LAG3 (CD223) is the third IR to be targeted in the clinic. It is a potential cancer immunotherapeutic target due to its negative regulatory role on T cells and its capacity, in combination with PD1, to mediate a state of exhaustion [PMID: 26018646]. LAG3 up-regulation is required to control overt activation and prevent the onset of autoimmunity. However, persistent antigen exposure in the tumor microenvironment results in sustained LAG3 expression, contributing to a state of exhaustion manifest in impaired proliferation and cytokine production. The exact signaling mechanisms downstream of LAG3 and interplay with other IRs remains largely unknown. However, the striking synergy between LAG3 and PD1 observed in multiple settings, coupled with the contrasting intracellular cytoplasmic domain of LAG3 as compared with other IRs, highlights the potential uniqueness of LAG3. There are now four LAG3-targeted therapies in the clinic with many more in preclinical development [PMID: 28258692].