Fungal infections of the central nervous system (CNS) represent severe clinical threats with high mortality, stemming from intricate molecular interplay between neurotropic fungi and specialized host defenses. This review dissects the mechanisms underpinning fungal CNS invasion—including enzymatic blood-brain barrier (BBB) disruption, transcellular transport, and "Trojan horse" evasion within phagocytes—alongside evolved immune escape tactics such as molecular camouflage by capsular polysaccharides, biofilm-mediated resistance, and immunosuppressive microenvironment shaping. Critically, CNS-resident immune cells, including microglia, utilize surface C-type lectin receptors (CLRs) and Toll-like receptors (TLRs) to initiate antifungal immunity through Syk/CARD9-dependent signaling and inflammasome activation. However, fungi subvert these defenses by neutralizing phagosomal acidity, inducing non-lytic expulsion, and hijacking metabolic pathways to enhance virulence and drug tolerance. The dynamic coevolutionary arms race manifests in chronic CNS colonization via Th2 polarization, contrasting with the dual-edged role of adaptive immunity where CD4⁺ T cell responses aid pathogen clearance yet exacerbate neuroinflammation. Overcoming therapeutic challenges, particularly limited antifungal BBB penetration and rising drug resistance, requires deciphering these host-pathogen molecular dialogues to design targeted interventions disrupting immune evasion or bolstering CNS-specific immunity.

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.