{
  "abstract": "Clear cell renal cell carcinoma (ccRCC) exhibits intra-tumoral heterogeneity and spatial complexity that restrict immune infiltration, yet the malignant populations driving spatial immune exclusion remain elusive. We integrated scRNA-seq, paired scATAC-seq, spatial transcriptomics, and multiple bulk cohorts to identify the malignant subpopulation driving ccRCC progression. Multi-omics analyses, including malignancy inference, epigenomic profiling, cell–cell communication, and spatial modeling, characterized its molecular features and clinical relevance. We identified a malignant subpopulation co-activating epithelial–mesenchymal transition (EMT) and inflammatory programs, termed the aggressive EMT–inflammatory clone (AEIC). AEIC exhibited pronounced genomic instability, enhanced stemness, and poor prognosis across multicenter cohorts (p < 0.001). Chromatin accessibility revealed a MAZ/RUNX1-centered network driving key AEIC signature genes such as TGFBI and COL6A2. Cell–cell communication analysis suggested AEIC interacts with NK_CD16− cells via the COL6A2–(ITGA1+ITGB1) axis. Spatial analyses showed AEIC-enriched regions forming an extracellular matrix-rich barrier associated with NK_CD16− cell exclusion, M2-like macrophage polarization, and increased genomic instability. Finally, an AEIC-derived 16-gene signature stratified prognosis across independent cohorts and was associated with distinct drug-sensitivity patterns, including increased predicted sensitivity to Bortezomib and AZD4547. Overall, AEIC is associated with spatial and epigenetic remodeling in ccRCC, and the AEIC-derived signature supports prognostic stratification and further exploration of potential therapeutic vulnerabilities associated with the AEIC phenotype.",
  "abstract_shown": true,
  "affiliations": [
    "College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 8,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Rifang Lan"
    },
    {
      "affs": [
        0
      ],
      "name": "Lixia Weng"
    },
    {
      "affs": [
        0
      ],
      "name": "Bingbing Cao"
    },
    {
      "affs": [
        0
      ],
      "name": "Aotuo Li"
    },
    {
      "affs": [
        0
      ],
      "name": "Jingyi Zhang"
    },
    {
      "affs": [
        0
      ],
      "name": "Hongbo Shi"
    },
    {
      "affs": [
        0
      ],
      "name": "Lei Yang",
      "orcid": "0000-0002-1133-9099"
    },
    {
      "affs": [
        0
      ],
      "name": "Yingli Lv"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/btwkjb6d8j18n.bib",
  "cited_by": 0,
  "doi": "10.3390/ijms27219668",
  "fulltext_url": null,
  "id": "btwkjb6d8j18n",
  "issns": [
    "1422-0067"
  ],
  "landing_url": "https://www.mdpi.com/1422-0067/27/21/9668",
  "language": null,
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2740|Renal cell carcinoma treatment"
    ]
  ],
  "openalex": "W7224135940",
  "pdf_url": null,
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-28",
  "publisher": "MDPI AG",
  "ris": "https://research.draconitic.com/paper/btwkjb6d8j18n.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:18:58Z",
      "native_id": "10.3390/ijms27219668",
      "source": "crossref",
      "url": "https://www.mdpi.com/1422-0067/27/21/9668"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2740|Renal cell carcinoma treatment",
      "subfield": "general"
    }
  ],
  "title": "An Epigenetically Remodeled EMT–Inflammatory Clone Associated with Spatial Immune Exclusion in Clear Cell Renal Cell Carcinoma",
  "title_text": "An Epigenetically Remodeled EMT–Inflammatory Clone Associated with Spatial Immune Exclusion in Clear Cell Renal Cell Carcinoma",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:18:58Z",
  "url": "https://research.draconitic.com/paper/btwkjb6d8j18n",
  "venue": "International Journal of Molecular Sciences",
  "versions": []
}