OTUD5-mediated deubiquitination of YAP in macrophage promotes M2 phenotype polarization and favors triple-negative breast cancer progression.

Macrophages, which are highly plastic, can be polarized to M1 or M2 subtypes according to the diverse signals in complex microenvironment. Studies have shown the activation of YAP, an oncogenic transcriptional co-activator, increased macrophage recruitment. However, its role in macrophage polarization remains to be elucidated, especially in triple-negative breast cancer (TNBC) progression. Here we found TNBC cells increased YAP expression in macrophages, which depended on OTUD5-mediated deubiquitination and stabilization of YAP, then the high expression of YAP polarized macrophage to the M2-like phenotype. Moreover, the elevation of YAP in M2-like macrophage promotes the pro-metastatic potential of TNBC cells via MCP-1/CCR2 pathway. We also observed high expression of YAP in M2 macrophage was negatively related to survival. Collectively, our finding suggested the therapeutic strategy that targets YAP+ M2 macrophage could be a novel option for TNBC treatment.