The study investigates the role of NSUN5, a 28S rRNA methyltransferase, in the immune evasion of malignant glioma. NSUN5 down-regulates β-catenin by promoting its mRNA degradation, enhancing phagocytosis of tumor-associated macrophages (TAMs). Specifically, NSUN5 methylates CTNNB1 chromatin-associated RNA (caRNA) through its methyltransferase activity, which is independent of its localization in the nucleolus. The m5C modification on CTNNB1 caRNA is subsequently oxidized to 5-hydroxymethylcytosine (5hmC) by TET2, leading to its degradation through recognition by the 5hmC-specific reader RBFOX2. The NSUN5/TET2/RBFOX2 signaling pathway regulates RNA metabolism and immune evasion in glioma. Additionally, NSUN5 is epigenetically suppressed by DNA methylation and negatively correlated with the IDH1-R132H mutation in glioma patients. Pharmacological inhibition of DNA methylation or targeting the IDH1-R132H mutant and CD47/SIRPα signaling synergistically enhances TAM-based phagocytosis and glioma elimination in vivo. These findings highlight NSUN5 as a potential target for glioma immune therapy.The study investigates the role of NSUN5, a 28S rRNA methyltransferase, in the immune evasion of malignant glioma. NSUN5 down-regulates β-catenin by promoting its mRNA degradation, enhancing phagocytosis of tumor-associated macrophages (TAMs). Specifically, NSUN5 methylates CTNNB1 chromatin-associated RNA (caRNA) through its methyltransferase activity, which is independent of its localization in the nucleolus. The m5C modification on CTNNB1 caRNA is subsequently oxidized to 5-hydroxymethylcytosine (5hmC) by TET2, leading to its degradation through recognition by the 5hmC-specific reader RBFOX2. The NSUN5/TET2/RBFOX2 signaling pathway regulates RNA metabolism and immune evasion in glioma. Additionally, NSUN5 is epigenetically suppressed by DNA methylation and negatively correlated with the IDH1-R132H mutation in glioma patients. Pharmacological inhibition of DNA methylation or targeting the IDH1-R132H mutant and CD47/SIRPα signaling synergistically enhances TAM-based phagocytosis and glioma elimination in vivo. These findings highlight NSUN5 as a potential target for glioma immune therapy.