Galectin-9 in cancer: Unraveling its diverse roles beyond immune regulation

Galectin-9 (Gal-9) is a tandem-repeat β-galactoside-binding lectin increasingly recognized as a context-dependent regulator of cancer biology that extends well beyond its canonical role as an immune checkpoint ligand. While Gal-9-mediated immune modulation (e.g., via TIM-3/VISTA) remains important, emerging evidence positions Gal-9 as an upstream organizer of tumor-intrinsic programs and microenvironmental crosstalk that shape angiogenesis, invasion and metastasis, therapy resistance, and maintenance of cancer stem-like states. These divergent outcomes are driven by multi-layered regulation of Gal-9, encompassing transcriptional and epigenetic control, post-translational modification, and context-specific processing/secretion, together with dynamic remodeling of the tumor glycome. In addition, Gal-9 signaling is contingent on cell type-specific receptor repertoires (e.g., TIM-3, VISTA, CD44 and related glycan-binding partners) across malignant, stromal, and immune compartments. This review proposes an integrated, mechanism-based framework to clarify why Gal-9 can exert either tumor-promoting or tumor-suppressive effects, depending on the cancer type and biological context. Rather than cataloging reported effects, we synthesize evidence to propose a context "decision model" in which Gal-9 activity is predicted by (i) the cellular source of Gal-9 (tumor cell vs myeloid/stromal compartments), (ii) Gal-9 biochemical state and post-translational processing, (iii) receptor expression and signaling competence of recipient cells, and (iv) the glycan landscape that governs ligand engagement. We further integrate these determinants with clinical observations to clarify why Gal-9 associates with opposite prognoses in different tumors, and we outline how this framework can stratify patients and guide therapeutic design. Finally, we evaluate Gal-9-targeted interventions-neutralizing antibodies, decoy receptors, and rational combinations with immunotherapy and standard modalities-through the lens of context dependence, highlighting actionable biomarkers and experimental readouts needed to translate Gal-9 biology into precision oncology.