Structural Evolution and Immunomodulatory Versatility of Fungal Immunomodulatory Proteins: Insights into Mechanisms and Bioproduction Strategies

Fungal immunomodulatory proteins (FIPs) are low-molecular-weight proteins from macrofungi that share the potential to modulate immune responses. Structurally, they fall into five subgroups, with the Fve-type and Cerato-type being the most representative. Originally, these proteins evolved in fungi for mycoparasitism and defense; their immunomodulatory, antitumor, anti-inflammatory, and hepatoprotective effects validated in human cells and animal models are surprisingly beneficial. Post-translational modifications and specific oligomeric states regulate the FIP functionality. These structural features critically govern receptor engagement and downstream signaling, whereby FIPs orchestrate immune responses via Toll-like receptor/NF-κB modulation and exert antitumor effects through EGF receptor/Akt interference. Recent advances in genomic mining and bioinformatics have accelerated novel FIP discovery, while scalable production is now achievable through optimized heterologous expression systems incorporating solubility-enhancing tags, promoter engineering, endotoxin removal, and tailored fermentation. This review examines the structure-activity relationships, mechanism-driven bioactivities, and bioproduction platforms of FIPs, highlighting their potential in biopharmaceutical and functional food applications.