{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T06:01:58Z","timestamp":1789970518959,"version":"4.0.1"},"reference-count":33,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T00:00:00Z","timestamp":1789948800000},"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. Cell Dev. Biol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Chemo-immunotherapy has improved clinical outcomes in non-small cell lung cancer (NSCLC), but resistance remains a major challenge. The tumor cell states and molecular mechanisms underlying treatment resistance are not fully understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Single-cell RNA sequencing data from NSCLC patients receiving chemo-immunotherapy were integrated with public transcriptomic cohorts and functional experiments. Resistance-associated tumor cell populations were identified, and key regulatory factors were investigated through bioinformatic analyses and experimental validation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Single-cell analysis identified a malignant epithelial cell subpopulation enriched in patients with stable disease, suggesting a resistance-associated tumor cell state. Genes derived from this population were associated with unfavorable prognosis and were used to construct a prognostic model with consistent performance across multiple independent cohorts. Among the candidate genes, CTCF was identified as a key regulator associated with poor survival and reduced immune infiltration. In an orthotopic lung tumor model, Ctcf knockdown enhanced the antitumor efficacy of pemetrexed combined with anti-PD-1 treatment and promoted CD8\n                      <jats:sup>+<\/jats:sup>\n                      T-cell activity. Mechanistically, CTCF directly upregulated RRM2 and CD276, which mediated chemotherapy resistance and immune suppression, respectively.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our findings identify CTCF as a critical regulator of chemo-immunotherapy resistance in NSCLC. The CTCF\u2013RRM2\/CD276 axis links tumor-intrinsic drug resistance with immune evasion and may represent a potential therapeutic target.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcell.2026.1922944","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T05:36:05Z","timestamp":1789968965000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrated single-cell and multi-cohort analyses reveal CTCF as a key regulator of chemo-immunotherapy resistance in lung adenocarcinoma"],"prefix":"10.3389","volume":"14","author":[{"given":"Hui","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Lung Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taiyang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Lung Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiwei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Tianjin Medical University","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Lung Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoran","family":"Yang","sequence":"additional","affiliation":[{"name":"Tianjin Medical University","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin\u2019s Clinical Research Center for Cancer","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Lung Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1453","DOI":"10.1200\/JCO-24-02239","article-title":"Neoadjuvant nivolumab plus ipilimumab Versus chemotherapy in resectable lung cancer","volume":"43","author":"Awad","year":"2025","journal-title":"J. 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