Novaferon gene modification promotes NK92 cell anti-tumor activity.

• NK92 cells expressing novaferon possessed enhanced cytotoxicity. • NK92-nova possessed activated JAK/STAT signaling pathway. • The cytotoxicity of NK92-nova was partially dependent on the NKG2D/NKG2DL pathway. With significant developments in chimeric antigen receptor T-cell therapy, adoptive immunotherapy has unlocked new levels of treatment for malignancies. Natural killer (NK) cells are promising alternative immune effector cells for this strategy. Multiple anti-tumor therapies are largely dependent on type I interferon (IFN) signaling. Type I IFNs enhance NK cell cytotoxicity. Novaferon (nova) is an unnatural, novel IFN-like protein produced by gene shuffling of IFN-α with strong biological activity. To augment the antitumor activity of NK cells, we generated NK92-nova cells that stably express nova. We found that NK92-nova cells mediated enhanced pan-cancer antitumor activity compared to NK92-vec cells. The increased antitumor activity was associated with the enhanced secretion of cytokines, such as IFN-γ, perforin, and granzyme B. Meanwhile, most of the activating receptors were upregulated in the NK92-nova cells. After co-culture with NK92-nova cells, the expression of NKG2D ligands on the HepG2 cells increased, resulting in an enhanced susceptibility of HepG2 cells to NK92 cell-mediated cytolysis. NK92-nova cells significantly inhibited HepG2 tumor growth in a xenograft model without systemic toxicity. Therefore, NK92-nova cells are a novel and safe strategy for cancer immunotherapy. [ABSTRACT FROM AUTHOR]