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These patients are also disadvantaged in responding to immunotherapies, the mechanisms of which remain to be elucidated. Here, we engineered a transgenic mouse model carrying either Y541S or D542G mutation in\n                    <jats:italic>ESR1<\/jats:italic>\n                    , mirroring the 2 most common mutations seen in patients.\n                    <jats:italic>\n                      ESR1\n                      <jats:sup>mut<\/jats:sup>\n                    <\/jats:italic>\n                    tumors do not differ in the total number of immune cells yet display downregulation in immune pathways and decreased immune-modulatory cytokines, including IL-17a and IL-1\u03b2. T cells and macrophages have lower IFN-\u03b3 and antigen presentation, respectively. Mechanistically,\n                    <jats:italic>\n                      ESR1\n                      <jats:sup>mut<\/jats:sup>\n                    <\/jats:italic>\n                    negatively regulates immune modulator expression and upregulates Stat5 to dampen cytokine expression. In concordance, validation on\n                    <jats:italic>\n                      ESR1\n                      <jats:sup>mut<\/jats:sup>\n                    <\/jats:italic>\n                    patient tumors shows decreased IL-17a and IL-1\u03b2. Collectively, our findings reveal that\n                    <jats:italic>ESR1<\/jats:italic>\n                    mutations contribute to an immunosuppressive tumor microenvironment by dampening cytokine secretion and immune cell activity.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.199927","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T18:00:41Z","timestamp":1772992841000},"source":"Crossref","is-referenced-by-count":2,"title":["Activating mutations in ESR1 contribute to an immunosuppressive breast tumor microenvironment by dampening cytokine secretion"],"prefix":"10.1172","volume":"11","author":[{"given":"Yu","family":"Gu","sequence":"first","affiliation":[{"name":"Rosalind and Morris Goodman Cancer Institute and"},{"name":"Faculty of Medicine and Health Sciences, Department of Biochemistry, McGill University, Montreal, Quebec, 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and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Ling","sequence":"additional","affiliation":[{"name":"Rosalind and Morris Goodman Cancer Institute and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9917-514X","authenticated-orcid":true,"given":"Adrian V.","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA."},{"name":"Women\u2019s Cancer Research Center, Magee-Womens Research Institute, UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2537-6923","authenticated-orcid":true,"given":"Steffi","family":"Oesterreich","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, 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