Small cell lung cancer (SCLC) is a particular subtype of lung cancer with high mortality. Recent advances in understanding SCLC genomics and breakthroughs of immunotherapy have substantially expanded existing knowledge and treatment modalities. However, challenges associated with SCLC remain enigmatic and elusive. Most of the conventional drug discovery approaches targeting altered signaling pathways in SCLC end up in the ‘grave-yard of drug discovery’, which mandates exploring novel approaches beyond inhibiting cell signaling pathways. Epigenetic modifications have long been documented as the key contributors to the tumorigenesis of almost all types of cancer, including SCLC. The last decade witnessed an exponential increase in our understanding of epigenetic modifications for SCLC. The present review highlights the central role of epigenetic regulations in acquiring neoplastic phenotype, metastasis, aggressiveness, resistance to chemotherapy, and immunotherapeutic approaches of SCLC. Different types of epigenetic modifications (DNA/histone methylation or acetylation) that can serve as predictive biomarkers for prognostication, treatment stratification, neuroendocrine lineage determination, and development of potential SCLC therapies are also discussed. We also review the utility of epigenetic targets/epidrugs in combination with first-line chemotherapy and immunotherapy that are currently under investigation in preclinical and clinical studies. Altogether, the information presents the inclusive landscape of SCLC epigenetics and epidrugs that will help to improve SCLC outcomes.

小细胞肺癌（SCLC）是肺癌的一种特殊亚型，死亡率很高。了解 SCLC 基因组学的最新进展和免疫疗法的突破极大地扩展了现有的知识和治疗方式。然而，与 SCLC 相关的挑战仍然神秘且难以捉摸。大多数针对 SCLC 信号通路改变的传统药物发现方法最终都进入了“药物发现的坟墓”，这要求探索除抑制细胞信号通路之外的新方法。长期以来，表观遗传修饰被证明是几乎所有类型癌症（包括 SCLC）肿瘤发生的关键因素。过去十年，我们对 SCLC 表观遗传修饰的理解呈指数级增长。本综述强调了表观遗传调控在小细胞肺癌的肿瘤表型、转移、侵袭性、化疗耐药性和免疫治疗方法中的核心作用。还讨论了不同类型的表观遗传修饰（DNA/组蛋白甲基化或乙酰化），它们可以作为预测、治疗分层、神经内分泌谱系确定和潜在 SCLC 疗法开发的预测生物标志物。我们还回顾了表观遗传靶点/表观药物与目前正在临床前和临床研究中正在研究的一线化疗和免疫疗法相结合的效用。总而言之，这些信息展示了 SCLC 表观遗传学和表外药物的包容性景观，这将有助于改善 SCLC 的结果。