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Updated: Jul 20, 2025
Screening Bioactive Nanoparticles in Phagocytic Immune Cells for Inhibitors of Toll-like Receptor Signaling
Published on: July 26, 2017
Site-specific nanoswitch circumventing immune resistance via activating TLR and inhibiting PD-L1/PD-1 axis
Yanyun Hao1, Hui Li1, Xiaoyan Ge1
1NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, Key Laboratory of Chemical Biology (Ministry of Education), Department of Pharmaceutics, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, PR China.
Abstract:
Immunotherapy has fundamentally altered cancer treatment; however, its effectiveness is clinically hampered by insufficient intratumoral T lymphocyte infiltration and failed T lymphocyte priming. Additionally, inducing cancer-specific immune responses while sparing normal cells remains challenging. Herein, we developed a redox-activatable polymeric nanoswitch (c-N@IM/JQ) that remained 'off' status in circulation but rapidly switched 'on' after entering the tumor. Toll-like receptor (TLR) 7/8 agonist (imidazoquinoline, IMQ) and bromodomain and extraterminal inhibitor (JQ1) are locked in c-N@IM/JQ with a redox-cleavable linker (switch off). Upon systemic administration, c-N@IM/JQ with c-RGD peptide modification preferentially accumulated at tumor sites and responded to the high glutathione levels to release native IMQ for fully mobilizing T lymphocyte army, and JQ1 for removing the programmed death ligand (PD-L)-1 protection on tumor cells (switch on). These strengthened T lymphocyte armies are easily accessible to these de-protected tumor cells, revitalizing the immune response against tumors.
Insights
This study introduces a novel redox-activatable polymeric nanoswitch for cancer immunotherapy. This nanoswitch enhances T lymphocyte infiltration and overcomes immune evasion by releasing key immune-activating agents within the tumor microenvironment.
Area of Science:
- Oncology
- Immunology
- Materials Science
Background:
- Cancer immunotherapy faces challenges with T cell infiltration and priming.
- Current strategies struggle to induce tumor-specific immunity while protecting healthy tissues.
Purpose of the Study:
- To develop a redox-activatable polymeric nanoswitch for enhanced cancer immunotherapy.
- To improve T cell responses and overcome immune evasion in tumors.
Main Methods:
- Developed a redox-activatable polymeric nanoswitch (c-N@IM/JQ) encapsulating Toll-like receptor (TLR) 7/8 agonist (imidazoquinoline, IMQ) and bromodomain and extraterminal inhibitor (JQ1).
- Utilized a redox-cleavable linker for controlled release within the tumor.
- Incorporated c-RGD peptide for tumor-specific accumulation.
- Leveraged high glutathione levels in tumors to trigger nanoswitch activation.
Main Results:
- The nanoswitch remained inactive in circulation but activated in the tumor microenvironment.
- Activated nanoswitch released IMQ to mobilize T lymphocytes and JQ1 to downregulate PD-L1 on tumor cells.
- Enhanced T lymphocyte infiltration and accessibility to tumor cells were observed.
- Revitalized anti-tumor immune responses.
Conclusions:
- The developed redox-activatable nanoswitch effectively enhances anti-tumor immunity.
- This platform shows promise for overcoming key limitations in current cancer immunotherapy.
- The strategy offers a targeted approach to cancer treatment by modulating the tumor microenvironment.
