Multiomics analysis of lung adenocarcinoma manifesting as radiological part-solid features in female never-smokers

Lung adenocarcinomas (LUADs) with part-solid radiological features exhibit slow progression to invasive malignancy; however, the key genomic alterations driving this progression remain poorly understood. We conducted a multiomics analysis of four components (distant and adjacent normal lung and solid [S] and ground-glass [GG] components) of part-solid-type LUADs in female never-smokers. Although GG and S components displayed similar mutational profiles, epithelial–mesenchymal transition and hypoxia pathways were significantly upregulated in the S component. Using single-cell RNA sequencing, we identified a novel cancer-associated secretory (CAS) cell population (SCGB3A2/CEACAM6+). The proportion of CAS cells and interleukin (IL)-1β+ macrophages showed a significant upward trend toward the S component. Spatial transcriptomic analysis revealed that IL-1β+ macrophages and CAS cells co-localized in invasive regions of the tumor. In conclusion, CAS cells and IL-1β+ macrophages play crucial roles in the progression from preinvasive to invasive LUADs, positioning them as promising targets for cancer prevention and therapeutic strategies.