Pancreatic cancer is a fatal cancer with poor prognosis and survival rate, often diagnosed usually in the advanced stage of disease. The conventional methods are usually considered for surgery or chemotherapy, and neo-adjuvant therapies have improved the survival rate in the 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) to the LiYF(4):Ce(3+)nanoparticles (SCNP-FA) with the photocleavage chemical molecule; firstly enters the cells through receptor-mediated endocytosis and then, releases FA intracellularly upon the trigger of radiation in a controlled manner. This nano-based approach induces ferroptosis to provoke immunogenic cell death (ICD) with higher generation of reactive oxygen species (ROS) and accumulation of lipid peroxides. It shows an abundant damage to the mitochondria and a decrease in mitochondrial membrane potential (MMP) upon treatment. This targeted therapy remodels the immunosuppressive tumor microenvironment and releases damage-associated molecular patterns (DAMPs) to initiate an immune response. These findings reveal the anti-tumor response with folate receptor-guided nanoparticles in pancreatic cancer.