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While most studies focus on T cells, innate immune populations such as macrophages are less well explored. In pediatric AML patients, we demonstrate that immunosuppressive macrophages dominate the AML microenvironment and support growth of\n                    <jats:italic>RUNX1::RUNX1T1<\/jats:italic>\n                    and\n                    <jats:italic>KMT2A<\/jats:italic>\n                    -rearranged leukemic blasts. In co-culture experiments, AML cells reprogrammed na\u00efve and pro-inflammatory macrophages toward an anti-inflammatory state, characterized by suppression of NF-\u03baB and other inflammatory pathways. This phenotypic switch requires direct cell contact and involves tunneling nanotube\u2013mediated transfer of AML mitochondria to macrophages associated with metabolic rewiring toward oxidative phosphorylation. Functionally, these reprogrammed macrophages exhibited impaired phagocytosis, convey chemoresistance and reduced T cell\u2013 and bispecific antibody\u2013mediated killing, facilitating immune escape. Our findings reveal a novel mechanism of immune suppression and suggest that targeting AML-macrophage interactions could enhance the efficacy of T cell\u2013based immunotherapies.\n                  <\/jats:p>","DOI":"10.1038\/s41375-026-03164-1","type":"journal-article","created":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T09:52:28Z","timestamp":1791539548000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mitochondria transfer via tunneling nanotubes drives macrophage immunosuppression and metabolic reprogramming in pediatric AML"],"prefix":"10.1038","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1302-0943","authenticated-orcid":false,"given":"Alicia","family":"Perzolli","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Farah","family":"Massaoudi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anita T.","family":"van Oort","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joost B.","family":"Koedijk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-9346-3701","authenticated-orcid":false,"given":"Elizabeth K.","family":"Schweighart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8259-9971","authenticated-orcid":false,"given":"Lennart A.","family":"Kester","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabienne","family":"Adriaanse","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6702-4045","authenticated-orcid":false,"given":"Kimberly","family":"Smit","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9690-1385","authenticated-orcid":false,"given":"Wilbert P.","family":"Vermeij","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4030-3228","authenticated-orcid":false,"given":"Bianca F.","family":"Goemans","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1825-1890","authenticated-orcid":false,"given":"Josef","family":"Vormoor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. 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OH has research funding from Roche and Syndax. CMZ has (consultancy) agreements with SUTRO Biopharma (Inc), Kestrel Therapeutics (Inc), Beigene, Syndax, Servier, Connect4Children, JSPHO, Jansen, Novartis, Abbvie, Sanofi, Roche, BMS and Enable Life Sciences.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"All methods were performed in accordance with relevant guidelines and regulations. All animal procedures involved in this study were approved by the Animal Welfare Body of the Princess M\u00e1xima Center for Pediatric Oncology and conducted in accordance with the Dutch Experiments on Animals Act (Wet op de dierproeven, WOD) under license AVD39900202216167. Informed consent was obtained from patients for the use of their material for research purposes. The Biobank & Data Access Committee of the Princess M\u00e1xima Center approved the use of these samples for the present study under PMCLAB2021.207.","order":2,"name":"Ethics","label":"Ethical declarations","group":{"name":"EthicsHeading","label":"Ethics"}}]}}