LAG-3 as the third checkpoint inhibitor

Lymphocyte activation gene 3 (LAG-3) is an inhibitory receptor that is highly expressed by exhausted T cells. LAG-3 is a promising immunotherapeutic target, with more than 20 LAG-3-targeting therapeutics in clinical trials and a fixed-dose combination of anti-LAG-3 and anti-PD-1 now approved to treat unresectable or metastatic melanoma. Although LAG-3 is widely recognized as a potent inhibitory receptor, important questions regarding its biology and mechanism of action remain. In this Perspective, we focus on gaps in the understanding of LAG-3 biology and discuss the five biggest topics of current debate and focus regarding LAG-3, including its ligands, signaling and mechanism of action, its cell-specific functions, its importance in different disease settings, and the development of novel therapeutics. LAG-3 is a T cell inhibitory receptor with a lot of promise as a target for immunotherapy, but considerable research will be needed to fully understand the nuances of this receptor and how best to target it, as outlined in this Perspective.

Automated summary

LAG-3 is an inhibitory receptor expressed by exhausted T cells and is considered a promising immunotherapeutic target. However, important questions regarding its biology and mechanism of action still exist. This Perspective discusses the gaps in understanding LAG-3 biology and the current debates and focus on five key topics, including its ligands, signaling and mechanism of action, cell-specific functions, importance in different disease settings, and the development of novel therapeutics.