ZNF460 Promotes the m6A Modification of COPS6 to Facilitate Immune Escape in Colorectal Cancer

Colorectal cancer (CRC) continues to be a significant global health concern. Emerging studies emphasize the tumor microenvironment (TME) as a key regulator of therapeutic response, particularly in its ability to suppress CD8⁺ T cell-mediated tumor clearance under chronic stimulation. However, the precise mechanisms responsible for this immunosuppressive effect remain unclear and require further exploration. Functional experiments evaluated CRC cell proliferation, migration, and invasion. CD8⁺ T cell infiltration and cytotoxicity were assessed using flow cytometry and LDH cytotoxicity assays. Mechanistic studies involved RNA immunoprecipitation (RIP), methylated RNA immunoprecipitation (MeRIP), chromatin immunoprecipitation (ChIP), and dual-luciferase reporter assays to investigate the METTL5/YTHDF1-mediated regulation of COPS6 and the transcriptional activation of METTL5 by ZNF460. An in vivo CRC mouse model was established. The results indicated COPS6 was significantly upregulated in CRC and associated with poor prognosis. Knockdown of COPS6 suppressed CRC proliferation, migration, and invasion while enhancing CD8⁺ T cell infiltration and cytotoxicity. METTL5 was identified as an upstream regulator of COPS6, stabilizing its mRNA via m6A modification in a YTHDF1-dependent manner. ZNF460 bound to the METTL5 promoter, enhancing its transcription. In vivo, depletion of ZNF460 or METTL5 inhibited tumor growth and increased CD8⁺ T cell activity, whereas METTL5 overexpression reversed these effects. The ZNF460/METTL5/COPS6 axis promotes CRC progression and immune evasion by regulating COPS6 stability and CD8⁺ T cell infiltration. Targeting this pathway may offer new therapeutic strategies for CRC treatment.