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With a focus on TNBC cell line, this study shows that hybrids with Pd- and Cu- in comparison to Pt-based counterparts exerted an advanced cytotoxic profile in terms of sustained cytotoxicity throughout all tested periods, well synchronized with an intensive and prolonged oxidative burst measured by 4-amino-5-methylamino-2\u2032,7\u2032-difluorofluorescein diacetate (DAF-FM), dihydroethidium (DHE), and dihydrorhodamine 123 (DHR-123) in the background. Translation to the orthotopic syngeneic mouse in vivo model confirmed their superiority toward Pt-based conjugates, as well as tamoxifen alone, with a more profound tumor-reducing potential of Cu-tamoxifen, which was finally restricted by its toxicity. Surprisingly, the tamoxifen vector per se, with an approx. 2-fold lower cytotoxic potential than Pt- and Cu-hybrids in vitro, showed exceptional tumor-reducing potential in vivo, profiled in the last days of the treatment period. Intensive infiltration of immune cells, preferentially lymphocytes, was observed in tumor samples from animals exposed to the tamoxifen vector, underscoring the ligand\u2019s immune potential and again suggesting that cytotoxicity is not a measure of successful treatment.<\/jats:p>","DOI":"10.3390\/molecules31091376","type":"journal-article","created":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T10:38:14Z","timestamp":1776854294000},"page":"1376","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["ER\u03b1-Independent Activity of Tamoxifen-Based Transition Metal Hybrids in Triple-Negative Breast Cancer Models In Vitro and In Vivo"],"prefix":"10.3390","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2289-946X","authenticated-orcid":false,"given":"Blagoje","family":"Murgani\u0107","sequence":"first","affiliation":[{"name":"Department of Radiobiology and Molecular Genetics, Institute of Nuclear Sciences \u201cVin\u010da\u201d, National Institute of Republic of Serbia, University of Belgrade, 11351 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6938-6154","authenticated-orcid":false,"given":"Tamara","family":"Krajnovi\u0107","sequence":"additional","affiliation":[{"name":"Department of Immunology, Institute for Biological Research \u201cSini\u0161a Stankovi\u0107\u201d, National Institute of the Republic of Serbia, University of Belgrade, 11108 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Du\u0161ko","family":"Dun\u0111erovi\u0107","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Institute of Pathology, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksandr","family":"Kazimir","sequence":"additional","affiliation":[{"name":"Institute for Drug Discovery, Faculty of Medicine, Leipzig University, 04103 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nasta","family":"Tani\u0107","sequence":"additional","affiliation":[{"name":"Department of Radiobiology and Molecular Genetics, Institute of Nuclear Sciences \u201cVin\u010da\u201d, National Institute of Republic of Serbia, University of Belgrade, 11351 Belgrade, Serbia"},{"name":"Department of Natural Sciences and Mathematics, State University of Novi Pazar, 36300 Novi Pazar, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikola","family":"Tani\u0107","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, Institute for Biological Research \u201cSini\u0161a Stankovi\u0107\u201d, National Institute of the Republic of Serbia, University of Belgrade, 11108 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4267-0603","authenticated-orcid":false,"given":"Evamarie","family":"Hey-Hawkins","sequence":"additional","affiliation":[{"name":"Institute of Inorganic Chemistry, Faculty of Chemistry and Mineralogy, Leipzig University, 04103 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8006-5079","authenticated-orcid":false,"given":"Danijela","family":"Maksimovi\u0107-Ivani\u0107","sequence":"additional","affiliation":[{"name":"Department of Immunology, Institute for Biological Research \u201cSini\u0161a Stankovi\u0107\u201d, National Institute of the Republic of Serbia, University of Belgrade, 11108 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9509-9098","authenticated-orcid":false,"given":"Sanja","family":"Mijatovi\u0107","sequence":"additional","affiliation":[{"name":"Department of Immunology, Institute for Biological Research \u201cSini\u0161a Stankovi\u0107\u201d, National Institute of the Republic of Serbia, University of Belgrade, 11108 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1044","DOI":"10.1016\/j.drudis.2019.02.012","article-title":"Anticancer Activity of Palladium-Based Complexes against Triple-Negative Breast Cancer","volume":"24","author":"Vojtek","year":"2019","journal-title":"Drug Discov. 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