Targeting the DNA Damage Response in Cancer

Abstract

ABSTRACT 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.