Neutrophil extracellular traps in antifungal immunity: mechanisms, dual roles, regulatory networks, and clinical perspectives

Abstract

Invasive fungal diseases (IFDs) are associated with substantial morbidity and mortality. Neutrophil extracellular traps (NETs) are a key effector mechanism of innate antifungal immunity, but they may also act as a double-edged sword. This review summarizes the biological basis of NETs, with an emphasis on lytic and non-lytic NET formation. We discuss how fungal species, morphotypes, cell wall components, and virulence factors regulate NET formation through pattern-recognition receptors (PRRs) and downstream signaling pathways. We also summarize the mechanisms by which pathogenic fungi evade NET-mediated host defense, including immune masking, virulence modulation, signaling interference, and competition for essential nutrients. Furthermore, we discuss how features of the tissue microenvironment, such as hypoxia, hemorrhage, co-infection, and metabolic status, modulate the protective and pathological functions of NETs. We then examine the diagnostic potential of NET-associated biomarkers and highlight therapeutic approaches aimed at modulating NET formation and clearance. Finally, we discuss unresolved issues related to cellular heterogeneity, molecular regulatory networks, and clinical translation, and provide perspectives on how multi-omics approaches, single-cell technologies, and precision immunomodulation may inform future research of IFDs. Overall, this review provides a conceptual framework for exploring NET-targeted diagnostic and therapeutic strategies against IFDs.