From orphan receptor to versatile regulator: Redefining LILRB3 as a context-dependent immune checkpoint and therapeutic target.

The immune system maintains homeostasis through a delicate balance between activation and inhibition. While activating pattern recognition receptors (PRRs) are well-established initiators of innate immunity, the role of inhibitory PRRs (iPRRs) in providing negative regulation is an emerging paradigm. Among these, Leukocyte Immunoglobulin-Like Receptor Subfamily B Member 3 (LILRB3), a myeloid-specific receptor, has recently undergone a dramatic conceptual transformation. Once considered a minor "orphan" receptor, LILRB3 is increasingly recognized as a context-dependent immune checkpoint with diverse immunoregulatory functions. Breakthrough studies in recent years have revealed its role as a putative cell surface receptor for APOE4 in Alzheimer's disease, a supporter of leukemia development via a non-canonical TRAF2-cFLIP-NF-κB signaling axis in acute myeloid leukemia (AML), and a genetic risk factor for kidney transplant failure in African American recipients. This review synthesizes these recent advances to present a unified framework of LILRB3 biology. We comprehensively detail its polymorphic gene structure, multi-domain architecture, and complex regulatory mechanisms governing its cell-type-specific expression. We expand upon its diverse ligand repertoire, encompassing both HLA-I-dependent and independent molecules, and dissect its versatile signaling pathways, from canonical ITIM-SHP1/2-mediated inhibition to non-canonical, phosphatase-independent functions. A central theme is the context-dependent role of LILRB3 across diseases: it can be detrimental in cancer by fostering an immunosuppressive microenvironment or beneficial in maintaining tissue homeostasis. Finally, we critically evaluate the translational landscape, including antagonistic/agonistic antibodies, CAR-T therapies, and biomarker-driven strategies, while addressing key challenges like cross-reactivity with LILRA6. By positioning LILRB3 within the emerging iPRR framework, this review highlights its potential therapeutic relevance across immunology, neurology, and oncology, and outlines a roadmap for future research and precision targeting.