Landscape of Cell States and Multicellular Ecotypes in Non-Small Cell Lung Cancer

Abstract

Non-small cell lung cancer (NSCLC) is the most prevalent type of lung cancer and remains a major global health burden. Comprehensive characterization of tumor microenvironment (TME) heterogeneity is critical for understanding tumor progression and clinical outcomes in NSCLC. In this study, we identified 34 transcriptionally defined cell states and 6 multicellular ecotypes using the EcoTyper framework, thereby systematically delineating the TME landscape of NSCLC. These cell states and ecotypes were further validated across 11 independent bulk transcriptomic cohorts, one single-cell RNA sequencing cohort, and one spatial transcriptomics cohort, demonstrating strong reproducibility and robustness. Prognostic analyses revealed that several cell states and ecotypes were significantly associated with patient survival outcomes in NSCLC. Transcriptional regulatory analysis further identified SP8, MAZ, and FOS as potential regulators involved in shaping NSCLC ecotypes. Collectively, this study provides a comprehensive atlas of TME-associated cell states and ecotypes in NSCLC, offering new insights into tumor heterogeneity and potential opportunities for personalized prognostic assessment and therapeutic intervention.