Mapping the clinical landscape of multifunctional CAR T cells: Targets, trends, and synergies.

Chimeric antigen receptor (CAR) T cell therapies have achieved remarkable and durable clinical responses in several hematological malignancies, yet their broader impact remains limited by toxicities and reduced efficacy, especially in solid tumors. Building on the successes and limitations of approved CAR therapies, more than 1,800 clinical trials were registered over the past decade. As of September 2025, 33% investigate next-generation CAR T products that incorporate auxiliary features intended to enhance safety and therapeutic efficacy (multifunctional CAR T cells). In this systematic review, we screened such multifunctional approaches across the complete landscape of CAR T cell trials registered at Clinicaltrials.gov. To provide a comprehensive discussion of this emerging paradigm and better understand its real-world impact, we classified multifunctional CAR trials as either safety or efficacy enhancements and monitored their registration frequency over the past 20 years. We describe each type of multifunctional CAR T cell currently present in clinical trials and discuss their subtypes and pervasiveness alongside the clinical results thus far available. Taken together, our mapping highlights three main developments: efficacy enhancements have advanced more rapidly than safety strategies both in number and diversity; multitargeting approaches have gained momentum; and combined strategies that simultaneously incorporate safety and efficacy enhancements are emerging to bridge individual shortcomings.