{
  "abstract": "BackgroundChronic inflammation may shift tissue-protective immunity toward a tumor-permissive microenvironment, but natural killer (NK)-cell remodeling in lung adenocarcinoma (LUAD) remains incompletely characterized. We investigated whether NK-cell depletion and state redistribution are reproducible tumor-associated features with biomarker or therapeutic relevance.MethodsTwo patient-matched single-cell RNA-sequencing cohorts (GSE131907 and E-MTAB-13526) were analyzed using patient-level paired tests. We assessed NK-cell abundance within the immune compartment, CD16-positive terminal and CD16-negative tissue-adapted fractions within NK cells, and pseudobulk expression. Chromatin accessibility was evaluated using GSE304741 GEX–ATAC data. TCGA-LUAD, Visium spatial transcriptomics, and six pretreatment immune checkpoint inhibitor (ICI) cohorts provided external assessment. Western blots in NK-92 cells examined SMAD2 phosphorylation and perforin/granzyme B expression after TGF-β1 stimulation with or without SB431542.ResultsIn GSE131907, NK-cell abundance and terminal-state fractions declined in all 10 matched patients, whereas tissue-adapted fractions increased (all P = 0.00293); these patterns were independently replicated. Pseudobulk effects showed moderate genome-wide concordance (Spearman’s ρ = 0.350), with 112/116 discovery-significant genes directionally concordant and 58 significant in both cohorts (FDR <0.05). In GSE304741, 15/19 prespecified promoters showed differential accessibility, with strong RNA–chromatin concordance (ρ = 0.851). TGF-β, hypoxia, MAPK, EGFR, and estrogen-related signatures changed concordantly across analytical contexts. TCGA-LUAD supported reduced inferred NK abundance and terminal cytotoxic programs. In three LUAD/nonsquamous NSCLC ICI cohorts, clinical benefit was associated with higher terminal cytotoxic activity (Hedges’ g = 0.445, P = 0.0319) and lower abundance-adjusted state balance (g = −0.487, P = 0.0192), but not NK abundance. Visium showed a nonsignificant NK-abundance decrease in four of five patients; NK-state estimates were method-dependent. Qualitative NK-92 immunoblots suggested increased SMAD2 phosphorylation and reduced perforin/granzyme B after TGF-β1, attenuated by SB431542.ConclusionLUAD exhibits reproducible NK-cell depletion accompanied by loss of terminal-state representation and relative enrichment of tissue-adapted states. Terminal cytotoxic programs and abundance-adjusted state balance warrant investigation as biopsy-based biomarkers, whereas KLRC1/NKG2A and TGF-β–hypoxia signaling remain therapeutic hypotheses requiring further validation. These findings do not establish a longitudinal premalignant trajectory.",
  "abstract_shown": true,
  "affiliations": [
    "The First Department of Clinical Medicine, Bengbu Medical University, Bengbu, Anhui, China",
    "Department of Stomatology, Bengbu Medical University, Bengbu, Anhui, China",
    "Department Mental Health, Bengbu Medical University, Bengbu, Anhui, China"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 7,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Luyuan Chang"
    },
    {
      "affs": [
        1
      ],
      "name": "Ruiqi Wang"
    },
    {
      "affs": [
        2
      ],
      "name": "Xin Chen"
    },
    {
      "affs": [
        2
      ],
      "name": "Yuantao Fang"
    },
    {
      "affs": [
        0
      ],
      "name": "Jiaqi Yan"
    },
    {
      "affs": [
        2
      ],
      "name": "Juan Chen"
    },
    {
      "affs": [
        2
      ],
      "name": "Jing Zhang"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/bvnse4zjw9rgx.bib",
  "cited_by": 0,
  "doi": "10.3389/fgene.2026.1999349",
  "fulltext_url": "https://www.frontiersin.org/articles/10.3389/fgene.2026.1999349/full",
  "id": "bvnse4zjw9rgx",
  "issns": [
    "1664-8021"
  ],
  "landing_url": "https://doi.org/10.3389/fgene.2026.1999349",
  "language": "en",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "lcc",
      "QH426-470"
    ],
    [
      "openalex",
      "2403|Immune Cell Function and Interaction"
    ]
  ],
  "openalex": "W7225236219",
  "pdf_url": null,
  "pmcid": null,
  "pmid": null,
  "published": "2026-11-04",
  "publisher": "Frontiers Media S.A.",
  "ris": "https://research.draconitic.com/paper/bvnse4zjw9rgx.ris",
  "sources": [
    {
      "first_seen": "2026-11-05T14:21:15Z",
      "native_id": "8926a73de8024e7faa65d208c20f8fd5",
      "source": "doaj",
      "url": "https://doi.org/10.3389/fgene.2026.1999349"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:2403|Immune Cell Function and Interaction",
      "subfield": "immunology"
    }
  ],
  "title": "Sequencing based dissection of inflammation associated natural killer cell remodeling in lung adenocarcinoma identifies state biomarkers and therapeutic vulnerabilities",
  "title_text": "Sequencing based dissection of inflammation associated natural killer cell remodeling in lung adenocarcinoma identifies state biomarkers and therapeutic vulnerabilities",
  "type": "peer-reviewed",
  "updated_at": "2026-11-06T14:20:44Z",
  "url": "https://research.draconitic.com/paper/bvnse4zjw9rgx",
  "venue": "Frontiers in Genetics",
  "versions": []
}