PARP7 Suppresses Radiation-induced Necroptosis and Abscopal Immunity

The abscopal effect, in which local radiotherapy (RT) drives regression of distant Tumors, remains unpredictable and mechanistically elusive. Using a panel of p53-null murine Breast Cancer Models, we identified tumor-intrinsic determinants of abscopal competence to RT and immune checkpoint inhibitors (ICI). Abscopal-competent Tumors exhibited heightened type I interferon stimulated gene (ISG) expression, induction of the Necroptosis mediator ZBP1, and recruitment of antigen-presenting cells (APCs) and effector T cells in distant Tumors. Transcriptomic analyses revealed PARP7 as a tumor-intrinsic suppressor of RT-induced ISGs and Necroptosis. Pharmacologic PARP7 inhibition amplified RT-driven ISGs and ZBP1-dependent Necroptosis. In vivo, PARP7 blockade combined with RT + ICI conferred abscopal competency to resistant Tumors, improving distant tumor control, systemic immune activation, and survival. Notably, ZBP1 loss abrogated these effects, preventing APC recruitment and T cell priming. These findings establish PARP7 and Necroptosis as opposing regulators of abscopal responses and nominate PARP7 inhibition as a strategy to overcome RT + ICI resistance.