NK cell-based immunotherapy.

NK cells have rapidly become a leading platform for cancer immunotherapy. Unlike T cells, NK cells recognize transformed cells through integrated signals from inhibitory and activating receptors, enabling allogeneic "off-the-shelf" therapies without risk of graft-versus-host disease and low rates of cytokine release syndrome and neurotoxicity. Refinement in sourcing of allogenic NK cells, especially umbilical cord blood and induced pluripotent stem cells, ex vivo activation and expansion, CAR engineering, and combinations with novel engagers have resulted in clinically applicable products with encouraging activity and excellent safety. However, barriers remain, including limited in vivo persistence, host rejection of allogeneic cells, and inefficient trafficking into solid tumors. Venues of progress include multiantigen and logic-gated CAR platforms, inducible safety switches, cytokine armoring, and metabolic and transcriptional rewiring to improve NK fitness. As NK cell therapies progress into the clinic, exploration of rational combinations with checkpoint inhibitors, small-molecule kinase inhibitors, chemotherapy, and radiotherapy warrant study.