FTO negatively regulates the cytotoxic activity of natural killer cells.

N 6 -Methyladenosine (m 6 A) is the most abundant epitranscriptomic mark and plays a fundamental role in almost every aspect of mRNA metabolism. Although m 6 A writers and readers have been widely studied, the roles of m 6 A erasers are not well-understood. Here, we investigate the role of FTO, one of the m 6 A 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 protein (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.