Adelheid Cerwenka

Since the postulation of the “missing‐self” concept, much progress has been made in defining requirements for NK‐cell activation. Unlike T lymphocytes that process signals from receptors in a hierarchic manner dominated by the T‐cell receptors, NK cells integrate receptor signals more “democratically.” Signals originate not only the downstream of cell‐surface receptors triggered by membrane‐bound ligands or cytokines, but are also mediated by specialized microenvironmental sensors that perceive the cellular surrounding by detecting metabolites or the availability of oxygen. Thus, NK‐cell effector functions are driven in an organ and disease‐dependent manner. Here, we review the latest findings on how NK‐cell reactivity in cancer is determined by the reception and integration of complex signals. Finally, we discuss how this knowledge can be exploited to guide novel combinatorial approaches for NK‐cell‐based anticancer therapies.