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Adv."],"published-print":{"date-parts":[[2026,5,8]]},"abstract":"<jats:p>\n                    T cell exhaustion is a major barrier to effective antitumor immunity, yet the tumor-intrinsic mechanisms remain poorly defined. Through single-cell and spatial proteomics analyses of esophageal squamous cell carcinoma (ESCC), we uncover two infection-like CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell trajectories, acute-like and chronic-like responses, whose fates are dictated by the tumor cell subtypes they encounter. This concept links tumor heterogeneity to the shaping of local immune niches. Mechanistically, we identify CDC28 protein kinase regulatory subunit 1B (CKS1B) as a tumor-intrinsic inducer of chronic-like exhaustion. CKS1B forms a complex with S-phase kinase-associated protein to promote interferon regulatory factor 3 (IRF3) ubiquitination and degradation, thereby suppressing type I interferon signaling and antigen presentation. This impairs tumor cell elimination and drives progressive CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell stimulation and exhaustion. Pharmacological blockade of the CKS1B-IRF3 interaction with 14i restores CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell function and synergizes with immune checkpoint blockade. The tumor-intrinsic oncogenic-immune axis, which connects cancer cell signaling to immune dysfunction, is conserved across multiple malignancies, establishing a conceptual and therapeutic framework for overcoming tumor-driven T cell exhaustion.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aec9179","type":"journal-article","created":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T17:59:26Z","timestamp":1778090366000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["CKS1B is a tumor-intrinsic factor driving CD8\n                    <sup>+<\/sup>\n                    T cell exhaustion via maintaining persistent tumor-antigen stimulation"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-6671-8827","authenticated-orcid":true,"given":"Siqi","family":"Yu","sequence":"first","affiliation":[{"name":"Department of Etiology and Carcinogenesis, National Cancer Center\/National 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China."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8174-6709","authenticated-orcid":true,"given":"Liang","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Etiology and Carcinogenesis, National Cancer Center\/National Clinical Research Center for Cancer\/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liping","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Etiology and Carcinogenesis, National Cancer Center\/National Clinical Research Center for Cancer\/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-5371-5578","authenticated-orcid":true,"given":"Yibo","family":"Yu","sequence":"additional","affiliation":[{"name":"Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wen","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Etiology and Carcinogenesis, National Cancer Center\/National Clinical Research Center for Cancer\/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0010-1445","authenticated-orcid":true,"given":"Shaosen","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Etiology and Carcinogenesis, National Cancer Center\/National Clinical Research Center for Cancer\/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China."},{"name":"Key Laboratory of Cancer Genomic Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4954-1011","authenticated-orcid":true,"given":"Chen","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Etiology and Carcinogenesis, National Cancer Center\/National Clinical Research Center for Cancer\/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China."},{"name":"Key Laboratory of Cancer Genomic Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China."},{"name":"Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 211166, China."},{"name":"CAMS Oxford 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