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The interferon pathway is known to promote immune recognition, but its sustained activation can contribute to adaptive immune exhaustion. In this study, we demonstrate that myeloid-specific deletion of Rictor in a mouse melanoma model enhances STAT1 signaling while reducing PD-L1 expression. Furthermore, IFN-\u03b3\u2013activated macrophages inhibited melanoma growth in a human skin organoid model. Notably, in vivo inhibition of AKT, in conjunction with anti\u2013PD-L1 therapy, suppressed tumor progression. Mechanistically, we identified IFN-\u03b3\u2013mediated downregulation of IGF-1 as a key event during inflammation, and showed that supplementation with recombinant IGF-1 dampens STAT1 activation. Our findings reveal that targeting the Rictor-AKT axis induces a dual effect - boosting pro-inflammatory signaling while downregulating immunosuppressive factors such as PD-L1 and IGF-1. These results support the potential of AKT inhibitors to enhance the efficacy of immune checkpoint therapies in melanoma patients.<\/jats:p>","DOI":"10.1038\/s41419-025-08367-5","type":"journal-article","created":{"date-parts":[[2025,12,22]],"date-time":"2025-12-22T07:25:14Z","timestamp":1766388314000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["mTORC2 inhibition reduces tumor burden via STAT1 activation and enhanced response to anti\u2013PD-L1 therapy"],"prefix":"10.1038","volume":"16","author":[{"given":"Anna","family":"Gschwendtner","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Birgit","family":"Sch\u00fctz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madalina A.","family":"Mirea","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver","family":"Eckel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikolaj Z.","family":"Kepa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie Deborah","family":"Fritsch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6701-4130","authenticated-orcid":false,"given":"Raimund","family":"Oberle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4349-0797","authenticated-orcid":false,"given":"Thomas","family":"Weichhart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Hengstschl\u00e4ger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5782-0681","authenticated-orcid":false,"given":"Mario","family":"Mikula","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,22]]},"reference":[{"key":"8367_CR1","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1001\/jamadermatol.2022.0160","volume":"158","author":"M Arnold","year":"2022","unstructured":"Arnold M, Singh D, Laversanne M, Vignat J, Vaccarella S, Meheus F, et al. 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