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Interleukin-10 (IL-10) is frequently upregulated in tumors, but the understanding of IL-10 in the tumor immune microenvironment is controversial. This study aims to determine the roles of IL-10 receptor alpha (IL-10R\u03b1) signaling in TAMs and explore the targetable mediators for GBM treatment. We found that growth of intracranial GBMs was delayed in engineered mice with myeloid-specific knock-out of IL-10R\u03b1, which was accompanied by changes in TAM phenotypes. Meanwhile, IL-10 expression in GBMs, which was largely accredited to TAMs, were not affected by IL-10R\u03b1 deficiency. RNA-sequencing analysis and immunostaining revealed cyclooxygenases COX-1\/2 as potential downstream effectors of IL-10R\u03b1 in TAMs. Pharmacological inhibition of COX-1\/2 suppressed bone-marrow derived macrophages (BMDM) polarization upon IL-4\/IL-10 treatment. Consistently, the COX inhibitor NS-398 mitigated intracranial GBM growth. In summary, we not only demonstrated the crucial roles of IL-10R\u03b1 but also discovered COX-1\/2 as downstream targets for pro-tumor phenotypes of TAMs in GBMs. These findings provide new clues for future development of immunotherapies for GBM treatment.<\/jats:p>","DOI":"10.1038\/s41419-026-09072-7","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T02:26:23Z","timestamp":1785119183000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cyclooxygenase-mediated IL-10R\u03b1 signaling underlies pro-tumor phenotypes of macrophages in glioma"],"prefix":"10.1038","volume":"17","author":[{"given":"Jiahui","family":"Zhou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingxi","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiangsheng","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fangzhen","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiwen","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiuhong","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huipeng","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2000-3255","authenticated-orcid":false,"given":"Wei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0817-9191","authenticated-orcid":false,"given":"Hai-bo","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3494-5534","authenticated-orcid":false,"given":"Aili","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9110-8804","authenticated-orcid":false,"given":"Bofeng","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6650-1831","authenticated-orcid":false,"given":"Wenchao","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,27]]},"reference":[{"key":"9072_CR1","first-page":"299","volume":"70","author":"AC Tan","year":"2020","unstructured":"Tan AC, Ashley DM, L\u00f3pez GY, Malinzak M, Friedman HS, Khasraw M. 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Tumor-bearing mice were euthanized when displaying neurological signs such as loss of balance. Ethics approval of use of the public sequencing data from human patients was exempted by the Medical Research Ethics Committee of The First Affiliated Hospital of the University of USTC.","order":2,"name":"Ethics","label":"Ethics","group":{"name":"EthicsHeading","label":"Ethics"}}],"article-number":"898"}}