{
  "abstract": "Background: Lung adenocarcinoma (LUAD) is the most common histological subtype of lung cancer, with a dismal prognosis partly attributed to immune evasion mediated by T cell dysfunction within the tumor microenvironment. However, the molecular determinants governing CD8 ⁺ cytotoxic T lymphocyte functional competence remain incompletely understood. Chloride intracellular channel 3 (CLIC3) has been implicated in cancer progression, but its role in T cell immunity within the LUAD TME is unknown.\n\nMethods: We performed single-cell RNA sequencing on tumor tissues from nine LUAD patients spanning three pathological stages (adenocarcinoma in situ [AIS], minimally invasive adenocarcinoma [MIA], and invasive adenocarcinoma [IAC]), integrated with spatial transcriptomics, TCGA-LUAD bulk RNA-seq analysis, and flow cytometric validation in an independent cohort of 32 LUAD patients. Functional module scoring and pseudotime trajectory analysis were applied to characterize CLIC3-associated CTL functional states.\n\nResults: CLIC3 was predominantly expressed in CTLs and showed a stage-associated decline from AIS to MIA to IAC. CLIC3 ⁺ CTLs exhibited significantly higher module scores for cytotoxicity, cytoskeleton remodeling, interferon signaling, and chemotaxis compared to CLIC3- CTLs. Pseudotime trajectory analysis indicated that CLIC3 ⁺ cells were positioned at one end of the inferred transcriptional continuum, corresponding to a functionally active state, while CLIC3 ⁻ cells were positioned at the other, corresponding to a dysfunctional state, accompanied by a decline in CD247, GZMB, PRF1, and TNF along the trajectory. High CLIC3 expression in TCGA-LUAD was associated with significantly longer overall survival. Flow cytometry showed a stage-associated decrease in CLIC3 expression on CD8 ⁺ T cells with increasing tumor invasiveness and poor differentiation.\n\nConclusions: CLIC3 serves as a novel marker of CTL functional competence in LUAD, and its stage-associated downregulation reflects T cell dysfunction during tumor progression. CLIC3 expression in CD8 ⁺ T cells may represent a predictive biomarker for immunotherapeutic response and a potential target for restoring T cell function in LUAD.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Pulmonary Medicine, Affiliated Cancer Hospital of Xinjiang Medical University , , ,",
    "Department of Urology, Affiliated Cancer Hospital of Xinjiang Medical University , , ,"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 4,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Yinglong Li"
    },
    {
      "affs": [
        1
      ],
      "name": "Yidan Nie"
    },
    {
      "affs": [
        0
      ],
      "name": "Zhigang Han"
    },
    {
      "affs": [
        0
      ],
      "name": "Tingting Yu"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/10rcj9phk6trh.bib",
  "cited_by": 0,
  "doi": "10.3389/fonc.2026.1975159",
  "fulltext_url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13662009/?tool=EBI",
  "id": "10rcj9phk6trh",
  "issns": [
    "2234-943X"
  ],
  "landing_url": "https://europepmc.org/article/PMC/PMC13662009",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2730|Cancer Immunotherapy and Biomarkers"
    ]
  ],
  "openalex": "W7214938706",
  "pdf_url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13662009/pdf/?tool=EBI",
  "pmcid": "PMC13662009",
  "pmid": null,
  "published": "2026-09-30",
  "publisher": "Frontiers Media SA",
  "ris": "https://research.draconitic.com/paper/10rcj9phk6trh.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:20Z",
      "native_id": "PMC:PMC13662009",
      "source": "europepmc",
      "url": "https://europepmc.org/article/PMC/PMC13662009"
    },
    {
      "first_seen": "2026-10-30T12:20:13Z",
      "native_id": "10.3389/fonc.2026.1975159",
      "source": "crossref",
      "url": "https://www.frontiersin.org/articles/10.3389/fonc.2026.1975159/full"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2730|Cancer Immunotherapy and Biomarkers",
      "subfield": "oncology"
    }
  ],
  "title": "Loss of CLIC3 in CD8+ cytotoxic T lymphocytes is associated with immune dysfunction and poor prognosis in lung adenocarcinoma",
  "title_text": "Loss of CLIC3 in CD8+ cytotoxic T lymphocytes is associated with immune dysfunction and poor prognosis in lung adenocarcinoma",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:20:13Z",
  "url": "https://research.draconitic.com/paper/10rcj9phk6trh",
  "venue": "Frontiers in oncology",
  "versions": []
}