Natural killer (NK) cells are an important member of the innate immune system and can participate in direct
tumor cell killing in response to
immunotherapies. One class of
immunotherapy is stimulator of
interferon gene (
STING) agonists, which result in a robust
type I interferon (IFN-I) response. Most mechanistic studies involving
STING have focused on macrophages and T cells. Nevertheless, NK cells are also activated by IFN-I, but the effect of
STING activation on NK cells remains to be adequately investigated. We show that both direct treatment with soluble
STING agonist cyclic di-
guanosine monophosphate-
adenosine monophosphate (
cGAMP) and indirect treatment with
cGAMP encapsulated in microparticles (MPs) result in NK cell activation in vitro, although the former requires 100× more
cGAMP than the latter. Additionally, direct activation with
cGAMP leads to NK cell death. Indirect activation with
cGAMP MPs does not result in NK cell death but rather cell activation and cell killing in vitro. In vivo, treatment with soluble
cGAMP and
cGAMP MPs both cause short-term activation, whereas only
cGAMP MP treatment produces long-term changes in NK cell activation markers. Thus, this work indicates that treatment with an encapsulated
STING agonist activates NK cells more efficiently than that with soluble
cGAMP. In both the in vitro and in vivo systems, the MP delivery system results in more robust effects at a greatly reduced dosage. These results have potential applications in aiding the improvement of
cancer immunotherapies.