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Here we present a multi\u2010signal responsive allosteric nanozyme platform that exploits tumor\u2010intrinsic stress amplification (TISA) to achieve spatiotemporally confined ferroptosis. The design integrates three microenvironmental cues\u2014reactive oxygen species (ROS), acidic pH, and elevated glutathione (GSH)\u2014as cooperative allosteric effectors: ROS primes the catalyst, acidic pH accelerates peroxidase\u2010like (POD\u2010like) activity, and intracellular GSH acts as a reversible brake to self\u2010limit activity post\u2010activation. Only upon convergence of all three signals does the nanozyme switch from an off\u2010state to a high\u2010turnover state, triggering localized lipid peroxidation and bypassing systemic oxidative damage. Across orthotopic and metastatic tumor models, TISA nanozymes selectively amplified ferroptotic stress in tumor tissue, overcame antioxidant buffering, and suppressed tumor growth with minimal off\u2010target toxicity. This multi\u2010layered gating and confinement strategy establishes a blueprint for precision ferroptosis nanomedicine and offers a generalizable approach to harness complex tumor microenvironment signals for safe and effective catalytic therapy.<\/jats:p>","DOI":"10.1002\/adhm.202505562","type":"journal-article","created":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T09:32:45Z","timestamp":1778059965000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Multi\u2010Signal Responsive Allosteric Nanozymes for Spatiotemporally Confined Ferroptosis via Tumor\u2010Intrinsic Stress Amplification"],"prefix":"10.1002","volume":"15","author":[{"given":"Jing","family":"Yang","sequence":"first","affiliation":[{"name":"School of Chemistry and Chemical Engineering Hunan University of Science and Technology Key Laboratory of Theoretical Organic Chemistry and Function Molecule Ministry of Education Hunan Provincial Key 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