Autophagy supports the storage of lytic granules in human NK cells.

Natural Killer (NK) cells are innate lymphoid cells that play an important role in immune defense against pathogens and tumors. Understanding the mechanisms that enhance NK cell effector functions could significantly improve current NK cell-based therapies. Autophagy is a lysosome-dependent degradation process essential for NK cell development and function. This study analyzed the autophagic potential of mature NK cell subsets in peripheral blood. We demonstrated that exposure to inflammatory cytokines reduces autophagy via mTOR signaling pathway. Specifically, the activation of NK cell receptors leads to a temporary decrease in autophagy, which is rapidly restored, demonstrating the dynamics of autophagy in response to activating signals. Importantly, continuous overexpression of key autophagy regulators significantly increased autophagic flux, which directly correlated with enhanced cytotoxicity and metabolic activity in NK cells. The increased cytotoxicity was supported by a greater accumulation of cytolytic granules and their associated proteins. Our findings indicate that activating stimuli reduce autophagy, whereas sustained autophagic activity under steady-state conditions is crucial for the formation and maintenance of cytolytic granules, supporting the persistent cytotoxic function of NK cells.