Tailoring CAR surface density and dynamics to improve CAR-T cell therapy

Chimeric antigen receptor (CAR)-T cell therapy has revolutionized the treatment landscape for relapsed and/or refractory B-cell neoplasms, garnering Food and Drug Administration/European Medicines Agency approval for six commercial products. Despite this success, challenges persist, including a relapse rate of 30-50% in hematologic tumors, limited clinical efficacy in solid tumors, and severe side effects. This review addresses the critical need for therapeutic enhancement by focusing on the often-overlooked strategy of modulating CAR protein density on the cell membrane. We delve into the key factors influencing CAR surface expression, such as CAR downmodulation following antigen encounter and antigen-related factors. The dynamics of CAR downmodulation remain underexplored; however, recent data point to its modification as a useful tool for improving functionality. Notably, transcriptional control of CAR expression and the incorporation of specific elements into the CAR design have emerged as interesting strategies to tailor CAR expression profiles. Therefore, controlling CAR dynamic density may represent an attractive strategy for achieving optimal therapeutic outcomes.