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Starting from the scaffold of MSA2, a non-CDN synthetic agonist that requires non-covalent dimerization via its benzo[b]thiophene core before binding to STING, we showed that its analogs bearing reactive functional groups readily and selectively formed covalent dimers under mild conditions and in complex envi- ronments. Caging one of the reactants with a self-immolative 𝛽-glucuronide moiety resulted in a two-component prodrug system that near-exclusively formed the active compounds in tumors overexpressing 𝛽-glucuronidase. These results exemplify the use of small-molecule recognition for on-site generation of active compounds from benign precursors.","abstract_html":"Pharmacological activation of STING holds promise in cancer treatment. A recent trend is the development of tumor-specific or conditionally activated STING agonists for enhanced safety and efficacy. Herein, we explored an unconventional prodrug activation strategy for on-tumor synthesis of a potent agonist. Starting from the scaffold of MSA2, a non-CDN synthetic agonist that requires non-covalent dimerization via its benzo[b]thiophene core before binding to STING, we showed that its analogs bearing reactive functional groups readily and selectively formed covalent dimers under mild conditions and in complex envi- ronments. Caging one of the reactants with a self-immolative 𝛽-glucuronide moiety resulted in a two-component prodrug system that near-exclusively formed the active compounds in tumors overexpressing 𝛽-glucuronidase. 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