**5. Trafficking of natural killer cells to the microenvironment of solid tumors**

Solid tumors hinder the infiltration and activation of NK cells at the tumor microenvironment (TME) leading to a challenge to NK cell efficacy [96]. The tumor suppresses cytotoxic responses by secreting IL-10, vascular endothelial growth factor (VEGF), prostaglandin E2 (PGE2), TGFβ indoleamine 2,3-dioxygenase (IDO), proteinase inhibitor-9 (PI-9), and arginase [97–99]. In addition to downregulating class I MHC, those cytokines gives rise to immature phenotype of dendritic cells [100].

In addition, the differentiation of myeloid derived suppressor cells (MDSCs) is controlled by some cytokines, such as TGF-β and PGE2. The MDSCs are then generated as highly heterogeneous population consisting of dendritic cells, granulocytes, and macrophages arrested at various differentiation stages [101]. The hypoxic tumor microenvironment results in the upregulation of arginase activity and inducible nitric oxide synthase (iNOS) by MDSCs that in turn inhibits T cells through NO signaling [102]. Moreover, this depletes arginine intracellularly and reactive oxygen species (ROS) production leading to shedding of NKG2D ligands, thus resulting in diminished immune-surveillance [102].
