Abstract Epigenetic and transcriptional changes are critical for metastasis, the major cause of cancer-related deaths. Metastatic tumor cells escape immune surveillance more efficiently than tumor cells in the primary sites, but the mechanisms controlling their immune evasion are poorly understood. We found that distal metastases are more immune inert with increased M2 macrophages compared to their matched primary tumors. Acetyl-lysine reader CECR2 is an epigenetic regulator upregulated in metastases and positively associated with M2 macrophages. CECR2 specifically promotes breast cancer metastasis in multiple mouse models, with more profound effect in the immunocompetent setting. Mechanistically, NF-κB family member RELA recruits CECR2 to activate CSF1 and CXCL1 , which are critical for macrophage-mediated immunosuppression at the metastatic sites. Furthermore, pharmacological inhibition of CECR2 bromodomain impedes NF-κB-mediated immune suppression by macrophages and inhibits breast cancer metastasis. These results reveal novel therapeutic strategies to treat metastatic breast cancer. Statement of Significance Comparison of matched primary breast tumors and distal metastases show that metastases are more immune inert with increased tumor promoting macrophages. Depletion or pharmacological inhibition of CECR2 inhibits breast cancer metastasis by suppressing macrophage inflammatory responses, nominating CECR2 as a promising therapeutic target for cancer metastasis.

CECR2 Drives Breast Cancer Metastasis by Suppressing Macrophage Inflammatory Responses