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Updated: Dec 7, 2025
Identifying PD-1/PD-L1 Inhibitors with Surface Plasmon Resonance Technology
Published on: May 2, 2025
Small-molecule MMP2/MMP9 inhibitor SB-3CT modulates tumor immune surveillance by regulating PD-L1
Youqiong Ye1,2,3, Xinwei Kuang4,5,6,7, Zuozhong Xie4,5,6,7
1Department of Dermatology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China. youqiong.ye@shsmu.edu.cn.
Background:
Immune checkpoint blockade (ICB) therapy has demonstrated considerable clinical benefit in several malignancies, but has shown favorable response in only a small proportion of cancer patients. Recent studies have shown that matrix metalloproteinases (MMPs) are highly associated with the microenvironment of tumors and immune cells. However, it is unknown whether MMPs are involved in immunotherapy.
Methods:
Here, we used integrative analysis to explore the expression landscape of the MMP family and its association with immune features across multiple cancer types. We used T cell cytotoxicity-mediated tumor killing assay to determine the co-cultured T cell activity of SB-3CT, an MMP2/9 inhibitor. We then used in vitro assays to examine the regulating roles of SB-3CT on PD-L1. We further characterized the efficacy of SB-3CT, in combination with anti-PD-1 and/or anti-CTLA4 treatment in mouse models with melanoma and lung cancer.
Results:
Our computational analysis demonstrated a strong association between MMP2/9 and immune features. We demonstrated that inhibition of MMP2/9 by SB-3CT significantly reduced the tumor burden and improved survival time by promoting anti-tumor immunity. Mechanistically, we showed that SB-3CT treatment significantly diminished both mRNA and protein levels of PD-L1 in cancer cells. Pre-clinically, SB-3CT treatment enhanced the therapeutic efficacy of PD-1 or CTLA-4 blockade in the treatment of both primary and metastatic tumors.
Conclusions:
Our study unraveled novel molecular mechanisms regarding the regulation of tumor PD-L1 and provided a novel combination therapeutic strategy of SB-3CT and ICB therapy to enhance the efficacy of immunotherapy.
Insights
Matrix metalloproteinase (MMP) inhibition with SB-3CT enhances anti-tumor immunity and improves immunotherapy response. This MMP2/9 inhibitor reduces PD-L1 expression, boosting efficacy of immune checkpoint blockade (ICB) therapy.
Area of Science:
- Oncology
- Immunology
- Biochemistry
Background:
- Immune checkpoint blockade (ICB) therapy offers benefits in cancer but has limited response rates.
- Matrix metalloproteinases (MMPs) are linked to tumor microenvironments and immune cells.
- The role of MMPs in immunotherapy remains largely unexplored.
Purpose of the Study:
- To investigate the association between MMPs and immune features in various cancer types.
- To explore the potential of MMP inhibition as a strategy to enhance immunotherapy.
Main Methods:
- Integrative analysis of MMP expression and immune features.
- In vitro assays using SB-3CT (an MMP2/9 inhibitor) to assess T cell activity and PD-L1 regulation.
- In vivo studies in mouse models of melanoma and lung cancer evaluating SB-3CT in combination with anti-PD-1/anti-CTLA4 therapy.
Main Results:
- MMP2/9 expression strongly correlates with immune features.
- SB-3CT treatment reduced tumor burden and improved survival by enhancing anti-tumor immunity.
- SB-3CT diminished PD-L1 expression in cancer cells and potentiated ICB efficacy in preclinical models.
Conclusions:
- Novel mechanisms linking MMPs, PD-L1 regulation, and immunotherapy response were uncovered.
- SB-3CT combined with ICB represents a promising therapeutic strategy to improve cancer immunotherapy outcomes.
