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Here, we show that human macrophages rely on autocrine macrophage migration inhibitory factor signaling to suppress p53 during M2-like transition. Disruption of this pathway led to activation of p53 and, unexpectedly, the nuclear receptor NR4A1, inducing a senescence-like state resembling interleukin (IL)-1\u03b2\u207a and IL-4 Induced 1 (IL4I1)\u207a TAM subsets observed across multiple cancers. These TAM-like macrophages exhibited a transcriptional program driven by NR4A1, similar to that induced in IL-1\u03b2\u207a TAMs by the combined action of tumor necrosis factor \u03b1 (TNF) and the cyclooxygenase-2-dependent arachidonic acid (AA) metabolite prostaglandin E2. They also upregulated the AA-selective acyl-CoA synthase ACSL4, which promoted cell survival and restrained IL-1\u03b2 release despite elevated\n                    <jats:italic>IL1B<\/jats:italic>\n                    expression. This effect was mediated through induction of the IL4I1\u207a TAM marker CD38, which drove the production of IL-10. Mechanistically, ACSL4 preserved the homeostatic function of stimulator of interferon genes (STING). Loss of ACSL4 resulted in extensive macrophage death and converted STING from a homeostatic regulator into a driver of IL-1 cytokine release. Finally, we show that the CDK4\/6 inhibitor abemaciclib repolarized TAM-like macrophages toward a more inflammatory phenotype through off-target inhibition of ACSL4. Abemaciclib enhanced inflammatory signaling by modulating ectodomain shedding, increasing TNF while reducing the release of its natural antagonist, TNF receptor II. Together, these findings clarify mechanisms underlying scRNA-seq\u2013defined TAM phenotypes, identify ACSL4 as a potential therapeutic target, and reveal how abemaciclib can promote inflammatory responses in cancer patients.\n                  <\/jats:p>","DOI":"10.1186\/s43556-026-00515-3","type":"journal-article","created":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T06:40:47Z","timestamp":1784270447000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Disruption of macrophage migration inhibitory factor signaling induces major tumor-associated macrophage phenotypes in human M2 macrophages"],"prefix":"10.1186","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3367-0823","authenticated-orcid":false,"given":"Dominik","family":"Klaver","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hubert","family":"Gander","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatrice","family":"Frena","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Martin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Amato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Richter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renate","family":"Pichler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9940-7326","authenticated-orcid":false,"given":"Martin","family":"Thurnher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,17]]},"reference":[{"key":"515_CR1","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1146\/annurev-pathmechdis-012418-012718","volume":"15","author":"M Locati","year":"2020","unstructured":"Locati M, Curtale G, Mantovani A. 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