Novel Lipid Metabolism-Related Gene Signature Associated with Clinical and Immune Features in Lung Adenocarcinoma Patients Experiencing Lymph Node Metastasis

Background: Accumulating evidence revealed that lipid metabolic reprogramming facilitates lymph node metastasis and cancer progression. This study aimed to perform comprehensive bioinformatic analyses of the lipid metabolism-related impact in lung adenocarcinoma (LUAD) patients experiencing lymph node metastasis (LNM). Methods: : Clinicopathological information and RNA-sequence data on LUAD patients were collected from the TCGA and GEO databases. Subsequently, 189 differentially expressed lipid metabolism-related genes (LMRGs) were screened for LUAD patients with and without LNM. Based on the risk scoring system related to prognosis, we further correlated the LMRGs with diverse clinicopathological outcomes, genomic alterations, and immune features, as well as immunotherapeutic responses and drug susceptibility. Results: : A three-gene lipid metabolic signature (GPD1L, SPHK1, and ST3GAL4) associated with tumor progression in LUAD with LNM was identified. Analyses revealed that the high-risk group had worse overall survival; an increased proportion of M0 macrophages and degranulating mast cell infiltration; increased non-responders to immunotherapy; and resistance to several common TKI drugs. Interestingly, we also found that high-risk patients had higher tumor mutation burdens and PDL-1 expression, suggesting that this subset of patients may benefit from immunotherapy plus LMRG-targeted therapy. Additionally, the results showed that the high-risk group's differentially expressed genes (DEGs) were enriched in the REACTIVE OXYGEN SPECIES pathway. Conclusions: : Our findings may provide new insights into molecular mechanisms and precision therapies of lipid metabolism-related LUAD regional metastasis.