Targeting the DNA damage response to reshape the tumor immune microenvironment

Abstract

The DNA damage response (DDR) maintains genome stability through coordinated DNA repair, replication-stress signaling, and cell-cycle control. In cancer, DDR dysregulation promotes genomic instability, clonal evolution, and treatment resistance, while simultaneously creating therapeutically exploitable vulnerabilities. DDR alterations also reshape the tumor immune microenvironment by influencing cytosolic nucleic-acid sensing, neoantigen generation, antigen presentation, inflammatory signaling, and immune checkpoint regulation. However, these effects are highly context dependent. Acute activation of the cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway may promote antitumor immunity, whereas persistent genomic stress and chronic inflammatory signaling can facilitate immune suppression and tumor progression. Clinically, mismatch repair deficiency and high microsatellite instability are established biomarkers for immune checkpoint blockade (ICB), whereas the predictive value of other DDR alterations remains variable. This review summarizes the major DDR pathways, their roles in tumor evolution and immune remodeling, and the rationale and limitations of combining DDR-targeted therapies with immunotherapy. We further discuss biomarker refinement, resistance mechanisms, and future strategies for translating genomic stress into durable antitumor responses.