LILRB4

Leukocyte immunoglobulin-like receptor B4 (LILRB4, also known as ILT3/CD85k) is a myeloid inhibitory receptor that modulates immune tolerance via cytoplasmic immunoreceptor tyrosine-based inhibitory motifs (ITIMs)^[1][2]. Mechanistically, LILRB4 suppresses FcγRI-mediated monocyte activation by dephosphorylating multiple kinases, including Lck, Syk, LAT, and Erk, thereby inhibiting pro-inflammatory cytokine production^[3]. LILRB4 exerts control over immune homeostasis in tumor microenvironments, dampening effector T cell function and promoting regulatory T cell differentiation^[4][5]. It functions through non-canonical pathways, such as the WNT signaling cascade, to regulate circadian disruption-induced mammary tumorigenesis^[6]. Compared with related isoforms in the LILRB family, LILRB4 contains two extracellular immunoglobulin-like domains and fewer intracellular ITIMs than murine gp49B, conferring unique ligand specificity and structural characteristics^[2]. In acute myeloid leukemia (AML) and multiple myeloma (MM), LILRB4 is highly expressed on monocytes, leukemic stem cells, and tumor-infiltrating myeloid-derived suppressor cells, correlating with poor patient prognosis^[7][8][9]. Targeted immunotherapies, including LILRB4-blocking antibodies and LILRB4-STAR-T cells, effectively restore T cell function, inhibit tumor growth, and reduce immunosuppressive microenvironments, demonstrating translational relevance^[9][6][4]. Structural studies highlight distinctive surface patches on the D1 domain and the D1D2 hinge region, guiding the design of selective agonists or inhibitors^[2]. These features position LILRB4 as a critical immune checkpoint with both mechanistic and therapeutic implications across cancer and metabolic diseases^[10][1].