Lair1, also known as Leukocyte-associated immunoglobulin (Ig)-like receptor 1 (CD305), belongs to the family of immune-inhibitory receptors. It is widely expressed on hematopoietic mature cells, especially immune cells. By modulating cytokine secretion and cellular functions, it plays a major negative immunoregulatory role. Four types of ligands including collagens have been described for Lair1, suggesting its potential role in immune-regulation on the extracellular matrix [2].

Lair1 has been implicated in multiple disease-related processes. In lung tumors, collagen-induced T cell exhaustion occurs through Lair1, leading to anti-PD-1/PD-L1 resistance. Reduction of tumor collagen deposition or abrogating Lair1 immunosuppression can sensitize resistant lung tumors to anti-PD-1 treatment [1]. Blocking Lair1 signaling in immune cells using antagonistic anti-Lair1 monoclonal antibodies inhibited the activity of immunosuppressive myeloid cells, reactivated T cells from cancer patients in vitro, and impeded tumor metastasis in a humanized mouse model [3]. In hepatocellular carcinoma, Lair1 promotes cell metastasis, induces M2-macrophage infiltration, and mediates resistance to T cells through specific pathways, and blocking it can combat cancer advancement [4,5]. In gliomas, Lair1 drives progression by facilitating focal adhesion kinase nuclear localization and supporting an immunosuppressive microenvironment [7]. In a model of subcutaneous S. aureus skin infection, Lair1 knock-out (KO) mice had significantly larger abscesses and areas of dermonecrosis, suggesting that Lair1 prevents excess inflammatory tissue damage [6].

In conclusion, Lair1 is a key immune-inhibitory receptor involved in negative immunoregulation. Model-based research, especially Lair1 KO mouse models, has revealed its crucial roles in various disease conditions such as cancer and infection-related inflammatory responses. These findings provide potential therapeutic strategies targeting Lair1 for treating autoimmune diseases and cancer [2,3,4,5,6,7].