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Tumor-infiltrating lymphocytes (TILs), CD4\u2009+, and CD8\u2009+\u2009T cell densities are markers of immune activity and breast cancer prognosis. We examined associations between lifetime reproductive hormone exposure, tumor immune infiltration, and survival among women with breast cancer.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The study included invasive breast cancer cases in the Women's Circle of Health Study and the Women\u2019s Circle of Health Follow-up Study. Lifetime endogenous hormone exposure (LHEendo) was defined as reproductive years plus pregnancy duration minus breastfeeding duration; lifetime exogenous hormone exposure (LHEexo) was defined as the combined cumulative duration of oral contraceptive and hormone replacement therapy use. TILs were scored as ordered percentage values from 0 to 100% stromal area; CD4\u2009+\u2009\/CD8\u2009+\u2009T cell densities were quantified by immunohistochemistry. TILs were modeled using ordinal logistic regression, and CD4\u2009+\u2009\/CD8\u2009+\u2009T cell densities were modeled using gamma generalized linear models among participants with positive density values, with covariates selected by directed acyclic graphs. Overall survival was assessed using Cox proportional hazards models, and breast cancer-specific survival was assessed using Fine-Gray competing-risk models.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Among 1195 women with valid TILs measurements, 553 and 610 had CD4\u2009+\u2009and CD8\u2009+\u2009T cell density data, respectively. Across all tumor molecular subtypes, a 1-year increment of LHEendo was associated with a 2.85% decrease in CD8\u2009+\u2009T cell density (95% CI \u2212\u20095.14%, \u2212\u20090.61%). LHEendo was associated with lower odds of being in a higher TIL level among women with hormone receptor (HR)\u2009+\u2009\/HER2- tumors (OR\u2009=\u20090.977, 95% CI 0.957, 0.997), although the interaction by molecular subtype was not statistically significant. LHEexo was associated with lower risk of all-cause mortality (HR\u2009=\u20090.979, 95% CI 0.960, 0.998). TIL-stratified analyses suggested that this association may be more apparent among women with TILs\u2009\u2265\u200950% (HR\u2009=\u20090.90, 95% CI\u2009=\u20090.82, 0.99; P-interaction\u2009=\u20090.10).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Lifetime endogenous hormone exposure was associated with lower CD8\u2009+\u2009T cell density overall, with exploratory findings of lower TIL levels among women with HR\u2009+\u2009\/HER2- tumors. Lifetime exogenous hormone exposure was associated with a lower risk of all-cause mortality, with possible variation by TIL levels.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00262-026-04471-3","type":"journal-article","created":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T10:02:37Z","timestamp":1783677757000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Association between cumulative lifetime exposure to reproductive hormones and tumor\u2010infiltrating lymphocytes, CD4\u2009+, and CD8\u2009+\u2009T cells among women with breast cancer"],"prefix":"10.1007","volume":"75","author":[{"given":"Yidan","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rand T.","family":"Akasheh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela R.","family":"Omilian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Qin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nur","family":"Zeinomar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Song","family":"Yao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chi-Chen","family":"Hong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa V.","family":"Bandera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine B.","family":"Ambrosone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thaer","family":"Khoury","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4105-828X","authenticated-orcid":false,"given":"Ting-Yuan David","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,10]]},"reference":[{"issue":"3","key":"4471_CR1","first-page":"229","volume":"74","author":"F Bray","year":"2024","unstructured":"Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I et al (2024) Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. 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