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Methuosis, a non\u2010apoptotic form of cell death, is largely unexplored for anti\u2010CSC therapy. Here we report a cobalt(III)\u2010cyclam complex (\n                    <jats:bold>1<\/jats:bold>\n                    ) incorporating pyrene and diflunisal moieties that induces features consistent with methuosis in a CSC model. Mechanistic investigations revealed that\n                    <jats:bold>1<\/jats:bold>\n                    induces phenotypes consistent with methuosis in breast CSCs, including extensive cytoplasmic vacuolation, elevated Rab7 and LAMP1 expression, activation of JNK and p38 MAPK pathways, G2\/M cell\u2010cycle arrest, augmented intracellular reactive oxygen species levels, and disruption of the mitochondrial membrane potential. Beyond direct cytotoxicity,\n                    <jats:bold>1<\/jats:bold>\n                    induces an anti\u2010breast CSC immunogenic response by perturbing the inhibitory damage\u2010associated molecular patterns axis through cyclooxygenase\u20102 downregulation. When formulated as polymeric nanoparticles and evaluated in a murine metastatic triple\u2010negative breast cancer model,\n                    <jats:bold>1<\/jats:bold>\n                    penetrates tumour tissue and suppresses tumour growth more than cisplatin. The nanoparticle formulation activates anti\u2010tumour immunity, characterised by enhanced infiltration of T cells and mature dendritic cells in tumours and tumour\u2010draining lymph nodes. Intratumoral T\u2010cell recruitment is associated with M2\u2010to\u2010M1 macrophage polarisation and depletion of myeloid\u2010derived suppressor cells. This work identifies\n                    <jats:bold>1<\/jats:bold>\n                    as the first metal complex shown to induce features consistent with methuosis in a CSC model.\n                  <\/jats:p>","DOI":"10.1002\/anie.8926368","type":"journal-article","created":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T05:40:56Z","timestamp":1789105256000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Induction of Methuosis in Breast Cancer Stem Cells by a Cobalt(III) Complex Evokes Immunotherapeutic Response"],"prefix":"10.1002","author":[{"given":"Jiaxin","family":"Fang","sequence":"first","affiliation":[{"name":"School of Chemistry University of Leicester  Leicester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-9966-6775","authenticated-orcid":false,"given":"Sijie","family":"Wen","sequence":"additional","affiliation":[{"name":"Beijing National Laboratory for Molecular Sciences Laboratory of Polymer Physics and Chemistry Institute of Chemistry Chinese Academy of Sciences  Beijing P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Feng","sequence":"additional","affiliation":[{"name":"School of Chemistry University of Leicester  Leicester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Ren","sequence":"additional","affiliation":[{"name":"School of Chemistry University of Leicester  Leicester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kuldip","family":"Singh","sequence":"additional","affiliation":[{"name":"School of Chemistry University of Leicester  Leicester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8159-8187","authenticated-orcid":false,"given":"Haihua","family":"Xiao","sequence":"additional","affiliation":[{"name":"Suzhou Institute of Pharmaceutical Innovation Soochow University  Suzhou P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-0013-5215","authenticated-orcid":false,"given":"Lingpu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Suzhou Institute of Pharmaceutical Innovation Soochow University  Suzhou P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7047-6384","authenticated-orcid":false,"given":"Kogularamanan","family":"Suntharalingam","sequence":"additional","affiliation":[{"name":"School of Chemistry University of Leicester  Leicester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,10]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.cdd.4401556"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41571\u2010020\u20100341\u2010y"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.24064"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00048059"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc1560"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cpt.2025.07.001"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.093575"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.03.042"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2023.1159409"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12967\u2010025\u201006121\u20101"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1450998"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2025.107945"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2014.02.028"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1158\/1541\u20107786.MCR\u201007\u20102036"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1039\/D3MD00155E"},{"key":"e_1_2_8_17_1","doi-asserted-by":"crossref","first-page":"1849","DOI":"10.3390\/ph18121849","article-title":"PI3K\/mTOR Inhibitor Induces Context\u2010Dependent Apoptosis and Methuosis in Cancer Cells","volume":"18","author":"Hua X.","year":"2025","journal-title":"Pharmaceuticals"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2024.1534217"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202404693"},{"key":"e_1_2_8_20_1","doi-asserted-by":"crossref","first-page":"218","DOI":"10.3390\/md22050218","article-title":"Novel Metabolites From the Marine\u2010Derived Fungus Peniophora sp. 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