An IGF2BP3-dependent metabolic circuit governs macrophage recruitment and immunosuppression in glioblastoma.

The glioblastoma microenvironment is highly immunosuppressive and enriched with macrophages, which critically promote tumor progression and confer resistance to current therapies. However, the molecular mechanisms by which glioblastoma cells orchestrate macrophage recruitment through post-transcriptional regulation remain poorly understood. Here, we identify a glioblastoma-intrinsic pathway whereby the m6A RNA modification reader IGF2BP3 couples RNA metabolism with metabolic competition and immune remodeling. Specifically, IGF2BP3 selectively binds and stabilizes m6A-modified transcripts encoding the methionine transporter SLC38A2, thereby enhancing methionine uptake by glioblastoma cells. This metabolic advantage creates a methionine-deprived state in neighboring macrophages, leading to reduced global m6A methylation and increased expression of the chemokine CCL5. Elevated CCL5 subsequently drives further macrophage infiltration, establishing a feedforward loop that amplifies nutrient competition and sustains immunosuppression within the tumor microenvironment. Together, our findings delineate an m6A-dependent metabolic circuit that governs macrophage recruitment in glioblastoma and suggest a therapeutic avenue to reprogram the tumor immune microenvironment.