Figure 1.

NK cells are key effectors of anti-tumor response and direct both the innate and the adaptive arms of the immune system. 1) NK cells are the first responders of the immune system and can directly recognize and lyse tumor cells. Activating receptors on NK cells recognize ligands that are mostly expressed on compromised cells while inhibitory receptors bind to self-ligands that mark healthy, normal cells. 2) NK cells also express the CD16 FcγRIII receptor that binds antibodies and triggers antibody-dependent cellular cytotoxicity (ADCC). This response contributes to efficacy of many of the antibody-based cancer therapeutics (e.g. Herceptin or Erbitux). 3) NK cells not only directly lyse compromised cells causing release of tumor antigens, but when activated release cytokines such as TNF-α and IFN-γ, the later known to induce PD-L1 expression, that can recruit other immune cells and inflame or “heat up” the tumor microenvironment priming it for immunotherapy. 4) Intratumoral NK cells produce chemoattractants CCL5 and XCL1 (5) as well as FLT3LG, the formative cytokine of rare intratumoral stimulatory dendritic cells (cDC1) (6) that can activate the adaptive immune response. NK cells have also been shown to directly recruit T cells by releasing cytokines such as IL-8, CCL3, and CCL5 (7). 5) Additionally, NK cells can release exosomes with cytotoxic activity and can contain effector miRNAs, cytokines, and display NK cell surface receptors.