Abstract The high mortality rate associated with ovarian cancer results from the failure of tumor-directed therapy to produce lasting treatment responses. Durable survival in patients with other solid tumors has recently been achieved using immune checkpoint antibodies, however similar results have not been observed in women with ovarian cancer. Published work from our lab demonstrates that combining poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors (PARPi) with immune checkpoint blockade can achieve long-term survival in ovarian cancer models. The scientific premise for this study is based accumulating evidence of a dynamic interaction between PARPi and the tumor microenvironment (TME) that regulates treatment response and disease outcomes. Work to date has identified a tumor-intrinsic mechanism by which PARPi interact with interferon gamma (IFNg) to promote immunogenic cell death in ovarian cancer cells. This results in activation of tumor immunity in vivo, associated with the successful induction of protective immune memory. Evidence that conditions in the tumor environment significantly modulate the therapeutic efficacy of PARP-inhibitors, termed “contextual synthetic lethality”, presents an opportunity to maximize patient outcomes and target treatment effects to the TME. Here we propose to examine the contribution of PARP trapping by different PARPi on these tumor-intrinsic mechanisms to determine whether we can induce similar results in BRCAwt cancers. We will additionally expand studies of tumor- extrinsic immune modulation by PARPi in the TME to test whether macrophage polarization can engage secondary mechanisms of CTLA4ab to enhance treatment outcomes. Finally we will validate candidate biomarkers of response in patients enrolled in two clinical trials, and will examine associations with immune profiling in collaboration with the Cancer Immune Monitoring Analysis Centers. With the rapid adoption of immune checkpoint antibodies and PARP-inhibitors for the treatment of ovarian cancer and other tumor types, this proposal has potential for immediate clinical impact through current and planned clinical trials.