Reprogrammed Fibrotic Niche Fuels Lung Cancer Initiation and Reciprocal Remodeling

Pulmonary Fibrosis (PF), an end-stage manifestation of interstitial lung diseases, is associated with largely unfavorable prognoses. Lung cancer (LC), a leading cause of nationally cancer-related mortality with progressively increasing incidence, exhibits pathological interconnections with PF. The chronic remodeling of the pulmonary microenvironment-including cellular components, extracellular matrix (ECM), inflammatory cytokine networks, and metabolic reprogramming-represents the core pathogenic mechanism underlying PF-LC comorbidity. This review systematically elaborates how the fibrotic microenvironment promotes malignant transformation of lung cancer via chronic inflammation, increased matrix stiffness, immunosuppressive regulation, and epigenetic modulation. Furthermore, we investigate the bidirectional crosstalk by which LC progression reciprocally modulates fibrotic processes. Finally, we integrate current clinical challenges and propose novel therapeutic strategies targeting the fibrotic microenvironment to address this lethal pathophysiological synergy.