Understanding CAR T cell-tumor interactions: Paving the way for successful clinical outcomes

Since their approval 5 years ago, chimeric antigen receptor (CAR) T cells have gained great importance in the daily clinical practice and treatment of hematological malignancies, although many challenges to their use remain, such as limited long-term CAR T cell efficacy due to disease resistance or recurrence. After a brief overview of CAR T cells, their approval, therapeutic successes, and ongoing limitations, this review discusses what is known about CAR T cell activation, their expansion and persistence, their mechanisms of cytotoxicity, and how the CAR design and/or tumor-intrinsic factors influence these functions. This review also examines the role of cytokines in CAR T cell-associated toxicity and their effects on CAR T cell function. Furthermore, we discuss several resistance mechanisms, including obstacles associated with CAR treatment of solid tumors. Finally, we provide a future outlook on next-generation strategies to further optimize CARs and improve clinical outcomes.