FTO degradation targeting enhances anti-tumor immunity

The m6A RNA demethylase Fat mass and obesity-associated protein (FTO) is aberrantly upregulated in numerous cancers and promotes tumor development and therapeutic resistance. Here, using public datasets and screening, we show that FTO is ubiquitinated at lysine 162 by its E3 ligase DTX2, followed by recognition by UFD1, leading to degradation in the proteasomes. Furthermore, we identified vitamin E succinate (VES) as a natural first-in-class degrader for FTO by binding to FTO and DTX2, thus enhancing FTO-DTX2 interaction, leading to increased FTO ubiquitination and degradation and enhanced anti-tumor immunity and response to immunotherapy. Genetic or pharmacological FTO knockdown by VES increased m6A methylation in the LIF gene and thus decreased LIF mRNA decay, and thus sensitized tumor cells to T cell-mediated cytotoxicity. Taken together, our findings elucidated the underlying molecular mechanism for FTO protein degradation and the first natural FTO degrader that reprograms the anti-tumor immunity. RNA Seq of MEL624 cells treated with Vehicle or 25uM Vitamin E succinate for 72 hours.