A conserved glycolytic malignant subcluster drives invasive progression through a PPIA-BSG metabolic-immune interaction in early lung adenocarcinoma

Background: Ground-glass nodules (GGNs) frequently represent early-stage lung adenocarcinoma (LUAD), but current histopathological and radiological modalities cannot reliably distinguish indolent precursor lesions from those likely to progress to invasive tumors.Robust cell-subcluster-specific biomarkers are therefore needed to improve risk stratification at this early stage of disease.Methods: To define the malignant epithelial subcluster associated with invasive progression, four single-cell RNA sequencing (scRNA-seq) datasets and one spatial transcriptomic dataset were integrated, yielding 621,778 cells and 53,492 spatial spots from precursor lesions, invasive tumors, metastatic lung cancers, and multiple primary LUADs.Results: Across independent datasets, C1 emerged as a conserved malignant epithelial subcluster marked by pronounced proliferative activity and enhanced glycolytic metabolism.Its representation increased sharply with tumor progression, from relative scarcity in preinvasive lesions to prominent enrichment in invasive adenocarcinoma and further expansion in metastatic LUAD.C1 also exhibited subcluster-dependent crosstalk with immunosuppressive SPP1 + macrophages through the PPIA-BSG axis.This interaction was selectively enriched in invasive tumors and was independently confirmed by spatial transcriptomics and multiplex immunohistochemistry. Notably, spatial proximity between C1 cells and SPP1 + macrophages was likewise concentrated in invasive adenocarcinoma, suggesting that this metabolic-immune interaction may be associated with progression toward invasive disease.Conclusions: These findings define a conserved glycolytic malignant epithelial subcluster whose abundance may improve recurrence risk stratification in early-stage disease.PPIA-BSG-mediated communication between C1 cells and SPP1 + macrophages further identifies a metabolic-immune interaction associated with invasive progression at the GGN stage.