<h3>Purpose/Objective(s)</h3> X-ray excited photodynamic therapy (XPDT) utilizes X-ray excited nano-scintillators as a light source for photodynamic therapy to treat solid tumors in deep tissues and stimulate immunogenic tumor necrosis. The goals of our study were twofold: (1) to assess the efficacy of a novel XPDT agent, pYSM, in enhancing the regression of murine pancreatic tumors using low doses of radiation, and (2) to evaluate the immunogenic effects of XPDT and immunotherapy in stimulating a systemic anti-tumor immune response. <h3>Materials/Methods</h3> pYSM was synthesized by coating Y<sub>2</sub>O<sub>3</sub>:Eu nanoparticles in a mesoporous silica shell before loading the shell with methylene blue dye as a photosensitizer and encapsulating the complex in polyethylene glycol to improve systemic circulation. The generation of reactive oxygen species from irradiating pYSM in solution was measured by a singlet oxygen sensor green (SOSG) assay. In vitro studies were conducted using Panc02, a murine pancreatic cell line, by culturing cells with pYSM and measuring the cell viability after irradiation. In vivo studies were performed using C57BL/6 mice with subcutaneous bilateral flank injections of Panc02 cells. A biodistribution assay was performed to confirm that the intravenous tail-vein injection of pYSM resulted in the accumulation of the XPDT agent within the tumor microenvironment. Only right-sided tumors were treated with either XPDT+immunotherapy, XPDT only, radiotherapy only, or pYSM only, and left-sided tumors were left untreated. Tumor growth delay curves were measured for both treated and untreated tumors, and flow cytometry was performed on both tumors to measure the immune response in all treatment groups. <h3>Results</h3> XPDT mediated by pYSM resulted in the greater generation of reactive oxygen species generation under a 10 Gy dose when compared to controls. And in vitro studies confirmed the greater cytotoxic effects of pYSM under X-ray irradiation as compared to controls. Additionally, in vivo studies showed the enhanced tumor regression of pYSM-mediated XPDT+immunotherapy as compared to controls in both right-sided (treated) and left-sided (untreated) tumors, suggesting an abscopal effect, as well as an increase in immune responses within the microenvironment of both right-sided and left-sided tumors. <h3>Conclusion</h3> pYSM is a novel, viable construct capable of performing XPDT to treat solid tumors. Additionally, XPDT mediated by pYSM combined with immunotherapy can generate a systemic anti-tumor immune response that leads to the regression of treated tumors as well as an abscopal effect. This combined treatment modality can be used to treat deep-seated solid tumors with poor immunogenic profiles.