Smart nano-PROTACs reprogram tumor microenvironment for activatable photo-metabolic cancer immunotherapy
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 ab...
| Main Authors: | , , , , |
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| Other Authors: | |
| Format: | Journal Article |
| Language: | English |
| Published: |
2022
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| Subjects: | |
| Online Access: | https://hdl.handle.net/10356/162219 |
| _version_ | 1826123395543072768 |
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| author | Zhang, Chi He, Shasha Zeng, Ziling Cheng, Penghui Pu, Kanyi |
| author2 | School of Chemical and Biomedical Engineering |
| author_facet | School of Chemical and Biomedical Engineering Zhang, Chi He, Shasha Zeng, Ziling Cheng, Penghui Pu, Kanyi |
| author_sort | Zhang, Chi |
| collection | NTU |
| description | 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. |
| first_indexed | 2024-10-01T06:03:57Z |
| format | Journal Article |
| id | ntu-10356/162219 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T06:03:57Z |
| publishDate | 2022 |
| record_format | dspace |
| spelling | ntu-10356/1622192022-10-10T05:24:21Z Smart nano-PROTACs reprogram tumor microenvironment for activatable photo-metabolic cancer immunotherapy Zhang, Chi He, Shasha Zeng, Ziling Cheng, Penghui Pu, Kanyi School of Chemical and Biomedical Engineering School of Physical and Mathematical Sciences Lee Kong Chian School of Medicine (LKCMedicine) Science::Medicine Cancer Immunotherapy Phototherapy 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. Agency for Science, Technology and Research (A*STAR) Ministry of Education (MOE) K.P. thanks 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), and A*STAR SERC AME Programmatic Fund (SERC A18 A8b0059) for the financial support . 2022-10-10T05:24:21Z 2022-10-10T05:24:21Z 2022 Journal Article 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-. https://dx.doi.org/10.1002/anie.202114957 1433-7851 https://hdl.handle.net/10356/162219 10.1002/anie.202114957 34927316 2-s2.0-85122069804 8 61 e202114957 en 2019-T1-002-045 RG125/19 RT05/20 MOE2018-T2-2-042 MOE-T2EP30220-0010 SERC A18 A8b0059 Angewandte Chemie (International ed. in English) © 2021 Wiley-VCH GmbH. All rights reserved. |
| spellingShingle | Science::Medicine Cancer Immunotherapy Phototherapy Zhang, Chi He, Shasha Zeng, Ziling Cheng, Penghui Pu, Kanyi Smart nano-PROTACs reprogram tumor microenvironment for activatable photo-metabolic cancer immunotherapy |
| title | Smart nano-PROTACs reprogram tumor microenvironment for activatable photo-metabolic cancer immunotherapy |
| title_full | Smart nano-PROTACs reprogram tumor microenvironment for activatable photo-metabolic cancer immunotherapy |
| title_fullStr | Smart nano-PROTACs reprogram tumor microenvironment for activatable photo-metabolic cancer immunotherapy |
| title_full_unstemmed | Smart nano-PROTACs reprogram tumor microenvironment for activatable photo-metabolic cancer immunotherapy |
| title_short | Smart nano-PROTACs reprogram tumor microenvironment for activatable photo-metabolic cancer immunotherapy |
| title_sort | smart nano protacs reprogram tumor microenvironment for activatable photo metabolic cancer immunotherapy |
| topic | Science::Medicine Cancer Immunotherapy Phototherapy |
| url | https://hdl.handle.net/10356/162219 |
| work_keys_str_mv | AT zhangchi smartnanoprotacsreprogramtumormicroenvironmentforactivatablephotometaboliccancerimmunotherapy AT heshasha smartnanoprotacsreprogramtumormicroenvironmentforactivatablephotometaboliccancerimmunotherapy AT zengziling smartnanoprotacsreprogramtumormicroenvironmentforactivatablephotometaboliccancerimmunotherapy AT chengpenghui smartnanoprotacsreprogramtumormicroenvironmentforactivatablephotometaboliccancerimmunotherapy AT pukanyi smartnanoprotacsreprogramtumormicroenvironmentforactivatablephotometaboliccancerimmunotherapy |