Cancer-associated fibroblasts in non-small cell lung cancer therapy: Challenges and opportunities

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related morbidity and mortality despite therapeutic advances. Current treatments offer limited benefit to many patients, a limitation closely linked to distinctive features of the tumor microenvironment (TME). As key components of the TME, cancer-associated fibroblasts (CAFs) promote a desmoplastic response, remodel the extracellular matrix, secrete cytokines, and directly shape tumor cell behavior. Consequently, therapeutic strategies targeting CAFs have attracted growing attention. However, due to substantial heterogeneity in CAF origin, definition, and function, combined with high plasticity, few therapeutic approaches targeting CAFs have proven effective; indeed, some interventions have paradoxically accelerated disease progression. This review examines CAF subsets in NSCLC and elucidates how CAFs influence the therapeutic efficacy of chemotherapy, radiotherapy, immunotherapy, and targeted therapy. Finally, we synthesize the translational progress of CAF-targeted strategies in NSCLC, emphasizing current limitations and future opportunities.