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To profile the immunological landscape of HGSOC, we conducted single-cell RNA sequencing (scRNA-seq) on 84,065 cells from tumor tissues of eight treatment-na\u00efve patients and one normal ovarian tissue, identifying six major cell clusters and revealing substantial immune cell infiltration. Further analysis of CD8\u207a T cells identified two key subpopulations\u2014precursor and terminally exhausted T cells\u2014and delineated their developmental trajectories. The accumulation of exhausted CD8\u207a T cells (Tex) suggested an immunosuppressive TME. Integrated trajectory inference and high-dimensional weighted gene co-expression network analysis (hdWGCNA) identified CCL3 as a novel hub gene specifically expressed in Tex cells. Communication analysis suggested that Tex cells may interact with M2 macrophages via the CCL3\u2013CCR1 ligand\u2013receptor axis. Functional validation confirmed that: (1) secretomes from Tex cells\u2014but not effector T cells\u2014significantly promoted M2 polarization in both THP-1 and bone marrow-derived macrophages (CD206\u207a THP-1: 83.8% vs. 51.4%, p\u2009&lt;\u20090.001; CD206\u207a BMDM: 72.4% vs. 41.5%, p\u2009&lt;\u20090.001); and (2) recombinant CCL3 acted synergistically with IL-4\/IL-10 to further enhance M2 polarization (59.2% vs. 37.7%, p\u2009=\u20090.008). Collectively, our findings unveil a previously unrecognized immunoregulatory axis whereby exhausted CD8\u207a T cells drive immunosuppression via CCL3\u2013CCR1\u2013mediated communication with M2 macrophages, presenting a promising therapeutic target to reverse the immune-cold TME in HGSOC.<\/jats:p>","DOI":"10.1038\/s41419-026-08772-4","type":"journal-article","created":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T21:45:19Z","timestamp":1781732719000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Exhausted CD8\u207a T cells promote ovarian cancer immunosuppression via CCL3-Driven M2 macrophage polarization"],"prefix":"10.1038","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1814-2528","authenticated-orcid":false,"given":"Yue","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junjie","family":"Yi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhefeng","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanheng","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4230-6449","authenticated-orcid":false,"given":"Mei","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1838-4255","authenticated-orcid":false,"given":"Xiaoting","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wentao","family":"Yue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,17]]},"reference":[{"key":"8772_CR1","first-page":"394","volume":"68","author":"F Bray","year":"2018","unstructured":"Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. 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Cell Rep Methods. 2023;3:100498.","journal-title":"Cell Rep Methods"}],"container-title":["Cell Death &amp; Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41419-026-08772-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-026-08772-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-026-08772-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T23:30:18Z","timestamp":1787787018000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41419-026-08772-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,17]]},"references-count":53,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["8772"],"URL":"https:\/\/doi.org\/10.1038\/s41419-026-08772-4","relation":{},"ISSN":["2041-4889"],"issn-type":[{"value":"2041-4889","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,17]]},"assertion":[{"value":"10 November 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 March 2026","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 April 2026","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 June 2026","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential competing interest.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"The study was conducted in accordance with the Declaration of Helsinki, as revised in 2013. The study was approved by the medical ethics committee of the Beijing Obstetrics and Gynecology Hospital, Capital Medical University. We have obtained informed consent from all patients. The animal experiments in this study have adhered to ARRIVE guidelines and were sanctioned by the Ethics Committee of Beijing Obstetrics and Gynecology Hospital, Capital Medical University.","order":2,"name":"Ethics","label":"Ethics Statement","group":{"name":"EthicsHeading","label":"Ethics"}}],"article-number":"757"}}