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The DNA damage response and cancer immunotherapy
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DOI：10.1038/s41568-026-00958-4.png)
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Abstract
En 中文
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. In this Review, Hong and Li explore how defects in DNA damage response (DDR) pathways shape tumour immunogenicity and influence responses to immune checkpoint inhibitors. They highlight shared immunological consequences across distinct DDR alterations, discuss mechanisms of resistance and evaluate therapeutic strategies integrating DDR-targeting agents with immunotherapy to improve clinical outcomes.
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