Targeting methionine-induced pyroptosis enhances anti-tumor immunity

Pyroptosis is an inflammatory form of programmed cell death that plays a critical role in tumor immunity. However, the metabolic signals involved in this process remain undefined. In the present study, we uncover that methionine metabolism plays an important role in the pyroptosis of bone marrow-derived macrophages (BMDMs). The depletion of methionine adenosyltransferase 2A ( Mat2a ) in macrophages leads to cell death by activating GSDME, resulting in suppression of tumor growth in vivo. Furthermore, pharmacological inhibition of MAT2A induces macrophage pyroptosis by activating Gasdermin E (GSDME) but not Gasdermin D (GSDMD). Moreover, we identify a natural compound 1,2,3,4,6-O-pentagalloylglucose (PGG), not only inhibiting the enzymatic activity of MAT2A but also promoting its proteasome degradation through E3 ligase SMURF1-mediated polyubiquitylation. Consequently, PGG can induce pyroptosis by cleaving GSDME in various tumor cells and suppress tumor cell growth through enhancing anti-tumor immune response. Collectively, our findings reveal that MAT2A is an essential metabolic regulator of pyroptosis, and PGG could potentially boost anti-tumor immunity by targeting MAT2A.