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.