Molecular Subtypes and Targeted Therapeutic Strategies in Small Cell Lung Cancer: Advances, Challenges, and Future Perspectives.

Small cell lung cancer (SCLC) is a highly aggressive malignancy characterized by rapid progression, early metastasis, and high recurrence rates. Historically considered a homogeneous disease, recent multi-omic studies have revealed distinct molecular subtypes driven by lineage-defining transcription factors, including ASCL1, NEUROD1, POU2F3, and YAP1, as well as an inflamed subtype (SCLC-I). These subtypes exhibit unique therapeutic vulnerabilities, thereby paving the way for precision medicine and targeted therapies. Despite recent advances in molecular classification, tumor heterogeneity, plasticity, and therapy resistance continue to hinder clinical success in treating SCLC patients. To this end, novel therapeutic strategies are being explored, including BCL2 inhibitors, DLL3-targeting agents, Aurora kinase inhibitors, PARP inhibitors, and epigenetic modulators. Additionally, immune checkpoint inhibitors (ICIs) show promise, particularly in immune-enriched subtypes of SCLC patients. Hence, a deeper understanding of SCLC subtype characteristics, evolution, and the regulatory mechanisms of subtype-specific transcription factors is crucial for rationally optimizing precision therapy. This knowledge not only facilitates the identification of subtype-specific therapeutic targets, but also provides a foundation for overcoming resistance and developing personalized combination treatment strategies. In the future, the integration of multi-omic data, dynamic molecular monitoring, and precision medicine approaches are expected to further advance the clinical translation of SCLC subtype-specific therapies, ultimately improving patient survival and outcomes.