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Among recent innovations, proteolysis\u2010targeting chimeras (PROTACs) represent a burgeoning chemical knockdown technology capable of degrading oncogenic protein homeostasis and inducing dynamic alternations within carcinoma settings, offering potential for antitumor manipulation. However, achieving selectivity in PROTACs that respond to disease environmental stimulation and precisely perturb on\u2010target proteins remains challenging. The multi\u2010step synthesis and limited permeability, attributed to high\u2010molecular\u2010weight and heterobifunctional structures, further hinder their in\u2005vivo efficacy. Herein, we present a unique TME\u2010responsive enzyme\u2010activated clickable PROTACs, which features a short peptide\u2010tagged pomalidomide derivative to undergo tumor\u2010specific cleavage by cathepsin protease to induce orthogonal crosslinking of the exposed cysteine with 2\u2010cyanobenzothiazole\u2010labeled epigenetic protein\u2010ligand JQ1, facilitating in\u2005situ degrader formation within tumor regions only. Systematic protein profiling and proteomic analysis revealed that such TME\u2010specific clickable\u2010PROTACs not only selectively eliminate epigenetic proteins without tedious pre\u2010synthesis to bridge disparate small\u2010molecule bi\u2010warhead fragments, but also demonstrated superior tumor penetration compared to conventional high\u2010molecular\u2010weight PROTACs. Importantly, these clickable\u2010PROTACs efficiently downregulated immune checkpoint programmed death\u2010ligand 1 (PD\u2212L1) both in\u2005vitro and in\u2005vivo, remodeling TME for enhanced therapeutics, especially in anti\u2010tumoral immunomodulation.<\/jats:p>","DOI":"10.1002\/anie.202423057","type":"journal-article","created":{"date-parts":[[2025,2,11]],"date-time":"2025-02-11T08:59:45Z","timestamp":1739264385000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Enzyme\u2010Activated Orthogonal Proteolysis Chimeras for Tumor Microenvironment\u2010Responsive Immunomodulation"],"prefix":"10.1002","volume":"64","author":[{"given":"Caixia","family":"Sun","sequence":"first","affiliation":[{"name":"School of Chemistry Chemical Engineering and Biotechnology Nanyang Technological University  21 Nanyang Link Singapore 637371 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