Flavones and Aminoflavones Increase the Cytotoxicity of NK Cells in Human Non‐Small Cell Lung Cancer

ABSTRACT Natural flavonoids (flavones) and synthetic aminoflavones are known for their anti‐cancer properties; however, their immunomodulation ability has been largely unexplored. This study determined that synthetic flavones and aminoflavones modulate the cytotoxicity of natural killer (NK) cells against lung cancer cells. Notably, flavones 2, 3, and 6 and aminoflavone 8 were shown to increase the cytotoxicity of NK‐92MI cells against A549 lung cancer cells without adversely affecting MRC5 normal cells. Aminoflavone 8 enhanced NK‐92MI cell cytotoxicity, as evidenced by the elevated expression of cytotoxic effectors, such as IFN‐γ, perforin, and granzyme B. Aminoflavone 8 also inhibited STAT3 phosphorylation in A549 lung cancer and NK‐92MI cells under co‐culture conditions. Moreover, aminoflavone 8 exhibited anti‐tumour effects in a lung cancer xenograft mouse model. Combined therapy with aminoflavone 8 and NK‐92MI cells had synergistic anti‐tumour effects without liver or kidney toxicity. Our analysis revealed that the amino group in the C6 position of aminoflavone 8 was crucial to the enhanced cytotoxicity of NK cells. These findings suggest that aminoflavone 8 can potentiate NK cell cytotoxicity against lung cancer cells, highlighting its potential as a novel therapeutic agent for the treatment of lung cancer.