Aim: Lung adenocarcinoma (LUAD), the most prevalent subtype of non-small cell lung cancer (NSCLC), presents significant clinical challenges due to its high mortality and limited therapeutic options. The molecular heterogeneity and the development of therapeutic resistance further complicate treatment, underscoring the need for a more comprehensive understanding of its cellular and molecular characteristics. This study sought to delineate novel cellular subpopulations and molecular subtypes of LUAD, identify critical biomarkers, and explore potential therapeutic targets to enhance treatment efficacy and patient prognosis. Methods: An integrative multi-omics approach was employed to incorporate single-cell RNA sequencing (scRNA-seq), bulk transcriptomic analysis, and genome-wide association study (GWAS) data from multiple LUAD patient cohorts. Advanced computational approaches, including Bayesian deconvolution and machine learning algorithms, were used to comprehensively characterize the tumor microenvironment, classify LUAD subtypes, and develop a robust prognostic model. Results: Our analysis identified eleven distinct cellular subpopulations within LUAD, with epithelial cells predominating and exhibiting high mutation frequencies in Tumor Protein 53 (TP53) and Titin (TTN) genes. Two molecular subtypes of LUAD [consensus subtype (CS)1 and CS2] were identified, each showing distinct immune landscapes and clinical outcomes. The CS2 subtype, characterized by increased immune cell infiltration, demonstrated a more favorable prognosis and higher sensitivity to immunotherapy. Furthermore, a multi-omics-driven machine learning signature (MOMLS) identified ribonucleotide reductase M1 (RRM1) as a critical biomarker associated with chemotherapy response. Based on this model, several potential therapeutic agents targeting different subtypes were proposed. Conclusion: This study presents a comprehensive multi-omics framework for understanding the molecular complexity of LUAD, providing insights into cellular heterogeneity, molecular subtypes, and potential therapeutic targets. Differential sensitivity to immunotherapy among various cellular subpopulations was identified, paving the way for future immunotherapy-focused research.
