# PARP7 Suppresses Radiation-induced Necroptosis and Abscopal Immunity

## TL;DR

This study shows that PARP7 suppression enhances the effectiveness of radiation therapy and immune checkpoint inhibitors by promoting necroptosis and immune responses in distant tumors.

## Contribution

The study identifies PARP7 as a novel tumor-intrinsic suppressor of abscopal responses and proposes its inhibition as a strategy to overcome resistance.

## Key findings

- PARP7 inhibition increases radiation-induced ISGs and ZBP1-dependent necroptosis.
- Blocking PARP7 combined with RT + ICI improves distant tumor control and systemic immune activation.
- ZBP1 loss prevents APC recruitment and T cell priming, highlighting its critical role.

## Abstract

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.