Depletion of the RNA‐Editing Enzyme ADAR1 Invigorates the Antitumor Immunity of NK Cells

Functional exhaustion and inefficient tumor infiltration rates limit the effectiveness of natural killer (NK) cell-based cancer immunotherapy. Although the role of adenosine deaminase acting on RNA 1 (ADAR1) in immune cells and tumorigenesis is gradually gaining attention, its role in NK cells is elusive. In this study, we find that ADAR1 expression level is increased in peripheral blood (PB)-NK cells from patients with melanoma, concurrently exhibiting impaired tumor killing capacity. ADAR1-knockdown NK cells show enhanced antitumor activity in vitro and in vivo. Compared with ADAR1^flox/flox wild-type (ADAR1 WT) mice, Ncr1^iCre/+;ADAR1^flox/flox conditional knockout (ADAR1 cKO) mice present improved tumor control and increased NK cell infiltration. RNA sequencing (RNA-seq) analysis reveals that ADAR1 knockdown in NK cells (NK shADAR1) exhibit an activation phenotype with high cell migration potential. A greater level of tumor infiltration by NK shADAR1 cells is verified in 3D Matrigel-spheroid experiments. Mechanistically, ADAR1 deficiency in NK cells is accompanied by CD38 expression decline via affecting its mRNA stability, resulting in increased cell mobility, proliferation, and tumor killing capacity. Our findings validate ADAR1 as an emerging therapeutic target for enhanced NK cell immunotherapy.