METTL3 abrogation promotes glioma progression through regulating the ISG15-FASN axis-mediated lipid metabolism in macrophages.

ABSTRACT: Tumor-associated macrophages (TAMs) constitute a pivotal cellular component within the intricate tumor microenvironment (TME). However, the relationship between the N6-methyladenosine (m6A) and metabolic pattern of TAMs remains poorly understood. Here we show that the m6A methyltransferase METTL3 is conspicuously downregulated in monocyte-derived macrophages from glioblastoma (GBM) patients. Conditional knockout of Mettl3 in myeloid cells augments lipid metabolism and accelerates glioma progression. Furthermore, we found that METTL3 deficiency facilitates fatty acid synthase (FASN) expression, while compromising CD8⁺ T cell response. Mechanistically, ISG15 is highly expressed in METTL3-deficient macrophages. ISG15 interacts with FASN and regulates FASN ISGylation and its stabili

SUBMITTER: Yin H 

PROVIDER: S-EPMC12873282 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature