小细胞肺癌（SCLC）是一种侵袭性肺神经内分泌恶性肿瘤，其特点是肿瘤免疫微环境（TIME）冷、免疫治疗获益有限、生存率低。与抗肿瘤免疫显着相关的 TIME 空间异质性尚未在 SCLC 中进行系统研究。我们对来自 44 个未经治疗的局限期 SCLC 肿瘤的 132 个组织微阵列核心进行了超高复数数字空间分析。结合来自当地队列的单细胞 RNA 测序数据和已发表的 SCLC 数据，我们建立了一个空间蛋白质转录组景观，涵盖超过 18,000 个基因和 60 种关键免疫肿瘤学蛋白质，这些蛋白质参与影响肿瘤发生、免疫调节和癌症代谢的信号通路跨越 3 个病理学定义的空间区室（泛 CK 阳性肿瘤巢；CD45/CD3 阳性肿瘤基质；肿瘤旁）。我们的研究描述了 SCLC 的空间转录组和蛋白质组 TIME 结构，表明通过典型的神经内分泌亚型标记指示了清晰的肿瘤内异质性；揭示了肿瘤巢中先天免疫细胞和功能受损的 B 细胞的富集，并提出了单核细胞/巨噬细胞潜在的重要免疫调节作用。我们将 RE1 沉默因子 (REST) 确定为 SCLC 的潜在生物标志物，与低神经内分泌特征、更活跃的抗肿瘤免疫和延长生存期相关。© 2024。作者。

Small cell lung cancer (SCLC) is an aggressive pulmonary neuroendocrine malignancy featured by cold tumor immune microenvironment (TIME), limited benefit from immunotherapy, and poor survival. The spatial heterogeneity of TIME significantly associated with anti-tumor immunity has not been systemically studied in SCLC. We performed ultra-high-plex Digital Spatial Profiling on 132 tissue microarray cores from 44 treatment-naive limited-stage SCLC tumors. Incorporating single-cell RNA-sequencing data from a local cohort and published SCLC data, we established a spatial proteo-transcriptomic landscape covering over 18,000 genes and 60 key immuno-oncology proteins that participate in signaling pathways affecting tumorigenesis, immune regulation, and cancer metabolism across 3 pathologically defined spatial compartments (pan-CK-positive tumor nest; CD45/CD3-positive tumor stroma; para-tumor). Our study depicted the spatial transcriptomic and proteomic TIME architecture of SCLC, indicating clear intra-tumor heterogeneity dictated via canonical neuroendocrine subtyping markers; revealed the enrichment of innate immune cells and functionally impaired B cells in tumor nest and suggested potentially important immunoregulatory roles of monocytes/macrophages. We identified RE1 silencing factor (REST) as a potential biomarker for SCLC associated with low neuroendocrine features, more active anti-tumor immunity, and prolonged survival.© 2024. The Author(s).