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

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.