Overcoming chimeric antigen receptor-T (CAR-T) resistance with checkpoint inhibitors: Existing methods, challenges,...

Immune checkpoint blockade is, as of today, the most successful form of cancer immunotherapy, with more than 43 % of cancer patients in the US eligible to receive it; however, only up to 12.5 % of patients respond to it. Similarly, adoptive cell therapy using bioengineered chimeric antigen receptorT (CAR-T) cells and T-cell receptor (TCR) cells has provided excellent responses against liquid tumours, but both forms of immunotherapy have encountered challenges within a tumour microenvironment that is both lacking in tumour-specific T-cells and is strongly immunosuppressive toward externally administered CAR-T and TCR cells. This review focuses on understanding approved checkpoint blockade and adoptive cell therapy at both biological and clinical levels before delving into how and why their combination holds significant promise in overcoming their individual shortcomings. The advent of next-generation checkpoint inhibitors has further strengthened the immune checkpoint field, and a special section explores how these inhibitors can address existing hurdles in combining checkpoint blockade with adoptive cell therapy and homing in on our cancer target for long-term immunity.