Inhibitory immune checkpoints in cancer immunotherapy

Monoclonal antibodies and other agents that inactivate immune checkpoints like PD-1 and CTLA-4 have been effective against only certain types of cancer and have had highly variable efficacy in patients. These limitations have hastened investigations of additional checkpoints that can serve as therapeutic targets. Nevertheless, no other approach has yet reached the effectiveness of PD-1 and CTLA-4 inactivation. Recent studies have shown that experimental inhibitory immune checkpoints and the drugs targeting them display unexpected or undesirable mechanisms of action or regulation, thus highlighting previously underappreciated complexities of immune checkpoint–based therapies. Understanding these nuances is crucial for developing more effective and safer therapies. This Review explores the intricacies surrounding inhibitory immune checkpoints and offers insights for improved therapeutic strategies in the future.