PROJECT SUMMARY/ABSTRACT Locally advanced cancers remain a therapeutic challenge to eradicate. The most successful treatments for such patients continue to combine decades old classical cytotoxic chemotherapies with radiotherapy. While chemo-radiotherapy improves tumor control, using non-targeted drugs increases normal tissue damage in the irradiated field along with systemic toxicities precluding further treatment intensification. Targeted delivery approaches can improve the chemo-radiotherapy paradigm by restricting highly potent radiosensitizers specifically to irradiated tumor targets that activate anti-tumor immune responses while simultaneously avoiding normal tissues. To test this hypothesis, we leveraged antibody drug conjugate (ADC) technology for receptor-restricted radiosensitization. ADCs split the roles of tumor targeting and killing into two distinct molecular tasks. Targeting is achieved by the antibody portion recognizing cell surface receptors preferentially found on tumor cells. Following cell surface receptor binding, ADCs are endocytosed and the attached drug payload warhead intracellularly released specifically within target cells. ADCs have been exclusively built by linking cytotoxic drugs to tumor targeting antibodies. The potent anti-tubulin drug monomethyl auristatin E (MMAE) is the most common ADC warhead. We discovered MMAE could also radiosensitize. Advancing to syngeneic murine models using our novel drug delivery vehicles, we have now provided the first demonstration that MMAE produces durable irradiated tumor control which is dependent on CD8 T cells and is enhanced by immune checkpoint inhibition. While antibody coupled, MMAE is target restricted. However once released, MMAE has dose limiting toxicities. To achieve increasingly precise tumor radiosensitization, we used orthogonal strategies and rationally constructed a first-in-class radiosensitizing ADC designed to inhibit DNA damage repair. As proof of concept, we conjugated anti-EG