Structure and Expression

• Galectin-9 (GAL9) is a member of the galectin family, characterized by a tandem repeat of carbohydrate recognition domain (CRD).
• Contains two structurally and functionally similar CRDs connected by a variable flexible linker peptide.
• Can build lattices and cross-link various glycoproteins.
• Present in almost all body tissues, synthesized by immune cells, endothelial cells, and epithelial cells.
• Upregulated by stimuli including interferon-γ, playing a crucial role in inflammation.

Immunological Functions

• Acts as an immunological checkpoint molecule by binding to TIM-3 on T-cells.
• Regulates T-cells, inducing: T-cell apoptosis and suppressing Th1 and Th17 responses.
• Involved in proliferation and function of T-regulatory cells, regulating immune tolerance and preventing autoimmunity.
• Regulates other immune cells such as; dendritic cells and natural killer cells, affecting both innate and adaptive immune systems.

Role in Disease and Pathology

• Associated with numerous pathological conditions:
• Cancer: Dual role, enhancing anti-tumor immunity in some contexts, promoting tumor immune evasion in others.
• Viral infections: Upregulated in chronic viral infections, including HIV and hepatitis B.
• Autoimmune diseases: Expression usually altered, making it a potential biomarker for diagnosis or target for therapy.

Therapeutic Applications and Clinical Development

• Increasing focus on therapeutic effects of GAL9:
• Cancer immunotherapy: Strategies focusing on the GAL9-TIM-3 pathway, either alone or with current checkpoint blockers.
• Ongoing clinical trials using GAL9 antagonists to boost antitumor immunity and GAL9 agonists to induce immune tolerance in autoimmune diseases.
• Development of GAL9-based antiviral approaches due to its role in viral infections.