Hypoxic Preconditioning Restores NK Cell Metabolic Fitness by Attenuating MAPK Signaling to Potentiate Antitumor Immunity in Lung Cancer

Solid tumor hypoxia is a major barrier to NK cell‐based immunotherapy. To address this challenge, we establish a hypoxic preconditioning (HPC) model. We find that acute hypoxia (AH; 1% O 2 ) significantly impairs NK92 cell cytotoxicity—such as granzyme B secretion and infiltration into lung cancer cell spheroids. In contrast, HPC pretreatment (gradual reduction from 5% to 1% O 2 ) remarkably restores these functions. Mechanistically, transcriptomic analysis reveals that HPC markedly attenuates hypoxia ‐induced aberrant MAPK pathway activation. MAPK attenuation under normoxia recapitulates HPC ‐like protection by promoting mitochondrial biogenesis and metabolic remodeling, thereby enhancing the antitumor activity of NK92 cells both in vitro and in vivo. Notably, systemic MAPK inhibitor injection increases NKp46 expression on endogenous NK cells in BALB/c mice. Importantly, this strategy is also effective in human induced pluripotent stem cell (hiPSC)‐derived induced NK (iNK) cells, supporting broader evaluation across NK cell platforms. Collectively, this study identifies the MAPK–mitochondrial metabolic axis as a critical regulator of hypoxia‐induced NK cell dysfunction and proposes metabolic preconditioning as a strategy to overcome solid tumor hypoxia.