FTO negatively regulates the cytotoxic activity of natural killer cells

N6-Methyladenosine (m6A) is the most abundant epitranscriptomic mark and plays a fundamental role in almost every aspect of mRNA metabolism. Although m6A writers and readers have been widely studied, the roles of m6A erasers are not well understood. Here we investigate the role of FTO, one of the m6A erasers, in natural killer (NK) cell immunity. We observe that FTO-deficient NK cells are hyperactivated. Fto knockout (Fto-/-) mouse NK cells prevent melanoma metastasis in vivo, and FTO-deficient human NK cells enhance the antitumor response against leukemia in vitro. We find that FTO negatively regulates IL-2/15-driven JAK/STAT signaling by increasing the mRNA stability of Suppressor of cytokine signaling proteins (SOCS) family genes. Our results suggest that FTO is an essential modulator of NK cell immunity, providing a new immunotherapeutic strategy for allogeneic NK cell therapies.