Lung cancer, the leading cause of cancer mortality, exhibits heterogeneity that enables adaptability, limits therapeutic success, and remains incompletely understood. Single-cell RNA sequencing (scRNA-seq) of metastatic lung cancer was performed using 49 clinical biopsies obtained from 30 patients before and during targeted therapy. Over 20,000 cancer and tumor microenvironment (TME) single-cell profiles exposed a rich and dynamic tumor ecosystem. scRNA-seq of cancer cells illuminated targetable oncogenes beyond those detected clinically. Cancer cells surviving therapy as residual disease (RD) expressed an alveolar-regenerative cell signature suggesting a therapy-induced primitive cell-state transition, whereas those present at on-therapy progressive disease (PD) upregulated kynurenine, plasminogen, and gap-junction pathways. Active T-lymphocytes and decreased macrophages were present at RD and immunosuppressive cell states characterized PD. Biological features revealed by scRNA-seq were biomarkers of clinical outcomes in independent cohorts. This study highlights how therapy-induced adaptation of the multi-cellular ecosystem of metastatic cancer shapes clinical outcomes.

肺癌是癌症死亡的主要原因，它表现出异质性，使适应性成为可能，限制了治疗的成功，并且仍未完全了解。转移性肺癌的单细胞 RNA 测序 (scRNA-seq) 使用从 30 名患者在靶向治疗之前和期间获得的 49 份临床活检样本进行。超过 20,000 个癌症和肿瘤微环境 (TME) 单细胞图谱揭示了丰富而动态的肿瘤生态系统。癌细胞的 scRNA-seq 照亮了临床检测之外的可靶向癌基因。作为残留疾病 (RD) 存活的癌细胞表达了肺泡再生细胞特征，表明治疗诱导的原始细胞状态转变，而在治疗进行性疾病 (PD) 中存在的癌细胞上调犬尿氨酸、纤溶酶原和间隙连接通路. RD 处存在活性 T 淋巴细胞和减少的巨噬细胞，并且免疫抑制细胞状态是 PD 的特征。scRNA-seq 揭示的生物学特征是独立队列临床结果的生物标志物。这项研究强调了治疗诱导的转移性癌症多细胞生态系统的适应如何影响临床结果。