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We used multi-omics on patients\u2019 samples to decipher immune alterations associated with azithromycin intake and post-transplantation relapsed malignancies. Azithromycin was associated with a network of altered energy metabolism pathways and immune subsets, including T cells biased toward immunomodulatory and exhausted profiles. In\u00a0vitro, azithromycin exposure inhibited T-cell cytotoxicity against tumor cells and impaired T-cell metabolism through glycolysis inhibition, down-regulation of mitochondrial genes, and up-regulation of immunomodulatory genes, notably SOCS1. These results highlight that azithromycin directly affects immune cells that favor relapse, which raises caution about long-term use of azithromycin treatment in patients at high risk of malignancies. The ALLOZITHRO trial was registered at www.clinicaltrials.gov as #NCT01959100.<\/jats:p>","DOI":"10.1182\/blood.2022016926","type":"journal-article","created":{"date-parts":[[2022,8,19]],"date-time":"2022-08-19T18:05:03Z","timestamp":1660932303000},"page":"2500-2513","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":35,"title":["Azithromycin promotes relapse by disrupting immune and metabolic networks after allogeneic stem cell transplantation"],"prefix":"10.1182","volume":"140","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9568-3358","authenticated-orcid":false,"given":"Nicolas","family":"Vallet","sequence":"first","affiliation":[{"name":"1Universit\u00e9 de Paris Cit\u00e9, INSERM 976, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9985-465X","authenticated-orcid":false,"given":"Sophie","family":"Le 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