CAR T cell cancer immunotherapy: who does the job?

Chimeric antigen receptor (CAR) T cells are capable to eliminate cancer cells in the treatment of hematologic malignancies, yet the efficacy is frequently inconsistent and limited by cancer cell resistance and antigen-loss resulting in early tumor relapses. While CAR T cells are deemed to be the primary effectors in controlling the tumor, maturing evidence indicates that therapeutic outcomes are shaped by a broader immune cell network involving both the endogenous adaptive and innate immunity. In this review, we reframe CAR T cell therapy as the induction of a multi-system immune response rather than a uni-directional cytotoxic cell-autonomous intervention. We discuss the respective contributions of CAR T cells, innate immune cells, and host adaptive immunity in controlling tumor progression and outline strategies to recruit innate immunity using TRUCKs, armored CAR T cells, as well as immunological adjuvants to surmount current limitations. Finally, we address the risks associated with excessive innate immune activation and propose that a calibrated, broad immune cell activation should be viewed as design principle for next-generation CAR T cell therapies.