Checkpoint nano-PROTACs for activatable cancer photo-immunotherapy
Checkpoint immunotherapy holds great potential to treat malignancies via blocking the immunosuppressive signaling pathways, which however suffers from inefficiency and off-target adverse effects. Herein, checkpoint nano-proteolysis targeting chimeras (nano-PROTACs) in combination with photodynamic t...
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| Main Authors: | , , , , , |
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| Other Authors: | |
| Format: | Article |
| Language: | English |
| Published: |
2023
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| Subjects: | |
| Online Access: | https://hdl.handle.net/10356/164392 |
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| Institution: | Nanyang Technological University |
| Language: | English |
| Summary: | Checkpoint immunotherapy holds great potential to treat malignancies via blocking the immunosuppressive signaling pathways, which however suffers from inefficiency and off-target adverse effects. Herein, checkpoint nano-proteolysis targeting chimeras (nano-PROTACs) in combination with photodynamic tumor regression and immunosuppressive protein degradation to block checkpoint signaling pathways for activatable cancer photo-immunotherapy are reported. These nano-PROTACs are composed of a photosensitizer (protoporphyrin IX, PpIX) and an Src homology 2 domain-containing phosphatase 2 (SHP2)-targeting PROTAC peptide (aPRO) via a caspase 3-cleavable segment. aPRO is activated by the increased expression of caspase 3 in tumor cells after phototherapeutic treatment and induces targeted degradation of SHP2 via the ubiquitin-proteasome system. The persistent depletion of SHP2 blocks the immunosuppressive checkpoint signaling pathways (CD47/SIRPα and PD-1/PD-L1), thus reinvigorating antitumor macrophages and T cells. Such a checkpoint PROTAC strategy synergizes immunogenic phototherapy to boost antitumor immune response. Thus, this study represents a generalized PROTAC platform to modulate immune-related signaling pathways for improved anticancer therapy. |
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