Real‐Time Evolutionary Landscape of the Bronchial Epithelium and Corresponding Dynamic Immune Cell Alterations in Lung Squamous Cell Carcinogenesis

Abstract The molecular mechanism by which tumor cells and their microenvironment evolve during lung squamous cell carcinoma (LUSC) carcinogenesis remains unclear, greatly limiting its early diagnosis and treatment effectiveness in patients. To replicate pathogenic processes and identify the determinants of cell evolution, a rat model is established using tobacco‐derived carcinogens. Here, a series of single‐cell transcriptome profiles of normal lung epithelium, hyperplasia, metaplasia, dysplasia, and squamous cell carcinoma in situ (CIS) to invasive squamous cell carcinoma (SCC) is presented. A large proportion of canonical copy number variations (CNVs) are detected in the hyperplasia/metaplasia stages, with their frequency increasing as the lesion progressed. Although bronchial epithelial cells exhibit substantial heterogeneity, three distinct cellular states are identified during their evolution into malignant cells. Immune sensing occurs at the earliest stages of cellular transformation. However, persistent exposure to carcinogens induces microenvironmental remodeling, which is characterized by monocyte‐derived macrophage infiltration, plasmacytoid dendritic cell expansion, and progressive T‐cell exhaustion. These findings depict the evolutionary trajectory of cancer and the immune microenvironment, emphasizing the need for CNV evaluation in early screening and immune‐based therapy for lesions at a high risk of progression to LUSC.