Fig. 2.

MHC I and the balance of stimulations and inhibitions dictate rules of engagement with cancer and stressed cells. Cancer and stressed cells expressing MHC I usually have multiple triggering ligands and can only escape NK cells if the balance of inhibitory signals is higher than activation. Cancer cells deficient in MHC I are killed through the “missing self” rule and are unlikely to escape NK cells, especially if the signaling balance favors activation. Unlicensed NK cells cannot kill through the “missing self” rule because they lack KIRS /CD94/NKG2A/B but are most likely to kill cancer and stressed cells that induce reasonable stimulation of NK cells due to the missing MHC I inhibition. Exhausted NK cells, usually having a dominance of inhibitory receptors, are less likely to kill cancer and stressed cells