Causal relationships between cerebrospinal fluid metabolites, immune cell traits, and head and neck cancers

Emerging evidence suggests that cerebrospinal fluid (CSF) metabolites may serve as valuable biomarkers in head and neck cancers (HNCs). However, their causal relationships and potential mechanisms remain underexplored. We conducted a bidirectional Mendelian randomization (MR) study to evaluate causal relationships between genetically predicted CSF metabolites, immune cell traits (ICTs), and HNC risk. Summary-level data were obtained from large-scale genome-wide association studies (GWAS), including 388 CSF metabolites (n = 291), 731 ICTs (n = 3,757), and HNCs (n = 373,122). Bidirectional MR was employed to investigate causal associations, with mediation analysis applied to assess the potential mediating role of ICTs. A series of sensitivity analyses were conducted to address heterogeneity and pleiotropy concerns. Forward MR identified nine CSF metabolites with causal associations: elevated citrulline and adenine correlated with reduced HNC risk, whereas hypoxanthine, N-acetylglutamate, N-acetylleucine, nicotinamide riboside, and X-24,813 conferred elevated risk. Dimethyl sulfone exhibited marginal protective effects. Reverse MR revealed tumor genetic susceptibility inversely modulated 12 metabolites, including pyroglutamine, 1-arachidonoyl-gpc (20:4n6), 3-hydroxy-2-ethylpropionate, 3-hydroxyoctanoate, 3-ureidopropionate, 7-methylguanine, adenine, guanosine, N2, and N2-dimethylguanosine, while elevating 2-aminophenol sulfate and N6-methyllysin. Mediation analyses suggested that CD45 on CD33br HLA DR + CD14dim and CD80 on granulocytes may potentially mediate the metabolite-HNC interactions. This study identifies bidirectional relationships between CSF metabolites and HNC risk and nominates ICTs as possible mediators. These findings implicate CSF metabolites in HNC pathogenesis and highlight their potential as diagnostic biomarkers and therapeutic targets, warranting experimental validation and clinical investigation.