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The efficacy of immune checkpoint inhibitor-based immunotherapy in triple-negative breast cancer has provided a rationale for exploring its expansion to other breast cancer subtypes. Immunosuppressive tumor-associated macrophages (TAMs) within the tumor microenvironment have been demonstrated as a formidable barrier to the efficacy of approved immunotherapy. We aimed to identify and therapeutically modulate pathways that regulate the immunosuppressive properties of TAMs for more effective breast cancer immunotherapies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We integrated analyses of publicly available human breast cancer single-cell RNA sequencing (scRNA-seq) datasets with scRNA-seq profiling of murine mammary tumors to identify the signaling pathways associated with immunosuppression. The therapeutic implications of our findings were subsequently assessed through both\n                      <jats:italic>in vitro<\/jats:italic>\n                      and\n                      <jats:italic>in vivo<\/jats:italic>\n                      models. Single-cell transcriptional profiling was further performed to characterize the tumor immune microenvironment and understand the mechanisms of therapeutic activity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We revealed a strong positive correlation between iron metabolic gene signature and immunosuppressive features in TAMs of breast cancers. We showed that iron treatment on primary macrophages enhanced the proliferation of activated T cells, which was accompanied by downregulation of immunosuppressive mediators in macrophages. Importantly, we demonstrated that iron supplementation augmented the antitumor effect of PD-1 based immunotherapy in two preclinical models, with increased infiltration and cytotoxic activity of CD8\u2009+\u2009T cells. Furthermore, iron treatment functionally reprogramed TAMs toward a less immunosuppressive state, potentially due to\u00a0the downregulation of NF-\u03baB inflammatory pathways and a shift in cellular metabolism.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings advance the pivotal roles of iron in modulating the functional phenotypes of TAMs and anti-tumor immunity, and suggest that iron supplementation may represent a valuable clinical strategy for\u00a0optimizing anti-PD-1 immunotherapy in breast cancer.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13046-026-03661-2","type":"journal-article","created":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T02:56:45Z","timestamp":1770865005000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Iron diminishes immunosuppressive macrophages and enhances anti-PD-1 immunotherapy in breast cancer models"],"prefix":"10.1186","volume":"45","author":[{"given":"Qingfei","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth L.","family":"Adams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rylee A.","family":"Poole","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tahereh","family":"Soleimani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grace Xiyu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hudie","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maegan L.","family":"Capitano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashiq","family":"Masood","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott I.","family":"Abrams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelvin P.","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siyuan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mateusz","family":"Opyrchal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,12]]},"reference":[{"key":"3661_CR1","doi-asserted-by":"publisher","first-page":"477","DOI":"10.3322\/caac.21863","volume":"74","author":"AN Giaquinto","year":"2024","unstructured":"Giaquinto AN, Sung H, Newman LA, Freedman RA, Smith RA, Star J, et al. 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