CHI3L2 (chitinase 3-like 2) is a secreted lectin that binds chitooligosaccharides and glycans with high affinity but lacks chitinase catalytic activity [UniProt]. Originally characterized as a poorly-studied protein despite high expression in glioblastoma 1, CHI3L2 functions primarily as a signaling molecule rather than an enzyme. Mechanistically, CHI3L2 activates ERK1/2 phosphorylation through MAPK pathways 2, though with distinct kinetics compared to related CHI3L1, resulting in inhibition rather than promotion of cell proliferation in some contexts 2. In T-cell acute lymphoblastic leukemia, CHI3L2 acts downstream of the SH2D1A super-enhancer to promote cell proliferation and inhibit apoptosis 3. Clinically, CHI3L2 demonstrates significant disease relevance across multiple malignancies. In glioblastoma, elevated CHI3L2 expression in tumor core and peritumoral brain zones correlates with shorter overall survival, progression-free survival, and tumor recurrence 4. In colorectal and lung cancers, CHI3L2 serves as a marker of clonally-expanded regulatory T cells associated with disease progression but also immunotherapy response 5. High CHI3L2 expression functions as an independent prognostic predictor in gliomas and associates with immune cell infiltration patterns 6. CHI3L2 also appears as a biomarker for intervertebral disc degeneration 7 and motor neuron degeneration in ALS, where expression negatively correlates with survival 8.