Targeted Therapy–Induced Interstitial Lung Disease in NSCLC: Mechanisms, Clinical Signatures, and a Precision Medicine Roadmap

Jia-feng Wang,1,* Lei-lei Jiang,2,* Meng-chuan Wang,3 Yang-ling Li1 1Department of Clinical Pharmacy, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People’s Hospital, School of Medicine, Westlake University, Hangzhou, Zhejiang, People’s Republic of China; 2The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui, People’s Republic of China; 3Affiliated Cixi Hospital, Wenzhou Medical University, Ningbo, Zhejiang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yang-ling Li, Department of Clinical Pharmacy, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People’s Hospital, School of Medicine, Westlake University, Hangzhou, Zhejiang, People’s Republic of China, Email [email protected] Meng-chuan Wang, Affiliated Cixi Hospital, Wenzhou Medical University, Ningbo, Zhejiang, People’s Republic of China, Email [email protected]: Molecularly targeted therapies have transformed the therapeutic landscape of non–small cell lung cancer (NSCLC), establishing precision oncology as the foundation of modern disease management. However, these advances are increasingly complicated by drug-induced interstitial lung disease (DILD), a potentially life-threatening adverse event that can disrupt treatment continuity and compromise clinical benefit. In this review, we provide a comprehensive evaluation of interstitial lung disease associated with targeted agents in NSCLC, including oncogene-directed tyrosine kinase inhibitors, antibody–drug conjugates (ADCs), and angiogenesis inhibitors. We summarize reported differences in ILD incidence, onset timing, clinical manifestations, and radiographic characteristics across targeted agents, with particular emphasis on high-risk populations and the elevated ILD incidence observed with deruxtecan-based ADCs. We further summarize current mechanistic evidence suggesting that DILD may arise from multiple overlapping processes, including immune-mediated inflammatory activation, direct epithelial cytotoxicity, off-target kinase inhibition, and payload-dependent bystander injury. Finally, we discuss current challenges and future directions for improving pulmonary safety, including real-world datasets, multi-omics approaches, and emerging AI-assisted tools for earlier detection and risk stratification. Importantly, the current evidence base remains limited by the predominance of retrospective studies, case reports, and incomplete mechanistic validation. These insights may help guide safer and more sustained implementation of targeted therapies in NSCLC.Keywords: non-small cell lung cancer, targeted therapy, interstitial lung disease, precision oncology, antibody–drug conjugates