Redefining CHI3L1: Therapeutic Opportunities at the Crossroads of Immune Suppression and Disease Progression.

Chitinase-3-like-1 (CHI3L1, also known as YKL-40) has been recognized as a biomarker of inflammation and tissue remodeling and has now emerged as a pseudoenzymatic immune checkpoint. Recent structural, immunological, and translational studies redefine it as an active regulator of immune suppression rather than a passive disease marker. Despite lacking catalytic activity, CHI3L1's conserved chitinase fold and glycan-decorated surface acts as a modular scaffold linking cytokine, metabolic, and stress signals to immune suppression and fibrotic remodeling. Through its chitinase-like structure it engages with receptor triad complex, including IL-13Rα2, TMEM219, and Galectin-3, activating signaling pathways such as MAPK, PI3K/AKT, and TGF-β/Smad. Through these interactions, CHI3L1 has been reported to promote fibroblast activation, angiogenesis, and immune suppression, creating environments where immune cells are excluded or silenced. These checkpoint-like effects are not limited to cancer; they also appear in fibrosis, infection, and neuroinflammatory diseases, linking CHI3L1 to a broad spectrum of immune-resistant conditions. This review integrates structural glycobiology, receptor pharmacology, and immunometabolic mechanisms to reveal CHI3L1 as a unifying regulator of stromal-immune crosstalk. It further highlights preclinical and clinical evidence demonstrating that antibody, RNA-based, and small-molecule inhibitors of CHI3L1 restore immune surveillance and limit pathological remodeling. Targeting this pseudoenzymatic checkpoint alongside canonical PD-1 and CTLA-4 blockade represents a promising strategy to overcome immune resistance and normalize pathogenic tissue remodeling across diverse diseases.