{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T06:56:08Z","timestamp":1790751368018,"version":"4.1.0"},"reference-count":25,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:00:00Z","timestamp":1790726400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      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\n                      <jats:sup>+<\/jats:sup>\n                      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                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We performed single-cell RNA sequencing on tumor tissues from nine LUAD patients spanning three pathological stages (adenocarcinoma\n                      <jats:italic>in situ<\/jats:italic>\n                      [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                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      CLIC3 was predominantly expressed in CTLs and showed a stage-associated decline from AIS to MIA to IAC. CLIC3\n                      <jats:sup>+<\/jats:sup>\n                      CTLs exhibited significantly higher module scores for cytotoxicity, cytoskeleton remodeling, interferon signaling, and chemotaxis compared to CLIC3- CTLs. Pseudotime trajectory analysis indicated that CLIC3\n                      <jats:sup>+<\/jats:sup>\n                      cells were positioned at one end of the inferred transcriptional continuum, corresponding to a functionally active state, while CLIC3\n                      <jats:sup>-<\/jats:sup>\n                      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\n                      <jats:sup>+<\/jats:sup>\n                      T cells with increasing tumor invasiveness and poor differentiation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      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\n                      <jats:sup>+<\/jats:sup>\n                      T cells may represent a predictive biomarker for immunotherapeutic response and a potential target for restoring T cell function in LUAD.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fonc.2026.1975159","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T06:05:37Z","timestamp":1790748337000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Loss of CLIC3 in CD8+ cytotoxic T lymphocytes is associated with immune dysfunction and poor prognosis in lung adenocarcinoma"],"prefix":"10.3389","volume":"16","author":[{"given":"Yinglong","family":"Li","sequence":"first","affiliation":[{"name":"Department of Pulmonary Medicine, Affiliated Cancer Hospital of Xinjiang Medical University","place":["Urumqi, Xinjiang, 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