Promising Targeted Therapies for Hemophagocytic Lymphohistiocytosis: A Translational Perspective Based on Immunopathology.

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is a severe and life-threatening hyperinflammatory disorder characterized by dysregulated immune activation, primarily driven by excessive stimulation of cytotoxic lymphocytes (CTLs) and macrophages. This uncontrolled immune response leads to cytokine-induced tissue damage and multiorgan dysfunction. HLH presents a significant clinical challenge due to its rapid progression and high mortality rate. In adult patients, current first-line treatment strategies, adapted from pediatric protocols such as HLH-94 and HLH-2004, achieve complete disease resolution in only approximately 50% of cases. The urgent need for more effective therapeutic options is underscored by the lack of targeted treatments and the persistent high mortality associated with HLH. However, the pathophysiology of HLH remains complex and incompletely understood, involving multiple immune dysregulations, diverse etiologies, and variable clinical presentations, making drug development particularly challenging. Drawing from recent advancements, this review provides a translational perspective on the immunopathological mechanisms underlying HLH, highlighting emerging therapeutic targets and novel treatments currently under clinical investigation. By synthesizing these insights, we aim to identify key opportunities for the development of innovative therapies to improve patient outcomes.