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Title: Smart nano-PROTACs reprogram tumor microenvironment for activatable photo-metabolic cancer immunotherapy
Authors: Zhang, Chi
He, Shasha
Zeng, Ziling
Cheng, Penghui
Pu, Kanyi
Keywords: Science::Medicine
Issue Date: 2022
Source: Zhang, C., He, S., Zeng, Z., Cheng, P. & Pu, K. (2022). Smart nano-PROTACs reprogram tumor microenvironment for activatable photo-metabolic cancer immunotherapy. Angewandte Chemie (International Ed. in English), 61(8), e202114957-.
Project: 2019-T1-002-045 
SERC A18 A8b0059
Journal: Angewandte Chemie (International ed. in English)
Abstract: Protease inhibitors can modulate intratumoral metabolic processes to reprogram the immunosuppressive tumor microenvironment (TME), which however suffer from the limited efficacy and off-targeted side effects. We report smart nano-proteolysis targeting chimeras (nano-PROTACs) with phototherapeutic ablation and cancer-specific protein degradation to reprogram the TME for photo-metabolic cancer immunotherapy. This nano-PROTAC has a semiconducting polymer backbone linked with a cyclooxygenase 1/2 (COX-1/2)-targeting PROTAC peptide (CPP) via a cathepsin B (CatB)-cleavable segment. CPP can be activated by the tumor-overexpressed CatB to induce the degradation of COX-1/2 via the ubiquitin-proteasome system. The persistent degradation of COX-1/2 depletes their metabolite prostaglandin E2 which is responsible for activation of immune suppressor cells. Such a smart PROTAC strategy synergized with phototherapy specifically reprograms the immunosuppressive TME and reinvigorates antitumor immunity.
ISSN: 1433-7851
DOI: 10.1002/anie.202114957
Rights: © 2021 Wiley-VCH GmbH. All rights reserved.
Fulltext Permission: none
Fulltext Availability: No Fulltext
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