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Triple\u2010negative breast cancer (TNBC) lacks estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2) and presents unique therapeutic challenges. Although no TNBC\u2010specific medicines exist, programmed cell death protein 1 (PD\u20101)\/programmed cell death ligand 1 (PD\u2010L1) immunotherapy shows promise. Gut microbiota has emerged as a regulator of breast cancer growth, and Traditional Chinese Medicine (TCM) is gaining attention in tumor therapy. This study aimed to evaluate the therapeutic potential of ginsenoside Rg3 and PD\u20101 immunotherapy in a TNBC mouse model and to assess the impact of gut microbiota and metabolites on treatment outcomes. Breast cancer cell lines (4\u2009T1, MDA\u2010MB\u2010231) were treated with Rg3 and evaluated for viability, apoptosis, migration, and invasion assays. In\u00a0vivo, 4\u2009T1 tumor\u2010bearing mice were randomized to receive Rg3, anti\u2010PD\u20101, or combination therapy; tumor growth and biocompatibility were assessed. Fecal samples underwent 16S rRNA gene sequencing and untargeted LC\u2013MS metabolomics with multivariate and statistical analyses. Ginsenoside Rg3 reshaped the tumor microenvironment by promoting M1 macrophage polarization, increasing CD8\n                    <jats:sup>+<\/jats:sup>\n                    and memory T cells, and upregulating Th1 and M1 cytokines while reducing immunosuppressive CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells, Treg cells, and M2 macrophages. Anti\u2010PD\u20101 monoclonal antibody (PD\u20101 mAb)\/Rg3 inhibited tumor growth, increased apoptosis, and enhanced M1 polarization and CD8\n                    <jats:sup>+<\/jats:sup>\n                    T\u2010cell responses, with combined treatment further amplifying these effects. Gut microbiota composition and abundance differed across groups, with specific metabolites influencing treatment success.\n                    <jats:styled-content style=\"fixed-case\">\n                      <jats:italic>Bacteroides vulgatus<\/jats:italic>\n                    <\/jats:styled-content>\n                    showed a positive correlation with sulforaphane\u2010cysteine, suggesting a role for gut microbiota metabolomics in modulating therapeutic benefits. Overall, this study highlights the potential of combining PD\u20101 immunotherapy with ginsenoside Rg3, underscoring the role of the gut microbiota and its metabolites in TNBC treatment.\n                  <\/jats:p>","DOI":"10.1002\/ptr.70278","type":"journal-article","created":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T06:28:45Z","timestamp":1774247325000},"page":"3190-3211","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Ginsenoside Suppresses Triple\u2010Negative Breast Cancer Growth and Synergizes With Programmed Cell Death Protein 1 (\n                    <scp>PD<\/scp>\n                    \u20101) Immunotherapy Through Gut Microbiota and Metabolic Regulation"],"prefix":"10.1002","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3336-9501","authenticated-orcid":false,"given":"Na","family":"Luo","sequence":"first","affiliation":[{"name":"Department of General Surgery Xiangya Hospital, Central South University  Changsha China"},{"name":"Clinical Research Center for Breast Cancer Control and Prevention in Hunan Province  Changsha China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Li","sequence":"additional","affiliation":[{"name":"Department of General Surgery Xiangya Hospital, Central South University  Changsha China"},{"name":"Clinical Research Center for Breast Cancer Control and Prevention in Hunan Province  Changsha China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of General Surgery Xiangya Hospital, Central South University  Changsha China"},{"name":"Clinical Research Center for Breast Cancer Control and Prevention in Hunan Province  Changsha China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of General Surgery Xiangya Hospital, Central South University  Changsha China"},{"name":"Clinical Research Center for Breast Cancer Control and Prevention in Hunan Province  Changsha China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kejing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of General Surgery Xiangya Hospital, Central South University  Changsha China"},{"name":"Clinical Research Center for Breast Cancer Control and Prevention in Hunan Province  Changsha China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,3,22]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22179644"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.3390\/nu13010201"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13046-022-02476-1"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-21-0515"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/fsn3.3168"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/onco.13887"},{"issue":"4","key":"e_1_2_13_8_1","first-page":"291","article-title":"Co\u2010Treatment With Ginsenoside 20(S)\u2010Rg3 and Curcumin Increases Radiosensitivity of MDA\u2010MB\u2010231 Cancer Cell Line","volume":"46","author":"Changizi V.","year":"2021","journal-title":"Iranian Journal of Medical 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