(T1106) TRANSFORMING THE THERAPEUTIC LANDSCAPE OF PANCREATIC CANCER THROUGH LOCAL DELIVERY OF AN IMMUNE-ACTIVATING SMALL MOLECULE AND CYTOKINE-INDUCED KILLER CELL SYNERGY
Professor National Dong Hwa University Shoufeng, Hualien, Taiwan
Abstract: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with a 5-year survival rate of less than 8%, primarily due to its fibrotic tumor microenvironment and cancer cell-mediated immune checkpoint regulation, which hinder drug penetration and suppress immune responses. This study investigated the potential of the small molecule n-butylidenephthalide (BP), delivered through a thermosensitive sustained-release hydrogel, in combination with cytokine-induced killer (CIK) cells, to enhance the therapeutic efficacy of CIK cells against PDAC. BP treatment significantly activated NK and NKT immune phenotypes (CD3⁺CD56⁺) in CIK cells by downregulating immune checkpoint markers (PD-1, CTLA-4) and the downstream mTOR signaling pathway. These modulations improved CIK-mediated cytotoxicity, demonstrating enhanced therapeutic potential for PDAC treatment. In a murine PDAC xenograft tumor model, the combination of CIK cells with BP-loaded hydrogel further amplified therapeutic efficacy, as evidenced by reduced tumor volume, quantified through fluorescence intensity analysis using IVIS imaging. Elevated Caspase-3 expression, reduced PD-L1 levels in tumor tissues, decreased fibrosis via α-SMA downregulation, and lower expression of pro-carcinogenic factors including Calpain-1 and Vimentin further corroborated these findings. These results highlight the ability of locally delivered BP via a sustained-release hydrogel to modulate the immunosuppressive tumor microenvironment and promote immune-mediated tumor destruction. The study provides compelling evidence supporting the use of BP and CIK cell-based strategies for advancing PDAC therapy and addressing the challenges posed by its highly immunosuppressive microenvironment.
Funding Source: The funding support from National Science and Technology Council, Taiwan (MOST-111-2221-E-259-001-MY3) is greatly apprecieted by the authors.
