Cuproptosis, caused by excessively high
copper concentrations, is urgently exploited as a potential
cancer therapeutic. However, the mechanisms underlying the initiation, propagation, and ultimate execution of cuproptosis in
tumors remain unknown. Here, we show that
copper content is significantly elevated in
gastric cancer (GC), especially in malignant
tumors. Screening reveals that METTL16, an atypical
methyltransferase, is a critical mediator of cuproptosis through the
m6A modification on FDX1
mRNA. Furthermore,
copper stress promotes METTL16 lactylation at site K229 followed by cuproptosis. The process of METTL16 lactylation is inhibited by
SIRT2. Elevated METTL16 lactylation significantly improves the therapeutic efficacy of the
copper ionophore-
elesclomol. Combining
elesclomol with AGK2, a SIRT2-specific inhibitor, induce cuproptosis in gastric
tumors in vitro and in vivo. These results reveal the significance of non-
histone protein METTL16 lactylation on cuproptosis in
tumors. Given the high
copper and
lactate concentrations in GC, cuproptosis induction becomes a promising therapeutic strategy for GC.