NSUN2/m5C/TPI1 axis promotes glycolysis and immune evasion in breast cancer

BACKGROUND: Aerobic glycolysis and immune evasion drive tumor development. 5-methylcytosine (m5C) methyltransferase NSUN2 acts as an oncogene in breast cancer (BC), but the molecular mechanisms remain incompletely elucidated. This study aimed to investigate the role of NSUN2 in BC and the underlying mechanisms. METHODS: In vitro experiments were conducted to determine cell proliferation, glycolysis, and immune evasion. Tumor growth was evaluated using a tumor-bearing mouse model. The interplay among NSUN2, YBX1, and TPI1 was evaluated by RNA immunoprecipitation, methylated RNA immunoprecipitation, and dual-luciferase reporter assay. RESULTS: The results showed that NSUN2 and TPI1 were highly expressed in BC cells. NSUN2 knockdown inhibited BC cell proliferation, glycolysis, and immune evasion, which was reversed by TPI1 overexpression. NSUN2 enhanced TPI1 stability by facilitating the m5C modification, which was recognized by YBX1. Moreover, overexpression of TPI1 reversed the inhibition of tumor growth, glycolysis, and immune cell infiltration induced by NSUN2 silencing in vivo. CONCLUSIONS: In conclusion, NSUN2 accelerates the progression of BC by promoting glycolysis and immune evasion. Mechanistically, NSUN2 promotes m5C methylation of TPI1 in a YBX1-dependent manner, which is associated with increased PD-L1 expression and immune-evasive phenotypes. These findings suggest that NSUN2 may be an effective therapeutic target for BC.