<scp>LAG</scp>3 (<scp>CD</scp>223) as a cancer immunotherapy target

<jats:title>Summary</jats:title><jats:p>Despite the impressive impact of <jats:styled-content style="fixed-case">CTLA</jats:styled-content>4 and <jats:styled-content style="fixed-case">PD</jats:styled-content>1‐<jats:styled-content style="fixed-case">PDL</jats:styled-content>1‐targeted cancer immunotherapy, a large proportion of patients with many tumor types fail to respond. Consequently, the focus has shifted to targeting alternative inhibitory receptors (<jats:styled-content style="fixed-case">IR</jats:styled-content>s) and suppressive mechanisms within the tumor microenvironment. Lymphocyte activation gene‐3 (<jats:styled-content style="fixed-case">LAG</jats:styled-content>3) (<jats:styled-content style="fixed-case">CD</jats:styled-content>223) is the third <jats:styled-content style="fixed-case">IR</jats:styled-content> to be targeted in the clinic, consequently garnering considerable interest and scrutiny. <jats:styled-content style="fixed-case">LAG</jats:styled-content>3 upregulation is required to control overt activation and prevent the onset of autoimmunity. However, persistent antigen exposure in the tumor microenvironment results in sustained <jats:styled-content style="fixed-case">LAG</jats:styled-content>3 expression, contributing to a state of exhaustion manifest in impaired proliferation and cytokine production. The exact signaling mechanisms downstream of <jats:styled-content style="fixed-case">LAG</jats:styled-content>3 and interplay with other <jats:styled-content style="fixed-case">IR</jats:styled-content>s remain largely unknown. However, the striking synergy between <jats:styled-content style="fixed-case">LAG</jats:styled-content>3 and <jats:styled-content style="fixed-case">PD</jats:styled-content>1 observed in multiple settings, coupled with the contrasting intracellular cytoplasmic domain of <jats:styled-content style="fixed-case">LAG</jats:styled-content>3 as compared with other <jats:styled-content style="fixed-case">IR</jats:styled-content>s, highlights the potential uniqueness of <jats:styled-content style="fixed-case">LAG</jats:styled-content>3. There are now four <jats:styled-content style="fixed-case">LAG</jats:styled-content>3‐targeted therapies in the clinic with many more in preclinical development, emphasizing the broad interest in this <jats:styled-content style="fixed-case">IR</jats:styled-content>. Given the translational relevance of <jats:styled-content style="fixed-case">LAG</jats:styled-content>3 and the heightened interest in the impact of dual <jats:styled-content style="fixed-case">LAG</jats:styled-content>3/<jats:styled-content style="fixed-case">PD</jats:styled-content>1 targeting in the clinic, the outcome of these trials could serve as a nexus; significantly increasing or dampening enthusiasm for subsequent targets in the cancer immunotherapeutic pipeline.</jats:p>