Comprehensive investigation of a new signature integrating lipid metabolism and immune-related genes for clear cell renal cell carcinoma prognosis and immunometabolism landscapes

Multi-omics studies have significantly advanced our understanding of ccRCC. These studies have revealed that aggressive ccRCC is closely associated with metabolic reprogramming, particularly involving lipid metabolism. Recent studies have highlighted the crosstalk between lipid metabolism and immune function in the tumor microenvironment (TME) of ccRCC. However, prognostic models integrating both pathways remain underdeveloped. A detailed analysis was conducted on the varied lipid metabolism subtypes utilizing 638 records of clear cell renal cell carcinoma from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, focusing on lipid metabolism genes and immune-related genes (LRGs). The clinical importance, functional status, TME interaction, and genetic alterations of various subtypes were further investigated. A novel grading system, the lipid-immune score (LIS), was created and validated. Two distinct subgroups, characterized by elevated expression of lipid metabolism genes and exhibiting traits of tumor metabolism and proliferation, are classified as lipid metabolism phenotypes. The lipid metabolism phenotype exhibits a more favorable prognosis, enhanced anti-tumor immunity, and increased sensitivity to immunotherapy. The expression of more LRGs, the enrichment of immunoreactive pathways, and the infiltration of effector immune cells are characterized as immunoreactive phenotypes. The prognosis for the immunoactive phenotype is unfavorable and is more prevalent in patients experiencing tumor progression. Furthermore, BAP1 is a pivotal mutant gene in the immunoactive subtype. LIS was ultimately shown as a reliable predictor of overall survival (OS) and immunotherapy outcomes in patients with clear cell renal cell carcinoma. We systematically analyzed immune- and lipid metabolism-related genes, identifying 2 distinct molecular subtypes with differing biological functions, immune profiles, and clinical outcomes. We also developed a LIS that effectively predicts patient prognosis and immunotherapy response, offering a new strategy for precision medicine in ccRCC. Our research elucidates the relationship between lipid metabolism and immune response, offering a distinctive strategy for therapeutic management and precision medicine in patients with clear cell renal cell carcinoma.