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DDR defects and pharmacologic inhibition can increase neoantigen formation, generate micronuclei and cytosolic nucleic acids, activate cGAS\u2013STING, DNA\u2010PK\u2013NF\u2010\u03baB, and ERV\u2010driven RIG\u2010I\/MDA5\u2013MAVS signaling, and alter antigen presentation and immune checkpoint expression. However, the same processes may also promote chronic interferon tolerance, PD\u2010L1 induction, lymphocyte stress, myeloid suppression, extracellular cGAMP degradation, stromal exclusion, and treatment resistance. This review frames DDR targeting around damage\u2010to\u2010immunity 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\u2010intrinsic and host\u2010cell sensing mechanisms, and discuss antigen\u2010processing defects, STING regulation, and microenvironmental barriers that shape divergent outcomes. We further review PARP, ATR, WEE1, ATM, and DNA\u2010PK inhibitor combinations with immunotherapy and other treatment modalities, emphasizing clinical evidence, scheduling, and host\u2010cell toxicity. Finally, we propose a modular biomarker framework integrating genomic, functional, immune\u2010context, spatial and dynamic readouts to guide patient selection, treatment adaptation, and precision therapeutic decision\u2010making.<\/jats:p>","DOI":"10.1002\/mco2.71020","type":"journal-article","created":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T07:47:31Z","timestamp":1790149651000},"source":"Crossref","is-referenced-by-count":0,"title":["Targeting the DNA Damage Response in Cancer"],"prefix":"10.1002","volume":"7","author":[{"given":"Yihuan","family":"Qiao","sequence":"first","affiliation":[{"name":"Department of Digestive Surgery Xijing Hospital of Digestive Diseases Fourth Military Medical University  Xi'an China"},{"name":"State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases Xijing Hospital of Digestive Diseases Fourth Military Medical University  Xi'an 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