Emapalumab in IFN-γ-Driven Hyperinflammatory Disorders: Mechanisms, Clinical Evidence, and Emerging Therapeutic Applications

Hyperinflammatory disorders are severe clinical syndromes characterized by uncontrolled immune activation, sustained release of inflammatory mediators, and multiorgan injury. Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are two representative hyperinflammatory syndromes. Growing evidence has identified interferon gamma (IFN-γ) as an important mediator, contributing to persistent immune activation and amplification of inflammatory responses. Emapalumab is a fully human, high-affinity monoclonal antibody targeting IFN-γ that exerts its therapeutic effects by selectively neutralizing IFN-γ and suppressing its downstream inflammatory activity. Clinical studies have established the therapeutic utility of emapalumab in primary HLH, while its potential applications are increasingly being explored in Still’s disease-associated MAS, secondary HLH, Chimeric antigen receptor (CAR) T-cell therapy-associated hyperinflammatory states, and hematopoietic stem cell transplantation-related settings. This review summarizes the biological basis of IFN-γ-driven hyperinflammation, the molecular mechanism of action of emapalumab, and current clinical evidence for its use in HLH, MAS, and other hyperinflammatory conditions, while discussing the limitations of existing evidence and priorities for future research.