FTO negatively regulates the cytotoxic activity of natural killer cells

Abstract

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. image The m6A RNA demethylase FTO suppresses the cytotoxic activity of natural killer cells by negatively regulating IL‐2/15‐driven JAK/STAT signaling. FTO‐deficient natural killer (NK) cells are hyper‐activated. FTO negatively regulates IL‐2/15‐driven JAK/STAT signaling in NK cells. FTO removes m6A marks from the mRNA of Suppressor of cytokine signaling proteins (SOCS) family genes increasing their stability.