Review Article: The Extracellular Matrix as a Barrier for CAR-T Cell Therapy in Solid Tumors.

Chimeric antigen receptor T (CAR-T) cell therapies, based on introducing a genetically modified T cell receptor to a patient's T cells, have transformed the treatment of hematological tumors. However, their efficacy in solid tumors is limited to date. Among the multiple barriers that shape CAR-T cell efficacy, including antigen heterogeneity, hypoxic tumor microenvironment (TME), and immunosuppressive cell populations, the altered extracellular matrix (ECM) has emerged as a dominant but understudied obstacle. In this review, we summarize the key ECM alterations characteristic of solid tumors and highlight the physical and molecular features that limit CAR-T cell function and promote exhaustion. We further discuss strategies to overcome these constraints and therapy resistance, as well as approaches to assess CAR-T therapy efficacy in clinically relevant models.