SenExo‐cCCT2 Reprograms Senescence Response and Anti‐Tumor Immunity Following FOLFIRINOX Chemotherapy in Pancreatic Ductal Adenocarcinoma

Abstract Combination chemotherapy and immunotherapy have failed to achieve breakthroughs in pancreatic ductal adenocarcinoma (PDAC). Chemotherapy‐induced senescence is a potential solution for this problem. This study integrates clinical samples with single‐cell transcriptomic sequencing, proteomics, and RNA sequencing and reveals that FOLFIRINOX (a combination regimen of 5‐fluorouracil, 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‐mediated DNA damage repair pathways by regulating small ubiquitin‐like modifier conjugation, thereby promoting tumor cell senescence. In the tumor immune microenvironment, cCCT2‐overexpressing senTCs exhibit a senescence‐associated secretory phenotype (SASP) with preferential secretion of CXCL10, which induces chemotaxis of CD8 + T‐cells. Based on the pro‐senescence and immune‐microenvironment‐remodeling effects of cCCT2, an engineered exosome‐loaded circRNA system, SenExo‐cCCT2 is developed. When combined with SenExo‐cCCT2, the FOLFIRINOX regimen enhances the capacity of pancreatic cancer cells to induce senescence. Subsequently, anti‐PD‐L1 therapy facilitates the immune‐mediated clearance of senTCs, markedly improving the therapeutic efficacy of combined chemotherapy and immunotherapy for pancreatic cancer.