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However, biomarkers and targets that reflect tumor evolution during CSCC progression at different time points within the same patient remain lacking. We integrated single-cell RNA sequencing with spatial transcriptomics from a series of human cervix uteri tissues spanning the cascade of cervical premalignant lesions and malignant progression obtained from the same patients. We found that fibroblasts and endothelial cells decreased, whereas immune cells (mainly T cells and B cells) increased during CSCC development. Moreover, the immune response-related GNLY-fibroblasts and GNLY-endothelial cells were significantly enriched during the PCT of CSCC. Additionally, a panel of gene signatures (CLDN1, ISG15, PTGDS) with clinical significance for the precise diagnosis and personalized treatment strategies of PCT was identified. This gene panel may serve as an auxiliary diagnostic indicator in cervical biopsy specimens and help identify lesions associated with malignant progression. CLDN1 and ISG15 promote CSCC progression, whereas PTGDS suppresses it. Moreover, ISG15, synthesized by inflammatory cancer-associated fibroblasts (CAFs), enhances the stability of FGF1, thereby activating the FGF1\/FGFR1\/PI3K\/AKT\/mTOR signaling pathway. FGFR1 and PI3K\/AKT\/mTOR inhibitors were found to suppress CSCC cell proliferation in vitro and tumor growth in vivo. High ISG15 and CLDN1 expression correlated with poor survival in cervical cancer tissue microarrays and with reduced immunotherapy response in exploratory public datasets, pending validation in CSCC cohorts. Our study defines the ecosystem of PCT from cell subpopulations, the communicating gene networks, and key signal transductions involved in PCT of CSCC. These findings offer new insights into the spatiotemporal evolution of the human cervix in premalignant and malignant lesions, paving the way for improved CSCC diagnosis and therapy.<\/jats:p>","DOI":"10.1038\/s41419-026-08960-2","type":"journal-article","created":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T05:24:50Z","timestamp":1780982690000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Integrated multi-omics profiling of treatment-naive cervix uteri premalignant lesions and cervical squamous cell carcinoma reveals ecosystem and drivers underlying cervical cancer progression"],"prefix":"10.1038","volume":"17","author":[{"given":"Yubing","family":"Zhou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanlin","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunxiao","family":"Ge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinxin","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hangrui","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanying","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3308-2447","authenticated-orcid":false,"given":"Chenchen","family":"Ren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianxu","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yamei","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4425-5625","authenticated-orcid":false,"given":"Kangdong","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-8474-0494","authenticated-orcid":false,"given":"Hui","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4174-4028","authenticated-orcid":false,"given":"Zigang","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,9]]},"reference":[{"key":"8960_CR1","doi-asserted-by":"publisher","first-page":"5377","DOI":"10.1158\/0008-5472.CAN-21-1862","volume":"81","author":"H Liu","year":"2021","unstructured":"Liu H, Dong Z. 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All protocols followed in this study were approved by the Committee on the Ethics of Animal Experiments of China-US (Henan) Hormel Cancer Institute, Zhengzhou, China, in compliance with the National Research Council\u2019s Guide for the Care and Use of Laboratory Animals. The use of human tissue samples in this study was approved by the ethics committee of Zhengzhou University (No. 20150305). Informed consent was obtained from all participants prior to sample collection.","order":2,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Ethics"}}],"article-number":"722"}}