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Further conjugation of the triphenylphosphonium moiety allows <jats:bold>M1<\/jats:bold> to undergo specific activation in the mitochondria, where mitochondria\u2010mediated apoptosis is observed. Moreover, <jats:bold>M1<\/jats:bold> has enormous effects on genomic DNA ascribed to FUDR's primary function of impeding DNA\/RNA synthesis combined with diminishing PP2A\u2010activated DNA repair pathways. Importantly, mechanistic studies highlight the PP2A obtrusion in FUDR\/5\u2010fluorouracil (5\u2010FU) therapy and underscore the importance of its inhibition to harbor therapeutic potential. HCT116 cell xenograft\u2010bearing mice that have a low response rate to 5\u2010FU show a prominent effect with <jats:bold>M1<\/jats:bold>, emphasizing the importance of DNA damage response targeting strategies using tumor\u2010specific microenvironment\u2010activatable systems.<\/jats:p>","DOI":"10.1002\/anie.202117075","type":"journal-article","created":{"date-parts":[[2022,2,8]],"date-time":"2022-02-08T13:49:41Z","timestamp":1644328181000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":59,"title":["DNA\u2010Damage\u2010Response\u2010Targeting Mitochondria\u2010Activated Multifunctional Prodrug Strategy for Self\u2010Defensive Tumor Therapy"],"prefix":"10.1002","volume":"61","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4220-8443","authenticated-orcid":false,"given":"Paramesh","family":"Jangili","sequence":"first","affiliation":[{"name":"Department of Chemistry Korea University  Seoul 02841 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