Proteomic stratification reveals immune metabolic heterogeneity in lung adenocarcinoma

OBJECTIVE: Lung Adenocarcinoma (LUAD) is a leading cause of cancer-related mortality worldwide. The relationship between metabolic reprogramming and immune infiltration has been identified as having a crucial impact on LUAD progression. The aim of this study is to achieve a deeper understanding of the interplay between the immune system and metabolism in the LUAD microenvironment. METHODS: A total of 213 treatment-naïve LUAD patients from two independent cohorts were enrolled. Using the proteomic data from one of the cohorts (n = 103), three molecular subtypes of LUAD were identified based on their immune signatures, clinical characteristics, metabolic reprogramming, and genomic features were analyzed. The data from the other cohort (n = 110) were used to validate the findings. RESULTS: Three subtypes with distinct immune environment (IM1-IM3) were identified in LUAD based on the proteomic dataset, each of which has distinctive clinical, immune, and metabolic characteristics. Among these subtypes, IM2, which has the highest immune infiltration and is more likely to benefit from immunotherapy. In contrast, IM3 was found to have the poorest prognosis, exhibits active hypoxia and glycosaminoglycan biosynthesis, and is thought to be associated with extracellular matrix remodeling and epithelial-mesenchymal transition activation. Additionally, the active glycosaminoglycan biosynthesis pathway in the IM3 subtype was associated with an immune-desert microenvironment. CONCLUSIONS: This study presents the proteomic immune stratification of LUAD, revealing the possible link between immune cells and reprogramming of LUAD metabolisms, which may be a viable therapeutic strategy to improve LUAD immunotherapy.