Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 61, Issue 8, Pages -Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.202114957
Keywords
Cancer Immunotherapy; PROTAC; Phototherapy; Tumor Microenvironment
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Funding
- Singapore Ministry of Education, Academic Research Fund Tier 1 [2019-T1-002-045, RG125/19, RT05/20]
- Academic Research Fund Tier 2 [MOE2018-T2-2-042, MOE-T2EP30220-0010]
- A*STAR SERC AME Programmatic Fund [SERC A18A8b0059]
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This study introduces smart nano-proteolysis targeting chimeras for photo-metabolic cancer immunotherapy, reprogramming the immunosuppressive tumor microenvironment by utilizing phototherapeutic ablation and cancer-specific protein degradation.
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 E-2 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.
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