Modulation of fibronectin extracellular matrix enhances anti-tumor efficacy of immune checkpoint blockade

The success of immune checkpoint inhibitors is limited by multiple factors, including poor T cell infiltration and function within tumors, partly due to a dense extracellular matrix (ECM). Here, we investigate modulating the ECM by targeting integrin α5β1, a major fibronectin-binding and organizing integrin, to improve immunotherapy outcomes. Use of a function-blocking murinized α5β1 antibody reduces fibronectin fibril formation, enhances CD8⁺ T cell transendothelial migration, increases vascular permeability, and decreases vessel-associated collagen. These changes culminate in improving the effectiveness of PD-L1 blockade, alone or with chemotherapy, in the E0771 breast cancer model. Clinically, high integrin alpha 5 (ITGA5) expression correlates with worse survival in patients treated with atezolizumab as monotherapy or combined with chemotherapy or anti-angiogenic therapies in numerous clinical trials. Overall, our studies suggest that ECM-modulating approaches could be used as a future strategy to increase the proportion of patients who respond to immune checkpoint inhibition and other immunotherapies.