Functional remodeling of tissue-resident macrophages leads to distinct immune microenvironment evolution and clinical manifestations in lung adenocarcinoma

Given the indispensable role in extracellular matrix remodeling and immunosuppressive microenvironment formation, the importance of tissue-resident macrophages (TRM) in the occurrence of early-stage cancer has been constantly mentioned. And it is noteworthy that the widespread application of low-dose CT (LDCT) has resulted in a marked increase in the proportion of early-stage patients for lung cancer in recent years, including plenty adenocarcinoma in situ (AIS) patients with ground-glass nodule (GGN) feature on imaging. The group of GGN-like AIS (AIS with ground-glass nodule feature) patients have gradually become a clinical challenge for thoracic surgeons, as surgically removed considered justified only when there is evident malignant progression risk. However, despite many teams, including ours, have proposed possible strategies for non-invasive and efficient assessing the malignant risk of GGN-like AIS patients, the unclear mechanism of the malignant progression for GGN-like AIS toward early-stage lung adenocarcinoma (LUAD) limits further clinical application and optimization. In this study, utilizing transcriptome, we classified TCGA-LUAD patients into distinct TRM functional states and conducted a comprehensive analysis of the physiological significance behind each subtype. Utilizing single-cell data, we have well mapped the results of transcriptome analysis at the cellular level and ultimately identified that KRT6A⁺ Ep may be the key epithelial subpopulation for the functional remodeling of TRM. Our study deepened the understanding of the malignant transformation mechanism of GGN-like AIS, as well as provided referential indicators for more personalized treatment and management of LUAD patients.