Natural killer cells and engagers: Powerful weapons against cancer

Summary Natural killer (NK) cells are innate immune effectors whose functions rely on receptors binding cytokines, recognizing self‐molecules, or detecting danger signals expressed by virus‐infected or tumor cells. The potent cytotoxic potential makes NK cells promising candidates for cancer immunotherapy. To enhance their activity strategies include cytokine administration, blocking of immune checkpoints, and designing of antibody‐based NK cell engagers (NKCEs). NKCEs represent a cutting‐edge approach to cancer therapy: they strengthen the NK‐to‐target cell interactions and optimize tumor killing, possibly overcoming the immunosuppressive tumor microenvironment. NK cells belong to the innate lymphoid cells (ILCs) and are categorized into different subsets also including cells with a memory‐like phenotype: this complexity needs to be explored in the context of cancer immunotherapy, particularly when designing NKCEs. Two strategies to enhance NK cell activity in cancer patients can be adopted: activating patients' own NK cells versus the adoptive transfer of ex vivo activated NK cells. Furthermore, the capability of NKCEs to activate γδ T cells could have a significant synergistic effect in immunotherapy.