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Here, we show that intratumoral levels of leptin (LEP), a factor contributing to the development of obesity, predict improved outcomes of breast and liver cancers. In contrast, these levels of LEP are associated with poor survival of patients with colon and esophageal cancers, where they are uniquely correlated with high IDO1 levels in tumor-associated myeloid cells. LEP-exposed human macrophages show elevated levels of multiple T cell\u2013activating factors but also show NF-\u03baB\u2013 and STAT3-dependent IDO1 induction, which synergize with IFN-\u03b3 in activating the kynurenine pathway, resulting in their T cell\u2013suppressive function. IDO1 inhibition reprograms the LEP-exposed macrophages from metabolic suppression to enhanced T cell\u2013stimulatory function. The double-edged impact of LEP on human myeloid cells helps explain obesity-associated immune dysfunction and the \u201cobesity paradox,\u201d suggesting that IDO1 inhibition may be selectively beneficial in patients who have obesity and cancer with high levels of LEP.<\/jats:p>","DOI":"10.1093\/jimmun\/vkag211","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T12:58:08Z","timestamp":1785157088000},"source":"Crossref","is-referenced-by-count":0,"title":["Split immunomodulatory impact of leptin on human myeloid cells: key role of IDO1 in counteracting the immunostimulatory effect of leptin"],"prefix":"10.1093","volume":"215","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9895-2496","authenticated-orcid":false,"given":"Bowen","family":"Dong","sequence":"first","affiliation":[{"name":"Department of Immunology, Roswell Park Comprehensive Cancer Center , Buffalo, NY,","place":["United States"]},{"name":"Department of Obstetrics, Gynecology & 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