Metabolites and metabolic pathway reactions links to sensitization of immunotherapy in pan-cancer

Metabolic features are crucial in tumor immune interactions, but their relationship with antitumor immune responses is not yet fully understood. This study used Mendelian randomization analysis to identify the causal relationships between blood metabolites and immune cells and to evaluate the effects of metabolic pathways and reactions on antitumor immune responses in various cancers. Levels of 156 metabolites exhibited significant associations with selected immune cells. Metabolic enrichment analysis indicated laurate, propionyl-carnitine, carnitine and l-acetylcarnitine are enriched in fatty acid (FA) metabolism pathways. These enriched pathways are significantly correlated to CD8⁺ T cell function signatures in tumor environment and favor better prognostic outcomes. Metabolic reactions contributing to better immunotherapy responses were identified and used to establish the immuno-metabolic reaction score (IMRS). IMRS were significantly correlated to CD8⁺ T cell infiltration levels and CD8⁺ T cell signature scores in either 10× Visium spatial transcriptomic or RNA-seq samples. Finally, IMRS could significantly predict favorable survival outcomes in different cancer patients treated with immunotherapy. Our study revealed a link between certain metabolites and their related metabolic pathways to tumor immune landscape and immune functions. These results could promote the accurate stratification of patients before treatment and improve the efficacy of immunotherapy.