The multi-omics landscape of lung adenocarcinoma evolution: deciphering metabolic reprogramming-driven immune escape and its implications in combined therapy

Abstract The progression of lung adenocarcinoma (LUAD) from pre-invasive lesions (atypical adenomatous hyperplasia/adenocarcinoma in situ) to invasive adenocarcinoma constitutes a complex, multi-dimensional, and dynamic process. While the genomic drivers underlying this transition have been extensively characterized, the mechanisms by which metabolic reprogramming remodels the tumor immune microenvironment to orchestrate immune escape remain a critical knowledge gap. Leveraging insights from multi-omics integration encompassing genomics, metabolomics, single-cell RNA sequencing, and spatial transcriptomics, this review systematically delineates the molecular mechanisms through which metabolic reprogramming acts as a pivotal driver of immune escape during LUAD evolution. We critically dissect the intricate metabolic-epigenetic-spatial-immune; specifically, we highlight the mechanism through which cancer cells impair immune effector function via nutrient deprivation and utilize oncometabolites to instigate epigenetic modifications, thereby imprinting an immunosuppressive phenotype at the genetic level. Furthermore, this review discusses the development of early-screening biomarkers based on metabolic signatures, as well as combination therapeutic strategies targeting dual metabolic-immune checkpoints. The aim is to provide a novel theoretical framework for improving clinical management and prognosis in patients with LUAD.