Cancer-associated fibroblasts in the lung cancer microenvironment from multi-dimensional mechanisms to therapeutic strategies.

BACKGROUND: 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. MAIN BODY: 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-β), Hepatocyte growth factor (HGF), and C-X-C motif chemokine ligand 12 (CXCL12), CAFs promote epithelial-mesenchymal 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. CONCLUSIONS: 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.