Small cell lung cancer (SCLC) is a rapidly growing, highly metastatic, and relatively immune-cold lung cancer subtype. Historically viewed in the laboratory and clinic as a single disease, new discoveries suggest that SCLC comprises multiple molecular subsets. Expression of MYC family members and lineage-related transcription factors ASCL1, NEUROD1, and POU2F3 (and, in some studies, YAP1) define unique molecular states that have been associated with distinct responses to a variety of therapies. However, SCLC tumors exhibit a high degree of intratumoral heterogeneity, with recent studies suggesting the existence of tumor cell plasticity and phenotypic switching between subtype states. While SCLC plasticity is correlated with, and likely drives, therapeutic resistance, the mechanisms underlying this plasticity are still largely unknown. Subtype states are also associated with immune-related gene expression, which likely impacts response to immune checkpoint blockade and may reveal novel targets for alternative immunotherapeutic approaches. In this review, we synthesize recent discoveries on the mechanisms of SCLC plasticity and how these processes may impinge on antitumor immunity.

中文翻译：

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杀死 SCLC：深入了解如何靶向变形肿瘤


小细胞肺癌（SCLC）是一种生长迅速、转移性高、相对免疫冷的肺癌亚型。历史上实验室和临床将 SCLC 视为单一疾病，但新发现表明 SCLC 包含多个分子亚型。 MYC 家族成员和谱系相关转录因子 ASCL1、NEUROD1 和 POU2F3（以及某些研究中的 YAP1）的表达定义了独特的分子状态，这些状态与对各种疗法的不同反应相关。然而，SCLC 肿瘤表现出高度的瘤内异质性，最近的研究表明肿瘤细胞可塑性和亚型状态之间的表型转换存在。虽然 SCLC 可塑性与治疗耐药性相关，并且可能驱动治疗耐药性，但这种可塑性背后的机制仍然很大程度上未知。亚型状态还与免疫相关基因表达相关，这可能会影响对免疫检查点封锁的反应，并可能揭示替代免疫治疗方法的新靶点。在这篇综述中，我们综合了有关 SCLC 可塑性机制以及这些过程如何影响抗肿瘤免疫的最新发现。