LAIR2 (leukocyte-associated immunoglobulin-like receptor 2) is a soluble immunoglobulin-like receptor that functions as an immune checkpoint modulator with context-dependent roles in cancer and placentation. LAIR2 acts as a soluble homolog that antagonizes the inhibitory collagen-binding receptor LAIR1, competing for the same ligands to prevent immune suppression 1. In cancer immunity, LAIR2 overexpression sensitizes immunotherapy-resistant tumors to anti-PD-1 blockade by abrogating LAIR1-mediated CD8+ T cell exhaustion induced by collagen in the tumor microenvironment 1. LAIR2 is expressed by regulatory T cells in head and neck cancer, creating an immunosuppressive microenvironment 2, and serves as a biomarker for T cell exhaustion in cholangiocarcinoma and esophageal squamous cell carcinoma 34. Conversely, LAIR2 exhibits tumor-suppressive functions through TGF-β signaling inhibition in esophageal cancer 4. In placentation, LAIR2 is a human-specific gene that promotes extravillous trophoblast invasion and is upregulated by maternal platelet-derived factors to inhibit platelet activation and fine-tune coagulation at the fetal-maternal interface 56. LAIR2 genetic variants associate with differential mRNA expression and susceptibility to autoimmune pemphigus foliaceus 7, indicating its broader immunoregulatory significance.