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CAFs have also been shown to promote resistance in lung cancer cells to epidermal growth factor receptor\u2010tyrosine kinase inhibitors (EGFR\u2010TKIs). However, the specific CAF subsets responsible for driving tumor advancement and resistance to EGFR\u2010TKIs in lung adenocarcinoma (LUAD) remain poorly understood.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We integrate multiple scRNA\u2010seq datasets to identify cell subclusters most relevant to tumor stage, patient survival, and EGFR\u2013TKIs response. Additionally, in vitro and in vivo experiments, clinical tissue sample immunohistochemistry and patient plasma ELISA experiments are performed to validate key findings in independent LUAD cohorts.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>By analyzing multiple scRNA\u2010seq and spatial transcriptomic datasets, we identified a unique subset of CXCL14+ myofibroblastic CAFs (myCAFs), emerging during the early differentiation phase of pan\u2010cancer invasiveness\u2010associated THBS2\u207a POSTN\u207a COL11A1\u207a myCAFs. Notably, plasma levels of CXCL14 in LUAD patients correlate significantly with tumor stage. Mechanistically, this subset enhances tumor aggressiveness through epithelial\u2010to\u2010mesenchymal transition and angiogenesis. Among standard treatment regimens, transitional CXCL14+ myCAFs specifically confer resistance to EGFR\u2010TKIs, while showing no significant impact on chemotherapy or immunotherapy outcomes. Through a pharmacological screen of FDA\u2010approved drugs, we identified Filgotinib as an effective agent to counteract the EGFR\u2010TKIs resistance conferred by this CAF subset.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>In summary, our study highlights the role of the differentiated stage from transitional CXCL14+ myCAFs to invasiveness\u2010associated myCAFs in driving tumor progression and therapy resistance in LUAD, positioning Filgotinib as a promising targeted therapy for this process. These insights may enhance patient stratification and inform precision treatment strategies in LUAD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Single\u2010cell analysis identifies transitional CXCL14<jats:sup>+<\/jats:sup> myofibroblastic cancer\u2010associated fibroblasts (myCAFs) predominantly exist in the advanced\u2010stage lung adenocarcinoma (LUAD).<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Transitional CXCL14<jats:sup>+<\/jats:sup> myCAFs fuel metastasis by promoting epithelial\u2013mesenchymal transition (EMT) and angiogenesis on the spatial level.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>CXCL14 is a potential diagnostic marker for LUAD patients and predict the occurrence of metastasis.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Transitional CXCL14<jats:sup>+<\/jats:sup> myCAFs induce the resistance to epidermal growth factor receptor\u2010tyrosine kinase inhibitors (EGFR\u2010TKIs) and JAK1 inhibitor, filgotinib could reverse the effect.<\/jats:p><\/jats:list-item><\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1002\/ctm2.70281","type":"journal-article","created":{"date-parts":[[2025,4,1]],"date-time":"2025-04-01T11:03:47Z","timestamp":1743505427000},"source":"Crossref","is-referenced-by-count":19,"title":["Transitional CXCL14<sup>+<\/sup> cancer\u2010associated fibroblasts enhance tumour metastasis and confer resistance to EGFR\u2010TKIs, revealing therapeutic vulnerability to filgotinib in lung adenocarcinoma"],"prefix":"10.1002","volume":"15","author":[{"given":"Weijiao","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Thoracic Surgery Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haitang","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anshun","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, First Affiliated Hospital of Wenzhou Medical University Wenzhou Medical University  Wenzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean R. 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