Depletion of RNA-editing enzyme ADAR1 invigorates NK cells anti-tumor immunity

Function exhaustion and inefficient tumor infiltration rate limit NK cells based cancer immunotherapy. Even though the role of ADAR1 in immune cells and tumorigenesis is gradually gaining attention, its role on NK cells is elusive. In this study, we found ADAR1 expression level was upregulated in peripheral blood (PB)-NK cells from patients with melanoma. ADAR1 knockdown NK cells showed enhanced anti-tumor activity in vitro and in vivo. NK cells specific Adar1 deletion mice showed better tumor control and higher NK cells infiltration level. RNA-seq analysis revealed that NK shADAR1 cells exhibited an activation phenotype with highly cell migration potential. Higher tumor infiltration level of NK shADAR1 cells were verified in three-dimensional (3D) Matrigel-spheroid experiment. Mechanically, we also observed ADAR1 deficiency in NK cells accompanied by RIG-I signaling pathway inhibition and CD38 expression decline, resulting in higher cell mobility, proliferation, and tumor killing capacity. These data suggest ADAR1 may be an emerging therapeutic target for enhanced NK cell immunotherapy.