Tumor cGAMP Awakens the Natural Killers

Abstract

Type I interferon (IFN) production within the tumor microenvironment is important in shaping the immune response to the tumor. In this issue of Immunity, Marcus et al. (2018) reveal that tumor cells produce 2'3'-cGAMP, which activates the STING pathway in non-tumor cells and leads to type I IFN production and the priming of natural killer cells for tumor rejection.

Figure 1.. Potential paracrine roles of 2’, 3’-cGAMP in the tumor microenvironment.

In addition to tumor cell intrinsic signaling (1), tumor-derived 2’, 3’-cGAMP can be recognized by leukocytes such as CD11b+ and B cells and subsequently activate STING, inducing type I interferon production by the leukocytes to prime NK cells for cytotoxic killing of tumor cells (2). Intercellular gap junctions enable transfer of this second messenger in adjacent cells, which has been linked to metastasis (3). It is also well established that the tumor vasculature responds to cyclic dinucleotides, though how this impacts the tumor microenvironment is poorly understood (4). Finally, STING activation in leukocytes or other cells by 2’, 3’-cGAMP could also promote production of immunosuppressive cytokines such as CCL2, which can recruit myeloid-derived suppressor cells (MDSCs) (5). Red = anti-tumorigenic effects and blue = potential pro-tumorigenic effects of STING agonism in the tumor microenvironment.