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Eukaryotic elongation factor 2 kinase (eEF2K), a stress\u2010responsive regulator of translational elongation, has emerged as a pivotal therapeutic target in triple\u2010negative breast cancer (TNBC) due to its critical role in sustaining cancer cell survival under nutrient stress. Building on our previous work identifying eEF2K as an oncogenic kinase, this study developed an eEF2K\u2010targeting PROTAC that exhibited potent antitumor activity against TNBC. Through a structure\u2010guided design, we identified a key allosteric pocket of eEF2K and linked its inhibitor 2S to a CRBN ligand to generate A6, a PROTAC that promotes eEF2K degradation via a conformationally optimized interface, achieving &gt;90% target depletion while preserving the total levels of its substrate eEF2. A6 exhibited anti\u2010proliferative effects across TNBC cell lines by degrading eEF2K. In Vivo and in TNBC organoid models, A6 treatment significantly suppressed tumor growth, with favorable tolerability. To further enhance tumor\u2010specific delivery, we engineered A6@ZIF\u20108, a pH\u2010sensitive nanocarrier that promotes drug accumulation at tumor sites compared to free A6, leading to improved therapeutic outcomes. Collectively, our data indicate that targeted degradation of eEF2K via PROTAC technology constitutes a novel and therapeutically relevant intervention strategy for TNBC.<\/jats:p>","DOI":"10.1002\/advs.202520863","type":"journal-article","created":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T12:29:35Z","timestamp":1769516975000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Targeted Degradation of eEF2K by a Structure\u2010Guided PROTAC Strategy for the Treatment of Triple\u2010Negative Breast Cancer"],"prefix":"10.1002","volume":"13","author":[{"given":"Shijun","family":"Cao","sequence":"first","affiliation":[{"name":"Department of Pathology The Affiliated Cancer Hospital of Xiangya School of Medicine Central South University \/Hunan Cancer Hospital Changsha Hunan China"},{"name":"Department of Pharmacy The Second Xiangya Hospital Central South University Changsha Hunan China"},{"name":"Hunan Provincial 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