Targeting the DNA Damage Response in Cancer

The DNA damage response (DDR) is increasingly recognized not only as a genome-maintenance network and source of synthetic-lethal vulnerabilities, but also as a regulator of tumor immunity. DDR defects and pharmacologic inhibition can increase neoantigen formation, generate micronuclei and cytosolic nucleic acids, activate cGAS-STING, DNA-PK-NF-κB, and ERV-driven RIG-I/MDA5-MAVS signaling, and alter antigen presentation and immune checkpoint expression. However, the same processes may also promote chronic interferon tolerance, PD-L1 induction, lymphocyte stress, myeloid suppression, extracellular cGAMP degradation, stromal exclusion, and treatment resistance. This review frames DDR targeting around damage-to-immunity conversion, asking when DNA damage becomes a productive antitumor immune signal and when it does not. We summarize targetable DDR modules across cancer types, examine tumor-intrinsic and host-cell sensing mechanisms, and discuss antigen-processing defects, STING regulation, and microenvironmental barriers that shape divergent outcomes. We further review PARP, ATR, WEE1, ATM, and DNA-PK inhibitor combinations with immunotherapy and other treatment modalities, emphasizing clinical evidence, scheduling, and host-cell toxicity. Finally, we propose a modular biomarker framework integrating genomic, functional, immune-context, spatial and dynamic readouts to guide patient selection, treatment adaptation, and precision therapeutic decision-making.