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.