RBFOX2 suppresses NETosis and glioma growth via 5hmC-dependent PDGFB decay

Neutrophil extracellular traps (NETs) are increasingly recognized as key regulators of tumor progression, yet the molecular circuitry that governs their induction in cancer remains elusive. Here, we identify the RNA-binding protein RBFOX2 as a tumor suppressor that curtails glioma growth by coordinately restraining tumor cell proliferation and NETosis. RBFOX2 expression is markedly reduced in glioma and positively correlates with patient survival. Mechanistically, RBFOX2 binds to 5-hydroxymethylcytidine (5hmC)-modified sites within PDGFB mRNA and promotes its decay, thereby dampening AKT-SP1 signaling and repressing CSF3 transcription. This repression limits neutrophil-mediated NET formation in the tumor microenvironment, as confirmed in PAD4 −/− mice and upon CSF3 neutralization. Collectively, our study uncovers a 5hmC-dependent post-transcriptional mechanism linking RBFOX2 to NETosis control and glioma suppression, revealing RBFOX2 as a potential biomarker and therapeutic lever and establishing a broader paradigm in which RNA-binding proteins couple post-transcriptional RNA modification and immune regulation in tumor evolution.