Overcoming stromal resistance in solid tumors with MMP2-engineered CAR-T cells

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.