小细胞肺癌（SCLC）传统上被认为是一种预后不佳的顽固性癌症，在过去的几十年里，治疗策略仅取得了有限的进展。 SCLC 的全面基因组评估表明，大多数肿瘤都存在肿瘤抑制基因 TP53 和 RB1 的缺失，但与非小细胞肺癌相比，未能识别出可靶向的改变。在 SCLC 发病机制中起关键作用的四种转录因子的表达状态定义了该疾病的不同分子亚型，有可能实现特定的治疗方法。 MYC 旁系同源物的过度表达和扩增也会影响 SCLC 的生物学和治疗脆弱性。过去几年中出现了其他几个有吸引力的靶点，包括 DNA 损伤反应途径的抑制剂、表观遗传修饰剂、抗体药物偶联物和嵌合抗原受体 T 细胞。然而，治疗耐药性的快速发展和缺乏有效选择 SCLC 患者的生物标志物是持续的挑战。新出现的单细胞 RNA 测序数据为了解 SCLC 的可塑性以及肿瘤内和肿瘤间异质性提供了见解，这些异质性可能与治疗耐药性相关。在这篇综述中，我们全面概述了 SCLC 基因组和转录组学特征的最新进展，特别关注转化为新治疗方法以改善患者预后的机会。© 2024。Springer Nature Limited。

Small-cell lung cancer (SCLC) has traditionally been considered a recalcitrant cancer with a dismal prognosis, with only modest advances in therapeutic strategies over the past several decades. Comprehensive genomic assessments of SCLC have revealed that most of these tumours harbour deletions of the tumour-suppressor genes TP53 and RB1 but, in contrast to non-small-cell lung cancer, have failed to identify targetable alterations. The expression status of four transcription factors with key roles in SCLC pathogenesis defines distinct molecular subtypes of the disease, potentially enabling specific therapeutic approaches. Overexpression and amplification of MYC paralogues also affect the biology and therapeutic vulnerabilities of SCLC. Several other attractive targets have emerged in the past few years, including inhibitors of DNA-damage-response pathways, epigenetic modifiers, antibody-drug conjugates and chimeric antigen receptor T cells. However, the rapid development of therapeutic resistance and lack of biomarkers for effective selection of patients with SCLC are ongoing challenges. Emerging single-cell RNA sequencing data are providing insights into the plasticity and intratumoural and intertumoural heterogeneity of SCLC that might be associated with therapeutic resistance. In this Review, we provide a comprehensive overview of the latest advances in genomic and transcriptomic characterization of SCLC with a particular focus on opportunities for translation into new therapeutic approaches to improve patient outcomes.© 2024. Springer Nature Limited.