Molecular heterogeneity of small cell lung cancer and new therapeutic possibilities: a narrative review of the literature

Background and Objective: Small cell lung cancer (SCLC) is an aggressive disease commonly occurring in individuals with a history of heavy smoking. Despite recent approvals of chemotherapy and immunotherapy in the first-line treatment of extensive-stage SCLC, it maintains a poor prognosis. Moreover, only a small percentage of patients benefits from the addition of immunotherapy to platinumbased chemotherapy. The lack of significant progress in therapeutic options unrevealed the urgent need for a deeper understanding of tumor biology and easy-to-use predictive biomarkers, aiming to better tailor the treatment strategy. The aim of this review is to summarize recent evidence about the biology, molecular heterogeneity, as well as tumor microenvironment (TME) of SCLC and their forefront therapeutic implications. Methods: A literature search was conducted using PubMed, focusing on articles published in English from 1981 to October 2024. Studies on SCLC biology and subclassification were selected for further analysis and integrated in the current narrative review. Key Content and Findings: SCLC entity implies four distinct molecular subtypes based on transcription factors expression, specifically achaete-scute homolog 1 (ASCL1), neurogenic differentiation 1 (NEUROD1), POU class 2 homeobox 3 (POU2F3), and yes-associated protein 1 (YAP1), reflecting the tumor heterogeneity in terms of gene expression, transcriptional profiles, immune infiltration, and treatment sensitivity. Recently, a new subgroup, "SCLC-I", has been proposed to replace the YAP1 subtype, showing higher responsiveness to immunotherapy. The TME, implying immune cell infiltration and their interactions with cancer cells, plays a crucial role in determining SCLC's sensitivity to immunotherapy. Conclusions: Advances in SCLC molecular characterization and the development of targeted therapies against specific molecular pathways might improve patients' clinical outcome, supporting a more personalized approach to this complex disease.