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In this study, scRNA-seq, scATAC-seq and spatial transcriptomics data are integrated to systematically characterize the features of the tumor microenvironment (TME). We identify tumor cell subclones and elucidate the impact of chromosomal abnormalities on their characteristic functions. We further identify transcription factor regulatory networks by analyzing tumor cell differentiation trajectories. Importantly, we integrate DNA methylation and SNP information to deeply dissect the tumor cell differentiation process, revealing the multilayer regulatory mechanisms of tumor-related genes. Additionally, we reveal the evolution of cellular states across ecotypes to provide a more comprehensive characterization of TME. Finally, we screened potential therapeutic agents targeting the molecular mechanisms underlying tumor cell differentiation (Amivantamab in ccRCC, Levothyroxine in BC, Ouabain in PCa) and signature genes of ecotype. In conclusion, our work establishes a comprehensive framework for tumor assessment and informs the development of precision therapeutic strategies.<\/jats:p>","DOI":"10.3390\/ijms27062712","type":"journal-article","created":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T09:35:57Z","timestamp":1773740157000},"page":"2712","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrating Multi-Omics Atlas to Uncover Genetic and Epigenetic Mechanisms and Reveal Cell State Evolution Across Ecotypes in Male Urological Cancers"],"prefix":"10.3390","volume":"27","author":[{"given":"Jing","family":"Bai","sequence":"first","affiliation":[{"name":"College of Bioinformatics Science and Technology, Department of Urology, Harbin Medical University, Harbin 150081, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"He","family":"Yu","sequence":"additional","affiliation":[{"name":"College of Bioinformatics Science and Technology, Department of Urology, Harbin Medical University, Harbin 150081, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Congxue","family":"Hu","sequence":"additional","affiliation":[{"name":"College of Bioinformatics Science and Technology, Department of Urology, Harbin Medical University, Harbin 150081, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yining","family":"Ma","sequence":"additional","affiliation":[{"name":"College of Bioinformatics Science and Technology, Department of Urology, Harbin Medical University, Harbin 150081, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mingjie","family":"Dong","sequence":"additional","affiliation":[{"name":"College of Bioinformatics Science and Technology, Department of Urology, Harbin Medical University, Harbin 150081, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liyuan","family":"Li","sequence":"additional","affiliation":[{"name":"College of Bioinformatics Science and Technology, Department of Urology, Harbin Medical University, Harbin 150081, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kaiyue","family":"Yang","sequence":"additional","affiliation":[{"name":"College of Bioinformatics Science and Technology, Department of Urology, Harbin Medical University, Harbin 150081, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhenzhen","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Intelligent Medicine and Technology (Big Data Research Center), Hainan Medical University, Haikou 571199, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3709-3656","authenticated-orcid":false,"given":"Yunpeng","family":"Zhang","sequence":"additional","affiliation":[{"name":"College of Bioinformatics Science and Technology, Department of Urology, Harbin Medical University, Harbin 150081, China"},{"name":"School of Intelligent Medicine and Technology (Big Data Research Center), Hainan Medical University, Haikou 571199, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xia","family":"Li","sequence":"additional","affiliation":[{"name":"College of Bioinformatics Science and Technology, Department of Urology, Harbin Medical University, Harbin 150081, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan","family":"Cao","sequence":"additional","affiliation":[{"name":"College of Bioinformatics Science and Technology, Department of Urology, Harbin Medical University, Harbin 150081, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"100964","DOI":"10.1016\/j.jpha.2024.100964","article-title":"Progress and application of intelligent nanomedicine in urinary system tumors","volume":"14","author":"Xiao","year":"2024","journal-title":"J. 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