biostudies-literatureShao NNational Natural Science Foundation of China (National Science Foundation of China)1313https://www.ebi.ac.uk/biostudies/studies/S-EPMC11791202biostudies-literatureUnknown16(1)The N⁶-methyladenosine binding protein YTHDF1, often upregulated in cancer, promotes tumor growth and hinders immune checkpoint blockade treatment. A comprehensive understanding of the molecular mechanisms governing YTHDF1 protein stability is pivotal for enhancing clinical response rates and the effectiveness of immune checkpoint blockade in cancer patients. Here, we report that USP5 interacts with YTHDF1, stabilizing it by removing K11-linked polyubiquitination. Insulin activates mTORC1, phosphorylating USP5 and promoting its dimerization, which binds to and protects YTHDF1 from degradation. Conversely, the CUL7-FBXW8 E3 ligase promotes YTHDF1 degradation. Deficiency in YTHDF1 or USP5 increases PD-L1 expression and suppresses immune-related gene expression, facilitating immuneNature communicationsUSP5 stabilizes YTHDF1 to control cancer immune surveillance through mTORC1-mediated phosphorylation.PMC11791202819722973210102482372748Peng XOng BXLv YXiang JXu FZhang LIdris MZhang QXi LCao YShao NLiu CXu XYue XfalseUSP5 stabilizes YTHDF1 to control cancer immune surveillance through mTORC1-mediated phosphorylation.The N⁶-methyladenosine binding protein YTHDF1, often upregulated in cancer, promotes tumor growth and hinders immune checkpoint blockade treatment. A comprehensive understanding of the molecular mechanisms governing YTHDF1 protein stability is pivotal for enhancing clinical response rates and the effectiveness of immune checkpoint blockade in cancer patients. Here, we report that USP5 interacts with YTHDF1, stabilizing it by removing K11-linked polyubiquitination. Insulin activates mTORC1, phosphorylating USP5 and promoting its dimerization, which binds to and protects YTHDF1 from degradation. Conversely, the CUL7-FBXW8 E3 ligase promotes YTHDF1 degradation. Deficiency in YTHDF1 or USP5 increases PD-L1 expression and suppresses immune-related gene expression, facilitating immune2025-01-01T00:00:00Z2025 Feb2026-06-01T11:02:44.066Z2025-04-04T01:36:15.969ZS-EPMC117912023990092110.1038/s41467-025-56564-9