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Chemotherapy\u2010induced senescence is a potential solution for this problem. This study integrates clinical samples with single\u2010cell transcriptomic sequencing, proteomics, and RNA sequencing and reveals that FOLFIRINOX (a combination regimen of 5\u2010fluorouracil, oxaliplatin, irinotecan, and leucovorin) treatment induces a higher proportion of senescent tumor cells (senTCs). This phenomenon is principally attributed to the presence of cCCT2, which inhibits SLX4 condensate\u2010mediated DNA damage repair pathways by regulating small ubiquitin\u2010like modifier conjugation, thereby promoting tumor cell senescence. In the tumor immune microenvironment, cCCT2\u2010overexpressing senTCs exhibit a senescence\u2010associated secretory phenotype (SASP) with preferential secretion of CXCL10, which induces chemotaxis of CD8\n                    <jats:sup>+<\/jats:sup>\n                    T\u2010cells. Based on the pro\u2010senescence and immune\u2010microenvironment\u2010remodeling effects of cCCT2, an engineered exosome\u2010loaded circRNA system, SenExo\u2010cCCT2 is developed. When combined with SenExo\u2010cCCT2, the FOLFIRINOX regimen enhances the capacity of pancreatic cancer cells to induce senescence. Subsequently, anti\u2010PD\u2010L1 therapy facilitates the immune\u2010mediated clearance of senTCs, markedly improving the therapeutic efficacy of combined chemotherapy and immunotherapy for pancreatic cancer.\n                  <\/jats:p>","DOI":"10.1002\/advs.202508431","type":"journal-article","created":{"date-parts":[[2025,7,21]],"date-time":"2025-07-21T10:24:32Z","timestamp":1753093472000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["SenExo\u2010cCCT2 Reprograms Senescence Response and Anti\u2010Tumor Immunity Following FOLFIRINOX Chemotherapy in Pancreatic Ductal Adenocarcinoma"],"prefix":"10.1002","volume":"12","author":[{"given":"Shuncang","family":"Zhu","sequence":"first","affiliation":[{"name":"Shengli Clinical Medical College of Fujian Medical University  Fuzhou 350001 P. R. 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