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.

Cryptococcus neoformans and its sister species Cryptococcus deuterogattii are important human fungal pathogens. Despite their phylogenetically close relationship, these two Cryptococcus pathogens are greatly different in their clinical characteristics. However, the determinants underlying the regulatory differences of their pathogenicity remain largely unknown. Here, we show that the forkhead transcription factor Hcm1 promotes infection in C. neoformans but not in C. deuterogattii. Monitoring in vitro and in vivo fitness outcomes of multiple clinical isolates from the two pathogens indicates that Hcm1 mediates pathogenicity in C. neoformans through its key involvement in oxidative stress defense. By comparison, Hcm1 is not critical for antioxidation in C. deuterogattii. Furthermore, we identified SRX1, which encodes the antioxidant sulfiredoxin, as a conserved target of Hcm1 in two Cryptococcus pathogens. Like HCM1, SRX1 had a greater role in antioxidation in C. neoformans than in C. deuterogattii. Significantly, overexpression of SRX1 can largely rescue the defective pathogenicity caused by the absence of Hcm1 in C. neoformans. Conversely, Srx1 is dispensable for virulence in C. deuterogattii. Overall, our findings demonstrate that the difference in the contribution of the antioxidant sulfiredoxin to oxidative stress defense underlies the Hcm1-mediated regulatory differences of pathogenicity in two closely related pathogens.