A single-cell lung cancer atlas reveals cellular and molecular drivers of metastasis and clinical outcome

Non-small-cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality, characterized by extensive cellular and molecular heterogeneity. Here, to capture this complexity, we present LuCaS+, a multicenter single-cell RNA sequencing atlas comprising over 2.5 million nuclei from 454 clinically annotated patients with NSCLC with long-term follow-up. LuCaS+ consists of a discovery dataset (Berlin and Cologne, 364 patients) and an independent validation dataset (Munich, 90 patients). Leveraging this dataset, we identified tumor subpopulations with high metastatic potential associated with oncogenic signaling, immune evasion and epithelial–mesenchymal transition. In early-stage adenocarcinoma (lung adenocarcinoma), these cells showed strong prognostic value. Integrating tumor and microenvironmental cell profiles improved survival prediction across all stages, identifying distinct tumor–immune–stromal interaction patterns. These included monocyte- and fibroblast-driven inflammation (lung adenocarcinoma), VEGF–TGFβ-mediated angiogenic feedback loops (lung squamous cell carcinoma) and immune-permissive niches promoting antitumor immunity. LuCaS+ offers a clinically anchored single-cell resource to enable personalized, biology-driven therapies in NSCLC.