Abstract B131: Radio-activated Nanoactivators Targeting Folate Receptors induce Mitochondrial Dysfunction and Reframe Immune Tumor Microenvironment in Pancreatic Cancer

Abstract Pancreatic cancer is a fatal cancer with a poor prognosis and survival rate, often diagnosed in the advanced stage of the disease. The conventional methods are usually considered for surgery or chemotherapy, and neo-adjuvant therapies have improved the survival rate in patients. Folic acid plays a crucial role in the synthesis, metabolism, and repair of DNA; thereby, it is considered one of the biomolecules for cancer-targeted therapy for highly expressed receptors to overcome poor vasculature and dense tumor stroma, as in pancreatic cancer. This study strategizes for improving the therapeutic efficacy of pancreatic cancer via folate receptor-guided nanoparticles. The conjugation of folic acid (FA) on the surface of LiYF4:Ce3+nanoparticles (SCNP-FA) with the photocleavage chemical molecule. The SCNP-FA nanoparticles enters the pancreatic cancer cells via receptor-mediated endocytosis which releases the folic acid upon the trigger of radiation effect, which causes cell death through ferroptosis confirmed through the GPX4 inhibition while other positive regulators such as CD71/transferrin, PTGS2/COX2 and 4-HNE showed increased expression levels as well as generation of reactive oxygen species (ROS) and regulation of lipid peroxides (LPO). The mitochondria, which are the major energy reservoir for the cancer cells’ growth, were disrupted and fragmented, and mitochondrial membrane potential was also decreased upon the treatment. Ferroptosis is immunogenic, as checked by immunogenic cell death markers such as CRT, HMGB1, which led to enhanced expression levels upon treatment. Targeting pancreatic tumor showed an immunosuppressive tumor microenvironment with enhanced dendritic cells, T cells, NK cells, and repolarization of M2 to M1 phenotype. This folate receptor-guided nano-based approach significantly improved the immune-based therapeutic effect in pancreatic cancer. Citation Format: Wen-Pin SU, Tanvi Gupta, Chen-Sheng Yeh. Radio-activated Nanoactivators Targeting Folate Receptors induce Mitochondrial Dysfunction and Reframe Immune Tumor Microenvironment in Pancreatic Cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B131.