Histological transformation in lung cancer: Mechanisms, clinical characteristics, and therapeutic approaches

Lung cancer, the leading cause of cancer-related mortality globally, exhibits remarkable histological plasticity, with non-small cell lung cancer (NSCLC) frequently transforming into small cell lung cancer (SCLC) as a resistance mechanism to targeted therapies and immunotherapies. The molecular mechanisms and treatments for SCLC transformation remain unclear. This review analyzes the mechanisms, molecular features, and treatment landscape of histological transformation, particularly in EGFR-mutant NSCLC. Key findings include: (1) RB1 and TP53 co-inactivation is a hallmark of transformed SCLC, enabling lineage plasticity via epigenetic and neuroendocrine changes; (2) the tumor immune microenvironment becomes immunosuppressive during transformation; and (3) new therapies targeting DLL3 and AURKA show promise in early trials. This study offers a comprehensive framework to understand histological transformation in lung cancer. It underscores the importance of routine re-biopsies for early detection and supports the development of biomarker-guided therapies. Future research should validate predictive biomarkers and optimizing combination therapies for transformed SCLC.