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Here we used genetically engineered mouse models with luminal mammary epithelial cell (MEC)-restricted gene disruption to investigate its role in breast cancer initiation. Loss of RUNX1 alone, or together with RB1, was insufficient to drive tumor formation. In contrast, combined loss of RUNX1 and p53 induced mammary tumors with full penetrance. These tumors contained ER\n                  <jats:sup>+<\/jats:sup>\n                  cancer cells and exhibited extensive T cell and macrophage infiltration, indicative of an immune hot microenvironment. Mechanistically, RUNX1-deficiency activated interferon signaling in luminal MECs, associated with derepression of RUNX1 target\n                  <jats:italic>STAT1<\/jats:italic>\n                  and enhanced inflammatory responses. Consistent with these findings, human ER\n                  <jats:sup>+<\/jats:sup>\n                  breast cancers with low\n                  <jats:italic>RUNX1<\/jats:italic>\n                  expression displayed elevated immune signatures and poorer patient survival. Together, our results identify RUNX1-loss as a driver of an immune-active subtype of ER\n                  <jats:sup>+<\/jats:sup>\n                  breast cancer.\n                <\/jats:p>","DOI":"10.64898\/2026.04.06.716728","type":"posted-content","created":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T17:45:24Z","timestamp":1775756724000},"source":"Crossref","is-referenced-by-count":0,"title":["RUNX1-deficiency drives immune-active ER\n                  <sup>+<\/sup>\n                  mammary tumorigenesis through activation of interferon signaling"],"prefix":"10.64898","author":[{"given":"Sen","family":"Han","sequence":"first","affiliation":[{"name":"Division of Genetics, Department of Medicine, Brigham and Women\u2019s Hospital, Boston, Massachusetts 02115, USA"},{"name":"Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, 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