Proteomic and lipidomic analyses reveal molecular subtypes and potential targets in early-stage lung adenocarcinoma among non-smokers

Early-stage lung adenocarcinoma (LUAD) in never smokers exhibits distinct biological features, yet the metabolic programs driving early invasion remain unclear. We integrate proteomic and lipidomic profiling of primary LUAD tumors from never smokers, matched normal adjacent tissues (NATs), and benign pulmonary nodules (BPNs). Integrated multi-omics analysis reveals coordinated dysregulation of lipid metabolism and immune signaling in early LUAD. Proteome-based network fusion stratifies invasive LUAD into immune-metabolic synergistic (IMS) and metabolic-stress-driven (MSD) subtypes. IMS tumors retain apolipoprotein-associated lipid modules and favorable immune features, whereas MSD tumors exhibit stress-response programs. Mechanistically, APOA1 and APOC1 emerge as key nodes linking lipid homeostasis to invasion, and their depletion promotes LUAD cell migration and invasion. We establish a two-protein, four-lipid diagnostic panel demonstrating robust performance across tissue and plasma cohorts. These findings provide a molecular basis for early detection and risk stratification in never smokers.