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Here we report a phenylselanyl cyclohexenone self\u2010immolative linker that couples ROS\u2010triggered cleavage with organoselenium\u2010mediated redox amplification within a single small\u2010molecule architecture. Oxidation of the selanyl group generates a selenoxide that undergoes aromatization\u2010assisted \u03b2\u2010elimination followed by 1,6\u2010self\u2010elimination, releasing the payload together with a redox\u2010active selenium species. The released selenium species is proposed to engage in a GSH\u2010dependent redox cycle that increases intracellular oxidative burden, thereby reinforcing ROS\u2010triggered activation and weakening antioxidant buffering. This modular motif enables the construction of carrier\u2010free prodrugs spanning chemotherapeutics and small\u2010molecule inhibitors. These prodrugs remain stable in neutral media yet are efficiently activated by endogenous ROS, achieving improved biodistribution, reduced systemic toxicity, and enhanced antitumor activity across breast cancer, pancreatic ductal adenocarcinoma, and patient\u2010derived leukemia models. By coupling selective activation with catalytic redox amplification, this ROS\u2010amplifying self\u2010immolative linker provides a modular strategy for overcoming redox\u2010associated drug resistance and for advancing the translational potential of small\u2010molecule prodrugs.<\/jats:p>","DOI":"10.1002\/anie.8965077","type":"journal-article","created":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T08:58:37Z","timestamp":1776934717000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Catalytic ROS\u2010Amplifying Self\u2010Immolative Linkers Enable Carrier\u2010Free Prodrugs for Refractory Tumors"],"prefix":"10.1002","volume":"65","author":[{"given":"Qiwei","family":"Zhou","sequence":"first","affiliation":[{"name":"Center of Drug Discovery State Key Laboratory of Natural Medicines Center of Drug Discovery China Pharmaceutical University  Nanjing 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