Immunomodulatory roles of nitric oxide in cancer: tumor microenvironment says “NO” to antitumor immune response

In recent years, an increasing number of studies have shown that there is an important connection between nitric oxide (NO) and the pathology of malignant diseases, but we are far from a complete comprehension of how this simple diatomic molecule contributes to tumorigenesis. The emerging identification of immune-mediated mechanisms regulated by NO may help to unravel the intricate and complex relationships between NO and cancer. Therefore, this review provides a summary of recent advances in our understanding of the immunomodulatory role of NO in cancer, and in particular the role of this pleiotropic signaling molecule as an immunosuppressive mediator in the tumor microenvironment. We will discuss the participation of NO in the different strategies used by tumors to escape from immune system-mediated recognition, including the acquisition of stem cell like capacities by tumor cells and the metabolic reprogramming of tumor infiltrating immune cells. Finally, we will also discuss different therapeutic strategies directed against NO for abating the immunosuppressive tumor microenvironment and to increase the efficacy of immunotherapy in cancer.