{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T01:25:07Z","timestamp":1788830707748,"version":"build-2803163510"},"reference-count":116,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T00:00:00Z","timestamp":1784678400000},"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>Lung cancer remains the leading cause of cancer-related mortality worldwide, and therapeutic outcomes are frequently compromised by drug resistance and the complex tumor microenvironment. Although malignant progression is fundamentally driven by genetic alterations, cancer-associated fibroblasts (CAFs) have emerged as critical regulators of tumor progression, immune evasion, and therapeutic resistance.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Main body<\/jats:title>\n                    <jats:p>This review systematically summarizes the multidimensional roles of CAFs in lung cancer pathogenesis. CAFs remodel the extracellular matrix to generate high-stiffness stromal barriers, thereby activating the Integrin\/Focal adhesion kinase (FAK)\/Yes-associated protein (YAP) mechanotransduction axis and impairing drug delivery. Through a multifaceted secretome that includes Interleukin-6 (IL-6), Transforming growth factor-beta (TGF-\u03b2), Hepatocyte growth factor (HGF), and C-X-C motif chemokine ligand 12 (CXCL12), CAFs promote epithelial\u2013mesenchymal transition and non-cell-autonomous resistance. Recent single-cell and spatial transcriptomic studies have further revealed functionally distinct CAF subpopulations associated with matrix remodeling, immune exclusion, and therapeutic response. In addition, CAF-derived small extracellular vesicles (sEVs) mediate bidirectional communication with tumor and immune cells, reinforcing tumor plasticity and immune evasion. CAFs also contribute to T-cell exclusion and suppressive myeloid-cell recruitment, thereby attenuating the efficacy of immune checkpoint blockade. Finally, we critically evaluate emerging therapeutic strategies targeting CAF-mediated pathways and discuss their translational opportunities and limitations.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Overcoming CAF-mediated resistance requires a shift from non-selective stromal depletion toward biomarker-guided stromal normalization and subtype-specific interventions. By integrating mechanistic and translational evidence, this review provides a comprehensive framework for developing more effective precision therapies in lung cancer.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fonc.2026.1866753","type":"journal-article","created":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T11:37:22Z","timestamp":1784720242000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Cancer-associated fibroblasts in the lung cancer microenvironment from multi-dimensional mechanisms to therapeutic strategies"],"prefix":"10.3389","volume":"16","author":[{"given":"Yikun","family":"Feng","sequence":"first","affiliation":[{"name":"First Teaching Hospital of Tianjin University of Traditional Chinese Medicine","place":["Tianjin, China"]},{"name":"National Clinical Research Center for Chinese Medicine","place":["Tianjin, 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