Merkel Cell Carcinoma (MCC) is a rare skin cancer with three times the mortality rate of melanoma. Despite its aggressive nature, MCC can induce strong anti-tumor immune responses underscored by an unusually high percentage of patients (~50%) who experience long-term response to PD-(L)1 immune checkpoint blockade (ICB). ICB works through reinvigoration of exhausted T cells indicating that reduced tumor-specific T-cell numbers, their increased terminal exhaustion, or both could limit anti-tumor immunity and patient response in ICB-resistant MCC. The Nghiem lab, at The University of Washington, is investigating if radiotherapy (RT) combined with DNA damage response (DDR) inhibitors can potentiate a form of proinflammatory cell death termed immunogenic cell death (ICD). It is hypothesized ICD induced by a combination of RT and DDR inhibitors will increase the anti-tumor T-cell pool by triggering enhanced dendritic cell (DC) activation and antigen cross presentation resulting in activation and expansion of rare or naïve tumor-specific T cells. Using three DDR inhibitors targeting either ATM, ATR or DNA-PK, relative tumor cell immunogenicity and ICD will be assessed across a panel of irradiated MCC cell lines in the presence or absence of inhibitor at various concentrations and radiotherapy doses. These in vitro studies will facilitate correlative analyses between ICD potency, DC activation and promotion of tumor-specific T-cell responses. Additionally, this research will enable identification of the most potent ICD inducing RT–DDR inhibitor combination and dose. Upon completion, this study will inform RT–DDR inhibitor therapeutic translation into clinical trials designed to test the ability of this novel combination to induce anti-tumor immunity in ICB-resistant MCC.