The deubiquitinase USP5 mediates anti-PD-L1 resistance in breast cancer by stabilizing FOXM1 to upregulate Nectin2.

USP5 is a deubiquitinating enzyme whose role in anti-PD-L1 resistance in breast cancer remains unclear. This study investigated whether USP5 contributes to resistance against the anti‑PD‑L1 antibody (atezolizumab) by regulating the FOXM1/Nectin2 axis. Anti-PD-L1-resistant and lung metastatic mouse models were established, combined with in vitro cellular assays, clinical sample analyses, and bioinformatics approaches. The results showed that USP5 was upregulated in breast cancer and stabilized FOXM1 via deubiquitination, which led to increased Nectin2 expression and resistance to CD8⁺ T cell-mediated killing. Knockdown of USP5 or its pharmacological inhibition with G9 synergized with anti-PD-L1 to suppress tumor growth, an effect that was reversible by Nectin2 overexpression. In conclusion, USP5 promotes breast cancer progression and anti-PD-L1 resistance by deubiquitinating FOXM1, thereby upregulating Nectin2 expression. Targeting USP5 enhances the efficacy of anti-PD-L1 therapy, offering a novel strategy to overcome immunotherapy resistance in breast cancer.