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Although trastuzumab has transformed HER2+\u2009BC treatment, its efficacy against BrM remains limited by brain-specific resistance mechanisms and heterogeneous blood\u2013brain barrier (BBB) permeability. Here, we investigated whether HER2-targeted radionuclide therapy (TRT) using the \u03b2-emitting radioimmunoconjugate [\n                    <jats:sup>177<\/jats:sup>\n                    Lu]Lu-DOTA-trastuzumab could overcome trastuzumab resistance in HER2+\u2009brain metastatic lesions. Brain-tropic cells retained HER2 expression but showed reduced sensitivity to trastuzumab, indicating the emergence of resistance mechanisms independent of target loss. By contrast, treatment with [\n                    <jats:sup>177<\/jats:sup>\n                    Lu]Lu-DOTA-trastuzumab produced robust DNA double-strand break-mediated cytotoxicity irrespective of trastuzumab sensitivity, demonstrating that resistance to antibody-mediated signaling inhibition does not confer cross-resistance to radiation-induced cell killing. In vivo, a single dose of [\n                    <jats:sup>177<\/jats:sup>\n                    Lu]Lu-DOTA-trastuzumab markedly reduced tumor progression and led to complete remission of established BrM in 40% of treated animals, whereas unconjugated trastuzumab showed minimal therapeutic benefit. Importantly, treatment was not associated with detectable neurotoxicity. While dynamic contrast-enhanced MRI demonstrated widespread BBB disruption across metastatic lesions, [\n                    <jats:sup>89<\/jats:sup>\n                    Zr]Zr-DFO-trastuzumab PET revealed marked heterogeneity in intracranial antibody delivery, with tracer uptake restricted to a subset of lesions. Collectively, these findings demonstrate that HER2-TRT can overcome trastuzumab resistance and eradicate brain metastatic lesions. Moreover, immuno-PET provides a non-invasive biomarker of intracranial antibody accessibility, supporting a theranostic strategy that combines patient stratification with TRT for HER2+\u2009BrM.\n                  <\/jats:p>","DOI":"10.1186\/s43556-026-00573-7","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T09:48:06Z","timestamp":1789379286000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["177Lu-trastuzumab radionuclide therapy: a promising strategy for trastuzumab-resistant brain metastases in HER2+\u2009breast cancer"],"prefix":"10.1186","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2525-9572","authenticated-orcid":false,"given":"Liliana","family":"Santos","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivanna","family":"Hrynchak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9","family":"Sereno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hugo R.S.","family":"Ferreira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magda","family":"Silva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Fonseca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Almeida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paulo","family":"Teixeira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4145-854X","authenticated-orcid":false,"given":"Antero J.","family":"Abrunhosa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7497-4129","authenticated-orcid":false,"given":"C\u00e9lia M. 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