Rethinking the immune recognition of cell walls in human fungal pathogens: Mechanisms, controversies and translational significance.

Fungal cell wall polysaccharides - such as β-glucans, chitin, and mannans - are key immunogenic structures recognized by Toll-like receptors and C-type lectin receptors on innate immune cells, initiating phagocytosis, cytokine production, and antigen presentation, and shaping downstream adaptive immunity. CD4+ T cells differentiate into Th1, Th2, Th17, and Treg subsets to maintain immune balance, whereas B cells contribute to fungal clearance and memory through species-specific antibodies. The boundary between protective and pathogenic immunity varies with fungal species, infection stage, and host immune status, collectively influencing PRR signaling and lymphocyte effector outcomes. This review summarizes recognition mechanisms, signaling pathways, and immunoregulatory roles of immune cells in response to fungal cell wall polysaccharides, highlighting the dual roles of innate and adaptive immunity in antifungal defense and immunopathology, and discussing current controversies, knowledge gaps, and prospects for immunomodulatory and vaccine-based antifungal strategies.