The study investigates the role of the gut microbiome in predicting immune-related adverse events (irAEs) associated with immune checkpoint inhibitors (ICIs). Using a comprehensive dataset of 16S rRNA and shotgun metagenome samples, the researchers developed a Random Forest (RF) classifier to distinguish between patients experiencing irAEs and those without. The classifier, based on 14 microbial features, demonstrated high discriminatory power (AUC = 0.88) and was validated in two independent cohorts. Functional analysis revealed that the gut microbiome in non-irAEs patients was characterized by increased menaquinone biosynthesis, with elevated expression of rate-limiting enzymes *menH* and *menC*. Metabolomics analysis confirmed higher serum menaquinone levels in non-irAEs patients. The study highlights the potential of microbial biomarkers, particularly menaquinone, for predicting and potentially preventing irAEs.The study investigates the role of the gut microbiome in predicting immune-related adverse events (irAEs) associated with immune checkpoint inhibitors (ICIs). Using a comprehensive dataset of 16S rRNA and shotgun metagenome samples, the researchers developed a Random Forest (RF) classifier to distinguish between patients experiencing irAEs and those without. The classifier, based on 14 microbial features, demonstrated high discriminatory power (AUC = 0.88) and was validated in two independent cohorts. Functional analysis revealed that the gut microbiome in non-irAEs patients was characterized by increased menaquinone biosynthesis, with elevated expression of rate-limiting enzymes *menH* and *menC*. Metabolomics analysis confirmed higher serum menaquinone levels in non-irAEs patients. The study highlights the potential of microbial biomarkers, particularly menaquinone, for predicting and potentially preventing irAEs.