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While anti-CD47 therapies can restore immune surveillance, their efficacy in TNBC is often limited by immune evasion and drug development challenges.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We investigated the crosstalk between the histone demethylase lysine-specific demethylase 1 (LSD1) and CD47 signaling in TNBC using\n                      <jats:italic>in silico<\/jats:italic>\n                      datasets, isogenic cell lines, conditional BRCA1 knockout models, and syngeneic mouse models. Techniques such as immunohistochemistry, multiplex immunofluorescence, immunoprecipitation, protein ubiquitination, chromatin immunoprecipitation, chemotaxis, flow cytometry, and phagocytosis assays were employed to examine the epigenetic regulation of CD47 by LSD1 and its impact on antitumor immunity. The efficacy of combining LSD1 inhibition with anti-CD47 therapy was evaluated in BALB\/cJ mice bearing TNBC tumors.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>In TNBC tumors, CD47 expression is positively correlated with elevated LSD1 levels, which are associated with increased infiltration of M2 macrophages and a concomitant decrease in M1 macrophages and CD8+T cells. Inhibition of LSD1 led to downregulation of CD47 by suppressing the expression and activity of its key transcriptional regulators, NF-\u03baB (p65) and STAT3, through distinct mechanisms. Loss of LSD1 reduced p65 transcription, which was linked to an accumulation of the repressive histone mark H3K9me2 at the p65 promoter. Conversely, LSD1 inhibition promoted polyubiquitination and subsequent destabilization of STAT3. LSD1 inhibition also enhanced phagocytosis and promoted M1 polarization of macrophages. CD47 downregulation induced the production of interferon-\u03b3 and Th1-type chemokines in TNBC cells, facilitating increased tumor infiltration of CD8+T cells. Furthermore, combining LSD1 inhibition with anti-CD47 therapy significantly improved antitumor efficacy compared with monotherapy in syngeneic tumor models, without inducing significant toxicity. This combination therapy also promoted a shift in macrophage polarization toward the M1 phenotype, further enhancing CD8+T\u2009cell infiltration within tumors. Depletion of CD8+T cells significantly diminished the antitumor efficacy of the combination therapy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Targeting LSD1 enhances the efficacy of anti-CD47 therapy by overcoming immune evasion, offering a promising strategy to improve immunotherapy outcomes in TNBC.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2025-014681","type":"journal-article","created":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T13:20:20Z","timestamp":1780579220000},"page":"e014681","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":2,"title":["Inhibition of histone demethylase LSD1 suppresses CD47 expression and enhances efficacy of CD47 blockade in breast 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