LILRB5 is an inhibitory leukocyte immunoglobulin-like receptor that functions as a checkpoint regulator on myeloid cells. Structurally, it contains immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in its cytoplasmic domain 1 and binds specifically to HLA class I free heavy chains, particularly HLA-B27 dimers, through its D1 and D2 immunoglobulin-like binding domains 2. LILRB5 mediates immune suppression through multiple mechanisms. Eph receptor family members (EphA7, EphB1) engage LILRB5 on myeloid cells, triggering bidirectional signaling that promotes immunosuppressive marker expression while inhibiting activating markers 3. Similarly, oligomeric cystatin C directly binds LILRB5, enhancing myeloid immunosuppression through phosphatase-dependent and TGF-β pathway signaling 4. Clinically, LILRB5 variants associate with serum creatine kinase levels in statin users 5 and are linked to severe insulin-deficient and mild age-related diabetes subtypes, suggesting therapeutic targeting potential 6. Sex-stratified genetic analysis reveals LILRB5 exhibits sex-dependent modulation of inflammatory protein levels in females 7. In cancer, myeloid cell-specific LILRB5 expression increases tumor growth and immunosuppressive myeloid populations while reducing functional T cell frequencies 3, positioning LILRB5 as a relevant immunotherapy target.