{
  "abstract": "BackgroundThe tumor microenvironment contributes to acquired resistance against osimertinib in non-small cell lung cancer (NSCLC), yet the key cell subpopulations and the underlying metabolic mechanisms remain incompletely elucidated.MethodsThe Scissor algorithm was applied to integrate bulk osimertinib-resistance transcriptomic profiles with single-cell RNA-seq data to pinpoint cell subpopulations functionally associated with the osimertinib resistant phenotype. AddModuleScore was applied to calculate scores for cholesterol metabolism-related modules. Gene-set enrichment analysis was carried out to uncover pathway alterations in osimertinib resistance-related macrophages. Cross-validation was performed in an independent dataset comparing treatment-naive and EGFR-tyrosine kinase inhibitors (EGFR-TKIs)-treated progressive-disease lesions. EGFR-mutant lung adenocarcinoma cells were treated with corresponding conditioned medium combined with osimertinib, followed by a panel of cell function assays, including cell proliferation, colony formation, and apoptosis. The gain- and loss- of function studies of APOE were conducted in THP-1 derived macrophages.ResultsOsimertinib-resistant associated Scissor+ cells were mainly enriched within macrophages, which exhibited prominent APOE-dependent cholesterol metabolic reprogramming. APOE was markedly up-regulated in Scissor+ macrophages and macrophages from EGFR-TKI-treated progressive-disease lesions. Macrophage-derived APOE shapes extracellular cholesterol availability in the microenvironment, which may promote intracellular free-cholesterol accumulation in tumor cells and counteract osimertinib-triggered apoptosis.ConclusionAPOE-dependent cholesterol metabolic reprogramming in macrophages is associated with osimertinib resistance in NSCLC and may contribute to therapeutic failure. Our results identify APOE as a hypothesis-generating candidate molecule that merits further pre-clinical investigation.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": "Original Research",
  "arxiv": null,
  "author_total": 8,
  "authors": [
    {
      "name": "Zhiyuan Gong"
    },
    {
      "name": "Zhao Gao"
    },
    {
      "name": "Jiachang Zhang"
    },
    {
      "name": "Limin Cao"
    },
    {
      "name": "Qicheng Zhang"
    },
    {
      "name": "Luoyi Li"
    },
    {
      "name": "Yidan Jia"
    },
    {
      "name": "Ke Xu"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/9e5r4jfx5w7n8.bib",
  "cited_by": 0,
  "doi": "10.3389/fimmu.2026.2001435",
  "fulltext_url": null,
  "id": "9e5r4jfx5w7n8",
  "issns": [
    "1664-3224"
  ],
  "landing_url": "https://www.frontiersin.org/articles/10.3389/fimmu.2026.2001435",
  "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": [
    [
      "feed-journal",
      "biology/immunology"
    ]
  ],
  "openalex": null,
  "pdf_url": null,
  "pmcid": null,
  "pmid": null,
  "published": "2026-11-09",
  "publisher": "Frontiers Media SA",
  "ris": "https://research.draconitic.com/paper/9e5r4jfx5w7n8.ris",
  "sources": [
    {
      "first_seen": "2026-11-09T12:20:31Z",
      "native_id": "10.3389/fimmu.2026.2001435",
      "source": "feed-frontiers",
      "url": "https://www.frontiersin.org/articles/10.3389/fimmu.2026.2001435"
    },
    {
      "first_seen": "2026-11-09T12:22:59Z",
      "native_id": "10.3389/fimmu.2026.2001435",
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      "url": "https://www.frontiersin.org/articles/10.3389/fimmu.2026.2001435/full"
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  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "feed-journal:biology/immunology",
      "subfield": "immunology"
    }
  ],
  "title": "Integration of bulk and single-cell transcriptomics via the Scissor algorithm reveals APOE-dependent cholesterol metabolic reprogramming in macrophages associated with osimertinib resistance in non-small cell lung cancer",
  "title_text": "Integration of bulk and single-cell transcriptomics via the Scissor algorithm reveals APOE-dependent cholesterol metabolic reprogramming in macrophages associated with osimertinib resistance in non-small cell lung cancer",
  "type": "peer-reviewed",
  "updated_at": "2026-11-09T12:22:59Z",
  "url": "https://research.draconitic.com/paper/9e5r4jfx5w7n8",
  "venue": "Frontiers in Immunology",
  "versions": []
}