The DNA damage response and cancer immunotherapy.

Abstract

The DNA damage response (DDR) and immune system serve as critical defence mechanisms, safeguarding genomic integrity and providing host protection, respectively. Emerging research reveals their interconnection in dictating the response to cancer immunotherapy. DDR-deficient tumours or those exposed to DDR inhibitors display genomic instability that generates two key immunogenic signals: neoantigens that activate tumour-specific T cells; and cytosolic DNA that stimulates the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, triggering type I interferon production and immune cell recruitment. These synergistic effects drastically enhance responsiveness to immune checkpoint blockade. This Review examines the molecular mechanisms by which DDR defects potentiate immunotherapy, including recent advances in DDR-targeted combination strategies. We further analyse resistance mechanisms and discuss innovative approaches to overcome therapeutic limitations, offering a comprehensive perspective on exploiting DDR deficiencies for improved cancer treatment outcomes.