{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nFCGR3A (also known as CD16a) is a central activating receptor prominently expressed on natural killer (NK) cells and select monocyte/macrophage subsets that mediates antibody‐dependent cellular cytotoxicity (ADCC). Engagement of FCGR3A by the Fc portion of immunoglobulin G1 is critical for many antibody‐based therapies. Multiple studies have shown that naturally occurring polymorphisms—most notably the 158 V/F variant—affect both the binding affinity of FCGR3A for IgG1 and its expression level. Patients carrying the high‐affinity V allele exhibit increased transcript levels and greater surface receptor density, resulting in enhanced rituximab, trastuzumab, cetuximab, and anti‐GD2‐mediated tumor cell killing. In addition, associations between FCGR3A single nucleotide polymorphisms and clinical outcomes have been documented in diverse conditions such as non‐Hodgkin lymphomas, Waldenström’s macroglobulinemia, diffuse large B‐cell lymphoma, head and neck cancer, and rheumatoid arthritis, while FCGR3A variants also influence infection risk in transplant patients."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn parallel, advances in antibody glyco‐engineering and receptor‐processing studies have further refined our understanding of FCGR3A function. For instance, removal of the core fucose from the N‑linked glycan on IgG1 markedly improves its affinity for FCGR3A—up to 50‐fold—by promoting favorable carbohydrate–carbohydrate interactions that alter Fc conformation. Structural analyses reveal that these interactions enable enhanced recruitment of effector cells even at lower antibody concentrations. Moreover, regulatory mechanisms such as proteolytic shedding of FCGR3A (mediated by ADAM17) and modulation by cytokines (e.g. TGF‑β via SMAD3 pathways) further influence receptor levels and downstream signaling. In addition, engineered bispecific constructs that target CD16 (FCGR3A) on NK cells, as well as studies on copy number variation and even missense mutations that alter membrane‐proximal cleavage sites, underscore how fine regulation of FCGR3A modulates both spontaneous and antibody‐triggered cytotoxicity. Collectively, these mechanistic insights illuminate how tailored modifications to antibodies and receptor expression can optimize the efficacy of immunotherapies across malignancies such as neuroblastoma, myelodysplastic syndromes, and neuromyelitis optica spectrum disorder."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "15", "end_ref": "25"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "A W Morgan, B Griffiths, F Ponchel, et al. 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