Abstract While major strides have been made in cancer treatment, the challenge remains to determine which patients will benefit most from a therapeutic regimen, which is the ultimate goal of personalized medicine. The key to choosing the most effective therapy for a given cancer is understanding the biological basis for differential outcomes and intrinsic sensitivity to cancer therapies. Almost all cancers are treated with cytotoxic chemotherapy and radiation therapy but the emerging clinical success of immunoncology (IO) drugs whose success is predicated on the biology of the immune infiltrate requires new tactics to model optimal combinations. As cytotoxic therapy is a critical component of cancer patient treatment, mammalian models that represent a range of DNA damage response deficits (DDRD), and hence sensitivity to different agents, would improve translational research. Likewise, the multiple mechanisms by which cancer evades the anti- tumor immunity need to be represented in translational research. Lack of diversity in most current preclinical models limits their applicability as a platform for systemic evaluation of these aspects of tumor biology. Given the range of IO approaches and the diversity of DDRD, a critical unmet translational requirement is a model system in which both the tumor DDRD and the immune infiltrate is defined so that combinations can be readily studied. We propose to use murine tumor derived transplants (mTDT) of Trp53 null mammary carcinomas that we have generated and characterized in regard to heterogeneity, relevance to human cancer, and reproducibility to credential the DDR deficits of these syngeneic carcinomas and to evaluate corresponding baseline immune cell infiltrates. We will implement multiplex analysis of tumor and immune features and correlate them with tumor response to radiation, a canonical DNA damaging therapy and arguably the most widely used cytotoxic therapy. The product of these studies is directly responsive to the FOA consisting of a protocol for standardized implementation of this model, comprehensive analysis of tumor types, and repository of specimens, data, and viable tissue. The success of this project will provide a means to conduct mechanistic and translational studies using defined tumor DDRD and immune infiltrate composition for developing patient- specific personalized therapy to IO and cytotoxic therapies.