Simple Summary: Current treatment options for advanced cervical cancer are limited, with a 5-year overall survival rate of 17%. New effective therapeutic approaches that can increase survival and reduce disparities are greatly needed. In this study, an approach using a multifunctional liquid immunogenic fiducial eluter (LIFE) that can provide image contrast and enhance therapeutic efficacy during hypo-fractionated radiotherapy is investigated. We found this technique provides both computed tomography (CT) and magnetic resonance imaging (MRI) image contrast to guide radiotherapy. Additionally, in a model of metastatic cervical cancer, local treatment with LIFE and radiotherapy resulted in distant disease control and improvement in survival. Successful development of this approach may provide a short therapeutic option that could enhance treatment outcomes and reduce disparities. LIFE Biomaterial may also significantly provide a cheaper and convenient alternative to prolonged systemic treatment with opportunities to increase access to care and reduce health outcome disparities. Globally, cervical cancer is the fourth leading cancer among women and is dominant in resource-poor settings in its occurrence and mortality. This study focuses on developing liquid immunogenic fiducial eluter (LIFE) Biomaterial with components that include biodegradable polymers, nanoparticles, and an immunoadjuvant. LIFE Biomaterial is designed to provide image guidance during radiotherapy similar to clinically used liquid fiducials while enhancing therapeutic efficacy for advanced cervical cancer. C57BL6 mice were used to grow subcutaneous tumors on bilateral flanks. The tumor on one flank was then treated using LIFE Biomaterial prepared with the immunoadjuvant anti-CD40, with/without radiotherapy at 6 Gy. Computed tomography (CT) and magnetic resonance (MR) imaging visibility were also evaluated in human cadavers. A pharmacodynamics study was also conducted to assess the safety of LIFE Biomaterial in healthy C57BL6 female mice. Results showed that LIFE Biomaterial could provide both CT and MR imaging contrast over time. Inhibition in tumor growth and prolonged significant survival (* p < 0.05) were consistently observed for groups treated with the combination of radiotherapy and LIFE Biomaterial, highlighting the potential for this strategy. Minimal toxicity was observed for healthy mice treated with LIFE Biomaterial with/without anti-CD40 in comparison to non-treated cohorts. The results demonstrate promise for the further development and clinical translation of this approach to enhance the survival and quality of life of patients with advanced cervical cancer. [ABSTRACT FROM AUTHOR]