Nitric Oxide Synthase 2-Dependent Metabolic Dysregulation, Immunosuppression, and Genomic Instability in Metastatic Triple-Negative Breast Cancer

RNA sequencing revealed NOS2-dependent loss of mRNA associated with regulation of chromosome and DNA replication, including cell cycle checkpoints, as well as mRNA associated with RNA demethylation, including tRNA demethylation. Immunoprofiling of the tumor microenvironment revealed immunosuppressed tumors that were low in T cells and high in myeloid derived suppressor cells expressing interferon gamma, which induces NOS2 expression.

Others have shown nitric oxide from immune cells suppresses tumor immunity. Here, we show nitric oxide from tumor cells plays a critical role in metastasis. Taken together, these data suggest high NOS2 in tumor cells drives metastasis through a broad accumulation of cancer-associated factors – including metabolic dysregulation, genetic instability, and immunosuppression – all of which contribute to aggressive metastasis.