Modulating tumor physical microenvironment for fueling CAR-T cell therapy

Chimeric antigen receptor (CAR) T cell therapy has achieved unprecedented clinical success against hematologic malignancies. However, the transition of CAR-T cell therapies for solid tumors is limited by heterogenous antigen expression, immunosuppressive microenvironment (TME), immune adaptation of tumor cells and impeded CAR-T-cell infiltration/transportation. Recent studies increasingly reveal that tumor physical microenvironment could affect various aspects of tumor biology and impose profound impacts on the antitumor efficacy of CAR-T therapy. In this review, we discuss the critical roles of four physical cues in solid tumors for regulating the immune responses of CAR-T cells, which include solid stress, interstitial fluid pressure, stiffness and microarchitecture. We highlight new strategies exploiting these features to enhance the therapeutic potency of CAR-T cells in solid tumors by correlating with the state-of-the-art technologies in this field. A perspective on the future directions for developing new CAR-T therapies for solid tumor treatment is also provided.