{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T12:58:56Z","timestamp":1781614736650,"version":"3.54.5"},"reference-count":10,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T00:00:00Z","timestamp":1761609600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T00:00:00Z","timestamp":1761609600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100017700","name":"Henan Provincial Science and Technology Research Project","doi-asserted-by":"publisher","award":["Grant No. 182102311141"],"award-info":[{"award-number":["Grant No. 182102311141"]}],"id":[{"id":"10.13039\/501100017700","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Transl Med"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Lung squamous cell carcinoma (LUSC) is a major challenge in oncology due to its high recurrence rate, highlighting the need to identify recurrence drivers. Based on the data provided by Zhang Zemin\u2019s team in their research, we selected survival metadata from 119 patients with lung squamous cell carcinoma and data on the proportions of 51 immune cell types. We then combined machine learning methods to analyze the intrinsic tumor factors and tumor microenvironment (TME) in the recurrence of lung squamous cell carcinoma (LUSC). Chi-square tests identified immune cell subsets enriched in recurrent patients, such as high-MKI67 Tregs, low-FGFBP2 NK cells, low-FOXP3 Tregs, and low-KLRB1 CD8\u2009+\u2009T cells. A random forest algorithm further pinpointed pathological response rate (PRR) as the primary predictive factor, with high-MKI67 Tregs as a key secondary contributor. Univariate and multivariate Cox regression analyses and Kaplan-Meier survival curves confirmed that pathological complete response (pCR) and low Treg_MKI67 expression were associated with better survival (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.0055 and\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.011, respectively). Patients achieving pCR and with low Treg_MKI67 expression had superior recurrence-free survival (RFS; 2-year RFS: 96.7% vs. 57.9% for non-pCR and high Treg_MKI67,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.00066). These findings underscore the prognostic value of PRR and TME markers. They also highlight the potential of using single-cell RNA sequencing and machine learning to guide personalized therapies and reduce recurrence risk by targeting Treg activity, laying the groundwork for integrating immune markers into clinical practice to improve LUSC prognosis.\n                  <\/jats:p>","DOI":"10.1186\/s12967-025-07193-9","type":"journal-article","created":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T13:28:28Z","timestamp":1761658108000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Which dominates recurrence: tumor or microenvironment?"],"prefix":"10.1186","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-7650-1040","authenticated-orcid":false,"given":"Guoqing","family":"Lyu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Deng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Man","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lihua","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sun","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanting","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenting","family":"Lv","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jincheng","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,28]]},"reference":[{"key":"7193_CR1","first-page":"229","volume":"74","author":"F Bray","year":"2024","unstructured":"Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: a cancer. J Clin. 2024;74:229\u201363.","journal-title":"J Clin"},{"key":"7193_CR2","doi-asserted-by":"publisher","first-page":"3081","DOI":"10.1016\/j.cell.2025.03.018","volume":"188","author":"Z Liu","year":"2025","unstructured":"Liu Z, Yang Z, Wu J, Zhang W, Sun Y, Zhang C, et al. A single-cell atlas reveals immune heterogeneity in anti-PD-1-treated non-small cell lung cancer. Cell. 2025;188:3081\u2013e309619.","journal-title":"Cell"},{"key":"7193_CR3","doi-asserted-by":"publisher","first-page":"218","DOI":"10.1038\/s41591-023-02660-6","volume":"30","author":"JS Deutsch","year":"2024","unstructured":"Deutsch JS, Cimino-Mathews A, Thompson E, Provencio M, Forde PM, Spicer J, et al. Association between pathologic response and survival after neoadjuvant therapy in lung cancer. Nat Med. 2024;30:218\u201328.","journal-title":"Nat Med"},{"key":"7193_CR4","first-page":"100420","volume":"3","author":"A Pataer","year":"2022","unstructured":"Pataer A, Weissferdt A, Correa AM, Vaporciyan AA, Sepesi B, Heymach JV, et al. Major pathologic response and prognostic score predict survival in patients with lung cancer receiving neoadjuvant chemotherapy. JTO Clin Res Rep. 2022;3:100420.","journal-title":"JTO Clin Res Rep"},{"key":"7193_CR5","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1080\/07357907.2019.1582848","volume":"37","author":"N Asai","year":"2019","unstructured":"Asai N, Kubo A, Suzuki S, Murotani K, Numanami H, Yoshikawa K, et al. CCR4 expression in Tumor-Infiltrating regulatory T cells in patients with squamous cell carcinoma of the lung: a prognostic factor for relapse and survival. Cancer Invest. 2019;37:163\u201373.","journal-title":"Cancer Invest"},{"key":"7193_CR6","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1007\/s00262-024-03762-x","volume":"73","author":"S Cai","year":"2024","unstructured":"Cai S, Yang G, Hu M, Li C, Yang L, Zhang W, et al. Spatial cell interplay networks of regulatory T cells predict recurrence in patients with operable non-small cell lung cancer. Cancer Immunol Immunother. 2024;73:189.","journal-title":"Cancer Immunol Immunother"},{"key":"7193_CR7","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1186\/s12967-022-03723-x","volume":"20","author":"J Pang","year":"2022","unstructured":"Pang J, Yu Q, Chen Y, Yuan H, Sheng M, Tang W. Integrating Single-cell RNA-seq to construct a neutrophil prognostic model for predicting immune responses in non-small cell lung cancer. J Translational Med. 2022;20:531.","journal-title":"J Translational Med"},{"key":"7193_CR8","doi-asserted-by":"publisher","first-page":"330","DOI":"10.1186\/s12967-025-06301-z","volume":"23","author":"C Ouyang","year":"2025","unstructured":"Ouyang C, Yu X, Wang H, Zeng P. Multidimensional bioinformatics perspective on smoking-linked driver genes and immune regulatory mechanisms in non-small cell lung cancer. J Translational Med. 2025;23:330.","journal-title":"J Translational Med"},{"key":"7193_CR9","doi-asserted-by":"publisher","first-page":"516","DOI":"10.1186\/s12967-022-03736-6","volume":"20","author":"Z Zhang","year":"2022","unstructured":"Zhang Z, Wiencke JK, Kelsey KT, Koestler DC, Christensen BC, Salas LA. HiTIMED: hierarchical tumor immune microenvironment epigenetic Deconvolution for accurate cell type resolution in the tumor microenvironment using tumor-type-specific DNA methylation data. 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Nat Rev Clin Oncol. 2025;22:592\u2013616.","journal-title":"Nat Rev Clin Oncol"}],"container-title":["Journal of Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12967-025-07193-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12967-025-07193-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12967-025-07193-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T12:31:23Z","timestamp":1781613083000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s12967-025-07193-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,28]]},"references-count":10,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["7193"],"URL":"https:\/\/doi.org\/10.1186\/s12967-025-07193-9","relation":{},"ISSN":["1479-5876"],"issn-type":[{"value":"1479-5876","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,28]]},"assertion":[{"value":"12 July 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 September 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 October 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The data utilized in this study were obtained from publicly available datasets provided by the Zemin Zhang team. As these data were fully anonymized and did not involve direct interaction with human subjects, no ethical approval or informed consent was required.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"All authors have consented to the publication of the manuscript.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to publish"}},{"value":"The authors declare no conflicts of interest.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}],"article-number":"1181"}}