Small Cell Lung Cancer Classification: Unraveling Heterogeneity to Enable Personalized Treatments

Abstract Small cell lung cancer (SCLC) is an aggressive thoracic disease characterized by rapid proliferation and early metastatic spread. The survival outcomes for SCLC patients remain notoriously poor, underlining that only modest improvements have been achieved in clinical settings to date. However, insights gained from human tumors and preclinical models in recent years have shed light on the heterogeneous molecular profile of SCLC. Numerous research groups have, therefore, begun to stratify SCLC into subgroups based on differential transcription factor expression, the tumor immune microenvironment, and other criteria. Since SCLC subtypes show major differences in their molecular landscape and biological behavior, they may offer unique therapeutic vulnerabilities and serve as a framework for future personalized clinical trials. Here, we summarize impactful classification attempts from the last ten years, highlighting discrepancies and connections between the nomenclature of each study, and expound upon relevant factors of SCLC biology influencing subtype composition and plasticity. This review delves into the implications of subgrouping for understanding and treating SCLC as well as potential future directions for SCLC research.