Decoding the genetic links between serum lipidomic profile, amino acid biomarkers, and programmed cell death protein-1/programmed cell death-ligand-1.

Abstract

Disruptions in lipid metabolism and amino acids have been increasingly linked to resistance to immunotherapy. However, the underlying mechanisms by which dysregulated serum lipid metabolism and amino acids affect the efficacy of immunotherapies through PD-1/PD-L1 expression and function remain poorly understood. To elucidate the potential associations between lipid metabolism, amino acids, and PD-1/PD-L1, we employed the powerful Mendelian randomization (MR) method, leveraging large-scale genome-wide association studies. In the present MR study, we identified a noteworthy negative association between alanine and PD-1 expression, implicating a regulatory role for alanine metabolism in modulating the immune response to cancer treatment. Additionally, we elucidated fourteen specific lipid metabolism biomarkers that were significantly linked to PD-L1 expression, including cholesterol and triglycerides. Glutamine and phenylalanine were also found to showcase an intriguing causal association with the expression of PD-L1. Eventually, we confirmed the potential roles of key genes involved in lipid and amino acids metabolism in influencing the response to immunotherapy. These findings provided new insights into the role of lipid metabolism as well as amino acids in regulating PD-1/PD-L1, suggesting that strategies targeting lipid and amino acid metabolisms may have therapeutic potential for improving the efficacy of immunotherapy.