Metabolome-microbiome convergence under circadian disruption accelerates mammary tumorigenesis: multi-omics...

Circadian rhythm disruption (CRD), common in shift work and jet lag, promotes mammary tumorigenesis through coordinated reprogramming of tumor metabolism and the local microbiome. CRD increased immunosuppressive metabolites - kynurenic acid, spermidine, and argininosuccinic acid - that suppressed effector T-cell activity and drove macrophage polarization toward anti-inflammatory phenotypes. 16S rRNA sequencing revealed enrichment of immune-modulatory Firmicutes and Bacilli within CRD tumors. Experimental and multi-omics integrative analyses strongly support metabolome-microbiome crosstalk driving immune suppression under CRD. Inhibition of arginase-1 (ARG1) with nor-NOHA restored cytotoxic T-cell responses and reduced lung metastases. These findings establish metabolome-microbiome interactions as a central mechanism of CRD-induced immunosuppression and metastasis, revealing potential therapeutic targets for circadian disruption-associated breast cancer.