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

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.

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.

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.