{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T06:12:47Z","timestamp":1767679967523,"version":"3.48.0"},"reference-count":101,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T00:00:00Z","timestamp":1767657600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontierspartnerships.org"],"crossmark-restriction":true},"short-container-title":["J. Pharm. Pharm. Sci."],"abstract":"<jats:p>Gastric cancer remains a highly prevalent and accounts for a notable proportion of global cancer mortality. Both Intrinsic and exogenous agents can exacerbate reactive oxygen species (ROS) related oxidized DNA base lesions and single stranded DNA breaks (SSBs). Base excision repair (BER) serves as the primary defense mechanism for repairing DNA damage induced by oxidative stress. DNA polymerase beta (Pol \u03b2) plays a critical role in BER and non-homologous end joining repair pathways. The Pol \u03b2 is the first perform gap-filling DNA synthesis by its polymerase activity and then cleave a 5\u2032-deoxyribose-5-phosphate (dRP) moiety via its dRP lyase activity. Furthermore, defect in POLB promotes genetic liability of the cancer cells for different targeted and synthetic lethality-based treatment strategies. In this review, we have provided a potential example to illustrate the mechanistic insight how PARP1 inhibitor (Olaparib) induces replication associated double strand breaks in POLB deficient cells and DNA mediated innate immune signal activation that likely enhances immune based therapy. Based on our previously published data and the current recent findings, POLB status of the patient likely provide genetic indicators to stratify gastric cancer patient. Overall, in this review article, we presented a new direction to highlight the opportunity to exploit POLB genetic defect in cancer cells to enhance treatment response and to explore synergistic effect to target gastric cancer cells that harbor aberrant DNA polymerase beta function with immune based therapeutic strategy.<\/jats:p>","DOI":"10.3389\/jpps.2025.15360","type":"journal-article","created":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T06:10:16Z","timestamp":1767679816000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Harnessing DNA polymerase beta defect enhances synthetic lethality and treatment response in gastric cancer cells: implication for immunotherapy"],"prefix":"10.3389","volume":"28","author":[{"given":"Aashirwad","family":"Shahi","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shengyuan","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dawit","family":"Kidane","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,1,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1146\/annurev.micro.59.031805.133658","article-title":"Genome-wide responses to DNA-damaging agents","volume":"59","author":"Fry","year":"2005","journal-title":"Annu Rev Microbiol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1146\/annurev.pharmtox.41.1.367","article-title":"Cellular responses to DNA damage","volume":"41","author":"Norbury","year":"2001","journal-title":"Annu Rev Pharmacol Toxicol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"4191","DOI":"10.2741\/2380","article-title":"DNA repair pathways and hereditary cancer susceptibility syndromes","volume":"12","author":"Spry","year":"2007","journal-title":"Front Biosci"},{"key":"B4","doi-asserted-by":"publisher","first-page":"436","DOI":"10.1038\/nature01408","article-title":"DNA damage and repair","volume":"421","author":"Friedberg","year":"2003","journal-title":"Nature"},{"key":"B5","doi-asserted-by":"publisher","first-page":"1195","DOI":"10.1096\/fj.02-0752rev","article-title":"Oxidative DNA damage: mechanisms, mutation, and disease","volume":"17","author":"Cooke","year":"2003","journal-title":"FASEB J"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1042\/bj3250001","article-title":"DNA glycosylases in the base excision repair of DNA","volume":"325","author":"Krokan","year":"1997","journal-title":"Biochem J"},{"key":"B7","doi-asserted-by":"publisher","first-page":"a012583","DOI":"10.1101\/cshperspect.a012583","article-title":"Base excision repair","volume":"5","author":"Krokan","year":"2013","journal-title":"Cold Spring Harbor Perspectives Biology"},{"key":"B8","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1016\/j.carrev.2006.02.002","article-title":"A concise review of DNA damage checkpoints and repair in mammalian cells","volume":"7","author":"Houtgraaf","year":"2006","journal-title":"Cardiovasc Revasc Med"},{"key":"B9","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1146\/annurev.biochem.73.011303.073723","article-title":"Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints","volume":"73","author":"Sancar","year":"2004","journal-title":"Annu Rev Biochem"},{"key":"B10","doi-asserted-by":"publisher","first-page":"544","DOI":"10.1016\/j.dnarep.2006.10.017","article-title":"The mechanics of base excision repair, and its relationship to aging and disease","volume":"6","author":"Wilson","year":"2007","journal-title":"DNA Repair (Amst)"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1256","DOI":"10.1126\/science.6351251","article-title":"Dietary carcinogens and anticarcinogens. 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