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We found that distant metastases are more immune inert with increased M2 macrophages compared to their matched primary tumors. The acetyl-lysine reader, cat eye syndrome chromosome region candidate 2 (CECR2), was the top up-regulated epigenetic regulator in metastases associated with an increased abundance of M2 macrophages and worse metastasis-free survival. CECR2 was required for breast cancer metastasis in multiple mouse models, with more profound effect in the immunocompetent setting. Mechanistically, the nuclear factor \u03baB (NF-\u03baB) family member v-rel avian reticuloendotheliosis viral oncogene homolog A (RELA) recruits CECR2 to increase chromatin accessibility and activate the expression of their target genes. These target genes include multiple metastasis-promoting genes, such as\n                    <jats:italic>TNC<\/jats:italic>\n                    ,\n                    <jats:italic>MMP2<\/jats:italic>\n                    , and\n                    <jats:italic>VEGFA<\/jats:italic>\n                    , and cytokine genes\n                    <jats:italic>CSF1<\/jats:italic>\n                    and\n                    <jats:italic>CXCL1<\/jats:italic>\n                    , which are critical for immunosuppression at metastatic sites. Consistent with these results, pharmacological inhibition of CECR2 bromodomain impeded NF-\u03baB\u2013mediated immune suppression by macrophages and inhibited breast cancer metastasis. These results reveal that targeting CECR2 may be a strategy to treat metastatic breast cancer.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.abf5473","type":"journal-article","created":{"date-parts":[[2022,2,2]],"date-time":"2022-02-02T13:53:15Z","timestamp":1643809995000},"source":"Crossref","is-referenced-by-count":131,"title":["CECR2 drives breast cancer metastasis by promoting NF-\u03baB signaling and macrophage-mediated immune suppression"],"prefix":"10.1126","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1370-670X","authenticated-orcid":true,"given":"Meiling","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Pathology, Yale School of Medicine, New Haven, CT 06520, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1578-9967","authenticated-orcid":true,"given":"Zongzhi Z.","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pathology, Yale School of 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