Taken together, our examination of the functional interplay between SETD2 and METTL3 mediated m6A using both genetic and pharmacologic methods to inhibit METTL3 in SETD2 WT and mutant contexts revealed that SETD2 deficient cells were preferentially sensitive to METTL3 loss, potentially through an impact on key metabolic processes like fatty acid oxidation or oxidative phosphorylation that SETD2 deficient RCC cells have become particularly reliant upon. Here, METTL3 is linked to renal cell carcinoma.