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MMP-2 Inhibitor-Mediated Tumor Microenvironment Regulation Using a Sequentially Released Bio-Nanosystem for Enhanced
Huifang Liu1, Dongqin Lei1, Jiong Li1
1Key Laboratory of Biomedical Information Engineering of Ministry of Education, Institute of Biomedical Photonics and Sensing, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, PR China.
Abstract:
Combining photodynamic therapy (PDT) with natural killer (NK) cell-based immunotherapy has shown great potential against cancers, but the shedding of NK group 2, member D ligands (NKG2DLs) on tumor cells inhibited NK cell activation in the tumor microenvironment. Herein, we assembled microenvironment-/light-responsive bio-nanosystems (MLRNs) consisting of SB-3CT-containing β-cyclodextrins (β-CDs) and photosensitizer-loaded liposomes, in which SB-3CT was considered to remodel the tumor microenvironment. β-CDs and liposomes were linked by metalloproteinase 2 (MMP-2) responsive peptides, enabling sequential release of SB-3CT and chlorin e6 triggered by the MMP-2-abundant tumor microenvironment and 660 nm laser irradiation, respectively. Released SB-3CT blocked tumor immune escape by antagonizing MMP-2 and promoting the NKG2D/NKG2DL pathway, while liposomes were taken up by tumor cells for PDT. MLRN-mediated photo-immunotherapy significantly induced melanoma cell cytotoxicity (83.31%), inhibited tumor growth (relative tumor proliferation rate: 1.13% of that of normal saline) in the xenografted tumor model, and enhanced tumor-infiltrating NK cell (148 times) and NKG2DL expression (9.55 and 16.52 times for MICA and ULBP-1, respectively), achieving a synergistic effect. This study not only provided a simple insight into the development of new nanomedicine for programed release of antitumor drugs and better integration of PDT and immunotherapy but also a novel modality for clinical NK cell-mediated immunotherapy against melanoma.
Insights
This study developed novel bio-nanosystems that combine photodynamic therapy and natural killer cell immunotherapy to overcome tumor immune escape. The system effectively boosts NK cell activity and inhibits melanoma growth by remodeling the tumor microenvironment.
Area of Science:
- Biomedical Engineering
- Cancer Immunotherapy
- Nanomedicine
Background:
- Combining photodynamic therapy (PDT) with natural killer (NK) cell immunotherapy shows promise for cancer treatment.
- Tumor cells can evade NK cell attacks by shedding NK group 2, member D ligands (NKG2DLs), hindering NK cell activation in the tumor microenvironment.
Purpose of the Study:
- To develop microenvironment-/light-responsive bio-nanosystems (MLRNs) for synergistic PDT and NK cell immunotherapy.
- To overcome tumor immune escape by targeting the NKG2D/NKG2DL pathway and remodeling the tumor microenvironment.
Main Methods:
- Assembled MLRNs containing SB-3CT and photosensitizer-loaded liposomes, linked by MMP-2 responsive peptides.
- Utilized sequential release of SB-3CT and chlorin e6 triggered by the tumor microenvironment and laser irradiation.
- Evaluated MLRN efficacy in melanoma cell cytotoxicity and a xenografted tumor model.
Main Results:
- MLRNs significantly induced melanoma cell cytotoxicity (83.31%) and inhibited tumor growth.
- Demonstrated a 148-fold increase in tumor-infiltrating NK cells and enhanced NKG2DL expression (MICA and ULBP-1).
- Achieved a synergistic therapeutic effect by blocking tumor immune escape and promoting NK cell activation.
Conclusions:
- Developed a novel nanomedicine for programmed drug release, integrating PDT and immunotherapy.
- MLRNs offer a promising strategy for NK cell-mediated immunotherapy against melanoma by overcoming immune evasion.
- Provides a new modality for clinical applications in cancer treatment.
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02:17The Tumor Microenvironment
01:27Tumor Immunotherapy