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

作者：Shun‐Cang Zhu, Yinhao Chen, Hongyi Lin, Jinpeng Lu, Yu Pan, Ge Li, Yongding Wu, Haoxiang Zhang, Xiaoxiao Huang, Yi‐Ting Chen, Huangjing Chen, Long Jin, Min Huang, Cheng‐Yu Liao, Long Huang, Yifeng Tian, Zuwei Wang, Qiaowei Li, Shi Chen · 发表于：Advanced Science · 年份：2025 · DOI：10.1002/advs.202508431 · 被引用次数：5 · 研究领域：Immunotherapy and Immune Responses、Cancer Immunotherapy and Biomarkers、Immune cells in cancer

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.