Platinum-based chemotherapy plus PD-1 axis blockade is the standard of care in the front-line treatment of extensive-stage small cell lung cancer (ES-SCLC). Despite the robust and consistent increase of long-term survival with PD-1 axis inhibition, the magnitude of the benefit from immunotherapy appears lower as compared to other solid tumors. Several immune evasive mechanisms have been shown to be prominently altered in human SCLC, including, among others, T cell exclusion, downregulation of components of the MHC-class I antigen processing and presentation machinery, or upregulation of macrophage inhibitory checkpoints. New immunotherapies aiming to target some of these dominant immune suppressive features are being intensively evaluated preclinically and clinically in SCLC. They include strategies to enhance the efficacy and/or reverse features that promote intrinsic resistance to PD-1 axis inhibition (e.g., restoring MHC-class I deficiency, targeting DNA damage response [DDR]), and novel immunomodulatory agents beyond T cell checkpoint blockers (e.g., T cell redirecting strategies, antibody drug conjugates [ADCs], or macrophage checkpoint blockers). Among them, DLL3-targeted bi-specific T-cell engagers (BiTEs) are the ones that have shown the most compelling preliminary evidence of clinical efficacy, and hold promise as therapies that might contribute to further improve patient outcomes in this disease. Here, we first provide a brief overview of key tumor microenvironment features of human SCLC. Then, we update the current clinical evidence with immune checkpoint blockade and review other emerging immunotherapy strategies that are gaining increasing attention in SCLC. We finally summarize our future perspective on immunotherapy and precision oncology for this disease.

中文翻译：

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小细胞肺癌癌症免疫治疗的事实和希望

铂类化疗加 PD-1 轴阻断是广泛期小细胞肺癌 (ES-SCLC) 一线治疗的标准治疗方法。尽管 PD-1 轴抑制可显着且持续地提高长期生存率，但与其他实体瘤相比，免疫疗法的获益程度似乎较低。一些免疫逃避机制已被证明在人类 SCLC 中显着改变，其中包括 T 细胞排斥、MHC I 类抗原加工和呈递机制成分的下调，或巨噬细胞抑制检查点的上调。针对这些主要免疫抑制特征的新免疫疗法正在 SCLC 的临床前和临床上进行深入评估。它们包括增强功效和/或逆转促进对 PD-1 轴抑制的内在抵抗的特征的策略（例如，恢复 MHC I 类缺陷、靶向 DNA 损伤反应 [DDR]），以及 T 细胞检查点阻断剂之外的新型免疫调节剂（例如，T 细胞重定向策略、抗体药物偶联物 [ADC] 或巨噬细胞检查点阻断剂）。其中，针对 DLL3 的双特异性 T 细胞接合剂 (BiTE) 已显示出最令人信服的临床疗效初步证据，并有望成为可能有助于进一步改善该疾病患者预后的疗法。在这里，我们首先简要概述人类 SCLC 的关键肿瘤微环境特征。然后，我们更新了免疫检查点阻断的当前临床证据，并回顾了在 SCLC 中日益受到关注的其他新兴免疫治疗策略。我们最后总结了我们对该疾病的免疫治疗和精准肿瘤学的未来展望。