The Five-Decade Journey of Small Cell Lung Cancer

Over the past 5 decades, small cell lung cancer (SCLC) has persisted as one of the most formidable malignancies, largely attributed to its aggressive early metastasis, limited therapeutic arsenal in both first-line and subsequent treatments, and rapid onset of treatment resistance. The dawn of a new era in the treatment of SCLC appeared in 2018, with the introduction of first-line chemotherapy combined with immune checkpoint inhibitors, as well as tarlatamab for later-line treatment. However, the improvements in survival, although tangible, were still unsatisfactory. Therefore, this review focuses on unraveling the mechanisms underlying cancer initiation, progression, and particularly metastasis, as well as emerging advances in molecular subtyping and drug resistance from the epigenetic perspective. Simultaneously, we outline their hallmark characteristics—high plasticity, heterogeneity, redundancy, and ambiguity driven by intercellular crosstalk under spatiotemporal dependency. Furthermore, we highlight the evolving progress of various successful drugs or therapeutic strategies and molecular biomarkers in clinical practice for SCLC, as well as promising agents under investigation. Finally, we also discuss how to leverage artificial intelligence and innovative biomedical technologies, as well as learn from various challenges in order to improve the therapeutic landscape of SCLC.