Related Experiment Video
Updated: Mar 17, 2026
Author Spotlight: Advancements in Hypoxia-Sensitive CAR-T Therapy for Enhanced Cancer Immunotherapy
Published on: June 14, 2024
Overcoming stromal resistance in solid tumors with MMP2-engineered CAR-T cells
Jiaxin Tu1, Yuge Zhu2, Xinyu Li1
1Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Biochemistry and Molecular Biology, Peking University Cancer Hospital & Institute, Beijing 100142, China.
Abstract:
Chimeric antigen receptor (CAR) T-cell therapy remains ineffective in most solid tumors due to extracellular matrix (ECM)-mediated stromal barriers. While prior ECM-remodeling strategies using multiple matrix metalloproteinases (MMPs) improved tumor infiltration, they increased vector complexity and raised translational concerns; conversely, single MMP7 overexpression enhanced infiltration without improving tumor control. Here, we identify matrix metalloproteinase-2 (MMP2) as a single ECM-degrading enzyme that simultaneously enhances CAR-T cell infiltration and antitumor efficacy. Mesothelin- and B7H3-targeted CAR-T cells co-expressing MMP2 preserved T-cell fitness while exhibiting superior ECM traversal and cytotoxicity in vitro, and these effects were abolished by the pan-MMP inhibitor GM6001. In a physiologically relevant, cancer-associated fibroblast (CAF)-enriched xenograft model, MMP2-engineered CAR-T cells displayed increased intratumoral accumulation and durable tumor control. These findings establish MMP2-based single-enzyme ECM remodeling as a simple, scalable, and clinically translatable strategy to overcome stromal resistance and advance CAR-T therapy for solid tumors.
Insights
Matrix metalloproteinase-2 (MMP2) enhances chimeric antigen receptor (CAR) T-cell therapy for solid tumors by degrading extracellular matrix barriers. This single-enzyme approach improves T-cell infiltration and antitumor efficacy, offering a scalable strategy.
Area of Science:
- Immunotherapy
- Oncology
- Biochemistry
Background:
- Chimeric antigen receptor (CAR) T-cell therapy faces challenges in solid tumors due to extracellular matrix (ECM) stromal barriers.
- Previous strategies using multiple matrix metalloproteinases (MMPs) increased complexity, while single MMP7 overexpression showed limited efficacy.
Purpose of the Study:
- To identify a single enzyme for effective ECM remodeling to enhance CAR T-cell therapy in solid tumors.
- To evaluate the efficacy of matrix metalloproteinase-2 (MMP2) in overcoming ECM-mediated resistance.
Main Methods:
- Engineered CAR T-cells (targeting mesothelin and B7H3) to co-express MMP2.
- In vitro assessment of ECM traversal, T-cell fitness, and cytotoxicity.
- In vivo evaluation in a cancer-associated fibroblast (CAF)-enriched xenograft model.
Main Results:
- MMP2 co-expression enhanced CAR T-cell infiltration and cytotoxicity by facilitating ECM traversal.
- MMP2's effects were confirmed by inhibition with the pan-MMP inhibitor GM6001.
- MMP2-engineered CAR T-cells demonstrated increased intratumoral accumulation and durable tumor control in vivo.
Conclusions:
- Matrix metalloproteinase-2 (MMP2) is a potent single enzyme for ECM remodeling in solid tumors.
- MMP2-based strategy offers a simple, scalable, and clinically translatable approach to overcome stromal resistance in CAR T-cell therapy.
Related Concept Videos
01:27Tumor Immunotherapy
02:30Metastasis
Epithelial-to-Mesenchymal Transition
The epithelial-to-mesenchymal transition or EMT is a developmental process commonly observed in wound healing, embryogenesis, and cancer metastasis. EMT is induced by transforming growth factor-beta (TGF-β) or receptor tyrosine kinase (RTK) ligands, which further...
01:19Mesenchymal Stem Cells
02:17The Tumor Microenvironment