical geneticists in academic, industrial, and clinical research settings worldwide.