FAK Inhibition Remodels the Metastatic ECM and Restores CD8+ T Cell Trafficking and Immunosurveillance

Abstract

Metastatic breast cancer remains largely incurable, driven in part by immunosuppressive microenvironments that limit CD8+ T cell-mediated clearance. Using a murine pulmonary metastatic breast cancer model, we show that the focal adhesion kinase (FAK) inhibitor VS-4718 promotes a CD8+ T cell-dependent regression of metastatic lesions by reprograming the metastatic microenvironment. VS-4718 reduced immunosuppressive myeloid and regulatory T cells while increasing CD8+ T cell infiltration. Cellular and secreted proteome profiling revealed that VS-4718 downregulates ECM components such as laminin 5 and collagen VIII1, which we show impair CD8+ T cell migration and activity. In human breast cancer cohorts, elevated LAMA5/COL8A1 expression and a FAK-dependent ECM signature associate with poor outcome and prognostic for residual disease. Intravital imaging demonstrated that VS-4718 enhances CD8 T cell extravasation and induces T cell-tumor cell contacts necessary for cytotoxicity. Ex vivo lung slice cultures recapitulated these findings, showing enhanced T cell swarming, metastatic cluster shrinkage, and apoptosis. These findings reveal how FAK inhibition remodels the metastatic ECM to potentiate coordinated CD8+ T cell responses. VS-4718 might aid in clearing metastases in breast cancer patients through modulating both stromal and immune components. STATEMENT OF SIGNIFICANCEFocal adhesion kinase (FAK) inhibition remodels collagen- and laminin-rich extracellular matrix barriers and alleviates physical constraints that limit CD8 T cell access and activity in metastases. This enhances infiltration, migration, and tumor cell engagement, and synergizes with PD-1 blockade, supporting combined therapeutic strategies in metastatic breast cancer.