Oral cancer, a rare cancer, represents a significant cause of morbidity and mortality. Almost half of oral cancers have been diagnosed in advanced stages, and the 5-year survival rate for patients with metastatic and recurrent oral cancer is dismal at 27.8%. Current treatment options are not effective in controlling metastatic spread and incur significant side effects. We discovered a disruptive technology in radiation oncology and cancer immunotherapy based on nanoscale metal-organic frameworks (nMOFs). nMOFs conjugated with immune modulators act as activable immunotherapeutics for personalized cancer vaccination. Upon X-ray irradiation, nMOFs release danger-associated molecular patterns and tumor antigens from cancer cells and deliver immune modulators as pathogen-associated molecular patterns for enhanced innate and adaptive immune responses. In combination with checkpoint inhibitors, nMOFs eradicate local, treated tumors and regress distant, untreated tumors. We will refine this technology and identify lead formulations with optimal efficacy and minimal toxicity for the treatment of recurrent and metastatic oral cancer. This grant will allow us to identify a lead candidate for Investigational New Drug-enabling studies in two years.