Challenges posed by fungi to host immunity: Mechanisms of immune evasion

Invasive fungal infections pose a growing global public health threat with high morbidity and mortality. Rising antifungal resistance and treatment failure are largely driven by fungal immune evasion, yet systematic integration of multi-layered immune evasion mechanisms and their translational therapeutic implications remains insufficient. This review dissects the core mechanisms of fungal immune evasion, defines key nodes of host–fungi interplay, and explores emerging targeted therapeutic strategies. Fungal pathogens deploy multifaceted strategies to evade immune surveillance, including surface polysaccharide antigenic variation, β-glucan masking through structural adaptation to escape pattern recognition receptor (PRR) detection, secretion of immune-suppressive immunomodulatory molecules, complement system interference, and biofilm formation resistant to immune clearance. Moreover, fungi hijack host negative immune regulatory pathways via key mediators Cbl-b, Clec2d, and STING, degrading core antifungal signals, suppressing pro-inflammatory responses, and enabling intracellular survival. Notably, CARD9/CLEC7A loss-of-function variants are associated with innate immune recognition defects, directly increasing host susceptibility to invasive fungal infections. In this context, therapeutic approaches targeting immune evasion mechanisms have been developed—including drug repurposing, β-glucan exposure inducers, IL-1Ra antagonists, biofilm inhibitors, and CARD9/Dectin-1 pathway agonists—to counteract fungal pathogenesis. This review provides a comprehensive framework for understanding fungal immune evasion and supports the development of more effective antifungal therapies to improve clinical outcomes.