小细胞肺癌（SCLC）是一种高度恶性和异质性的癌症，治疗选择和预后预测模型有限。在这里，我们通过蛋白质组学分析分析了手术切除的福尔马林固定石蜡包埋 (FFPE) 样本，并将 SCLC 分为三种蛋白质组亚型（S-I、S-II 和 S-III），具有不同的临床结果和化疗反应。蛋白质组亚型是一个独立的预后因素，并且比当前的肿瘤淋巴结转移或退伍军人管理局肺研究组分期方法表现更好。可以使用来自独立队列的 FFPE 活检样本进一步验证分型结果，将分析扩展到手术和活检样本。 S-II 亚型的特征尤其表明了免疫疗法的潜在益处。 S-III（预后最差的亚型）中差异性过表达的蛋白质使我们能够提名潜在的治疗靶点，表明患者的选择可能为之前失败的临床试验带来新的希望。最后，对接受免疫治疗的 SCLC 患者的独立队列的分析验证了 S-II 患者在一线免疫治疗后具有更好的无进展生存期和总生存期的预测。总的来说，我们的研究为未来的临床研究提供了理论依据，以验证当前的研究结果，从而实现更准确的预后预测和精确的治疗。© 作者 2024。由牛津大学出版社和科学出版社代表北京基因组研究所出版，中国科学院/中国国家生物信息与遗传学中心。

Small cell lung cancer (SCLC) is a highly malignant and heterogeneous cancer with limited therapeutic options and prognosis prediction models. Here, we analyzed formalin-fixed, paraffin-embedded (FFPE) samples of surgical resections by proteomic profiling, and stratified SCLC into three proteomic subtypes (S-I, S-II, and S-III) with distinct clinical outcomes and chemotherapy responses. The proteomic subtyping was an independent prognostic factor and performed better than current tumor-node-metastasis or Veterans Administration Lung Study Group staging methods. The subtyping results could be further validated using FFPE biopsy samples from an independent cohort, extending the analysis to both surgical and biopsy samples. The signatures of the S-II subtype in particular suggested potential benefits from immunotherapy. Differentially overexpressed proteins in S-III, the worst prognostic subtype, allowed us to nominate potential therapeutic targets, indicating that patient selection may bring new hope for previously failed clinical trials. Finally, analysis of an independent cohort of SCLC patients who had received immunotherapy validated the prediction that the S-II patients had better progression-free survival and overall survival after first-line immunotherapy. Collectively, our study provides the rationale for future clinical investigations to validate the current findings for more accurate prognosis prediction and precise treatments.© The Author(s) 2024. Published by Oxford University Press and Science Press on behalf of the Beijing Institute of Genomics, Chinese Academy of Sciences / China National Center for Bioinformation and Genetics Society of China.