FcRn-targeted therapeutics: Neonatal fc receptor at the Interface of balancing immune modulation and persevering protective humoral immunity

The neonatal Fc receptor (FcRn) is a central regulator of humoral immunity that controls the intracellular trafficking and serum persistence of immunoglobulin G (IgG) and albumin. Through pH-dependent binding in endosomes, FcRn rescues IgG and albumin from lysosomal degradation and mediates their recycling or transcytosis, thereby maintaining systemic IgG homeostasis and influencing antibody distribution across tissues and mucosal surfaces. In addition to its homeostatic role, FcRn contributes to immune surveillance by regulating immune complex transport, facilitating antigen presentation, and supporting antiviral antibody activity at epithelial barriers. Although these functions are critical for host defense, FcRn can also extend the half-life of pathogenic IgG and immune complexes that drive inflammation and tissue injury in autoantibody-mediated diseases. This has led to the development of therapeutic FcRn blockers to selectively reduce circulating IgG levels. FcRn blockers have demonstrated clinical efficacy in several autoimmune disorders. Recent evidence also suggests that FcRn has complex roles in viral infections. By stabilizing antiviral IgG and mediating immune complex trafficking, FcRn may enhance protective immunity. However, certain viruses exploit FcRn to invade tissue, and persistent IgG-virus immune complexes also contribute to inflammatory pathology during certain infections. Consequently, FcRn blockade is being explored not only for autoimmune diseases but also as a potential strategy to treat viral infections. This review distinguishes itself by integrating FcRn biology across autoimmunity and viral infection, critically evaluating how FcRn-targeted therapies influence pathogenic autoantibodies, antiviral immunity, and vaccine responsiveness, emphasizing the need for human-derived models to optimize dosing and preserve immune competence.