{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"Research Square"}],"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T15:24:58Z","timestamp":1786116298535,"version":"build-2736575974"},"posted":{"date-parts":[[2026,8,6]]},"group-title":"In Review","reference-count":0,"publisher":"Springer Science and Business Media LLC","license":[{"start":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T00:00:00Z","timestamp":1785974400000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,3,12]]},"abstract":"<title>Abstract<\/title>\n                <p>The loss of IFN\u03b3 signaling in cancer cells causes primary and acquired resistance to immunotherapy. Using a patient-derived JAK2-deficient melanoma cell line, we have developed a co-culture system to model acquired resistance to immunotherapy. Genome-wide genetic screens uncover that protein neddylation can be targeted to restore sensitivity to PD1 blockade in co-cultures, and in MHC-I and\/or JAK\/STAT-deficient murine tumors. Analysis of the Jak2-deficient murine tumors with scRNA-seq reveals a heightened cancer-intrinsic inflammatory signature when neddylation is absent, which causes an influx of stimulatory antigen presenting cells. In patients with melanoma, tumors with low cancer-intrinsic neddylation exhibit elevated IFN signatures and are associated with dendritic cell infiltration. Mechanistically, neddylation deletion stabilizes chromatin-bound cGAS in JAK2-deficient cancer cells, which is responsible for the superior response to PD1 blockade, and the recruitment of pro-inflammatory innate immune cells. Altogether, we demonstrate the broad therapeutic potential of protein neddylation in overcoming resistance to immunotherapy.<\/p>","DOI":"10.21203\/rs.3.rs-9107846\/v1","type":"posted-content","created":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T08:59:36Z","timestamp":1786006776000},"source":"Crossref","is-referenced-by-count":0,"title":["Targeting cancer-intrinsic protein neddylation bypasses the loss of JAK\/STAT signaling and overcomes acquired resistance to immunotherapy"],"prefix":"10.21203","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6142-6628","authenticated-orcid":false,"given":"Yumeng","family":"Mao","sequence":"first","affiliation":[{"name":"Uppsala University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0949-4329","authenticated-orcid":false,"given":"Marta Rubies","family":"Bedos","sequence":"additional","affiliation":[{"name":"Uppsala University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yonglin","family":"Lu","sequence":"additional","affiliation":[{"name":"Uppsala University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eirini","family":"Voutsinou","sequence":"additional","affiliation":[{"name":"Uppsala University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irineos","family":"Papakyriacou","sequence":"additional","affiliation":[{"name":"Uppsala University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liam","family":"Alford","sequence":"additional","affiliation":[{"name":"Uppsala University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebeca","family":"Parracho","sequence":"additional","affiliation":[{"name":"Uppsala University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vaishnavi","family":"Iyer","sequence":"additional","affiliation":[{"name":"Uppsala University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3669-8458","authenticated-orcid":false,"given":"Antoni","family":"Ribas","sequence":"additional","affiliation":[{"name":"U.C.L.A."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","container-title":[],"original-title":[],"link":[{"URL":"https:\/\/www.researchsquare.com\/article\/rs-9107846\/v1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.researchsquare.com\/article\/rs-9107846\/v1.html","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T08:59:36Z","timestamp":1786006776000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.researchsquare.com\/article\/rs-9107846\/v1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,6]]},"references-count":0,"URL":"https:\/\/doi.org\/10.21203\/rs.3.rs-9107846\/v1","relation":{},"subject":[],"published":{"date-parts":[[2026,8,6]]},"subtype":"preprint"}}