Synergistic Anti-Tumor Efficacy of Modified FOLFIRINOX and NK Cell Therapy in Pancreatic Ductal Adenocarcinoma.

BACKGROUND/OBJECTIVES: Pancreatic ductal adenocarcinoma (PDAC) presents a formidable challenge in oncology due to its aggressive progression, propensity for early metastasis, and resistance to conventional therapies. The development of effective and less toxic treatments is crucial for improving the prognosis of PDAC. We aimed to investigate the synergistic antitumor potential of modified FOLFIRINOX (mFOLFIRINOX) combined with natural killer (NK) cell therapy in PDAC models. METHODS: We evaluated changes in NK-cell-activating ligands and apoptosis-inducing receptor expression after mFOLFIRINOX treatment both in vitro and in vivo. Subsequently, NK cells were administered to mFOLFIRINOX-pre-treated PDAC cells to assess NK cell cytotoxicity, immune responses, and tumor progression both in vitro and in vivo mouse models. RESULTS: Treatment with mFOLFIRINOX led to the significant upregulation of NK-cell-activating ligands and apoptosis-inducing receptors across the PDAC cell lines and tumor cells collected in vivo, thereby enhancing their susceptibility to NK-cell-mediated cytotoxicity. In comparison with either treatment alone, mFOLFIRINOX and NK cell combination therapy resulted in enhanced cytolysis in all cell lines. In vivo studies demonstrated that combination therapy substantially inhibited tumor growth and prolonged survival in a mouse model. CONCLUSIONS: mFOLFIRINOX combined with NK cell therapy demonstrates enhanced antitumor activity against PDAC, potentially improving clinical outcomes. These findings highlight the need for continued research to optimize this combination strategy for clinical utility.