Natural Killer (NK) cells are innate immune cells that play a crucial role in the anti-tumor response by recognizing and destroying abnormal cells. They rely on various mechanisms, including the secretion of lytic granules, expression of death receptors, and production of cytokines, to fulfill their anti-tumor function. NK cells interact with other immune cells in the tumor microenvironment, contributing to the overall anti-tumor response. This review focuses on NK cell activation and cytotoxicity mechanisms, serial killing, and their interactions with other immune cells. Key topics include the formation of the immune synapse, the role of activating and inhibitory receptors, the dynamics of cytotoxic activity, and the crosstalk between NK cells and other immune cells such as macrophages, myeloid-derived suppressor cells, dendritic cells, neutrophils, and adaptive immune cells. The review also discusses the clinical implications of NK cell-based therapy and the challenges in improving NK cell activity for cancer immunotherapy.Natural Killer (NK) cells are innate immune cells that play a crucial role in the anti-tumor response by recognizing and destroying abnormal cells. They rely on various mechanisms, including the secretion of lytic granules, expression of death receptors, and production of cytokines, to fulfill their anti-tumor function. NK cells interact with other immune cells in the tumor microenvironment, contributing to the overall anti-tumor response. This review focuses on NK cell activation and cytotoxicity mechanisms, serial killing, and their interactions with other immune cells. Key topics include the formation of the immune synapse, the role of activating and inhibitory receptors, the dynamics of cytotoxic activity, and the crosstalk between NK cells and other immune cells such as macrophages, myeloid-derived suppressor cells, dendritic cells, neutrophils, and adaptive immune cells. The review also discusses the clinical implications of NK cell-based therapy and the challenges in improving NK cell activity for cancer immunotherapy.