Light-Triggered PROTAC Nanoassemblies for Photodynamic IDO Proteolysis in Cancer Immunotherapy.
Jiwoong ChoiByeongmin ParkJung Yeon ParkDongwon ShinSangmin LeeHong Yeol YoonKwangmeyung KimSun Hwa KimYongju KimYoosoo YangMan Kyu ShimPublished in: Advanced materials (Deerfield Beach, Fla.) (2024)
While proteolysis-targeting chimeras (PROTACs) hold great potential for persistently reprogramming the immunosuppressive tumor microenvironment (ITM) via targeted protein degradation, precisely activating them in tumor tissues and preventing uncontrolled proteolysis at off-target sites remain challenging. Herein, we report a light-triggered PROTAC nanoassembly (LPN) for photodynamic indoleamine 2,3-dioxygenase (IDO) proteolysis. The LPN is derived from the self-assembly of prodrug conjugates, which comprise a PROTAC, cathepsin B-specific cleavable peptide linker and photosensitizer, without any additional carrier materials. In colon tumor models, intravenously injected LPNs initially silence the activity of PROTACs and accumulate significantly in targeted tumor tissues due to an enhanced permeability and retention (EPR) effect. Subsequently, the cancer biomarker cathepsin B begins to trigger the release of active PROTACs from the LPNs through enzymatic cleavage of the linkers. Upon light irradiation, tumor cells undergo immunogenic cell death (ICD) induced by photodynamic therapy (PDT) to promote the activation of effector T cells, while the continuous IDO degradation of PROTAC simultaneously blocks tryptophan metabolite-regulated regulatory T cell-mediated immunosuppression. Such LPN-mediated combinatorial photodynamic IDO proteolysis effectively inhibits tumor growth, metastasis and recurrence. Collectively, this study presents a promising nanomedicine, designed to synergize PROTACs with other immunotherapeutic modalities, for more effective and safer cancer immunotherapy. This article is protected by copyright. All rights reserved.
Keyphrases
- cancer therapy
- photodynamic therapy
- drug delivery
- cell death
- gene expression
- transcription factor
- fluorescence imaging
- signaling pathway
- dendritic cells
- young adults
- papillary thyroid
- small molecule
- hydrogen peroxide
- regulatory t cells
- endothelial cells
- risk assessment
- radiation therapy
- radiation induced
- cell proliferation
- amino acid
- binding protein
- free survival
- human health