HAVCR2 (Hepatitis A Virus Cellular Receptor 2), also known as TIM-3 (T cell immunoglobulin and mucin domain-containing protein 3), is an immune checkpoint molecule primarily expressed on activated T cells, regulatory T cells (Tregs), and innate immune cells like dendritic cells and macrophages. Structurally, it contains an immunoglobulin variable (IgV) domain, a mucin domain, and an intracellular tyrosine phosphorylation motif. Functionally, HAVCR2 regulates immune tolerance and homeostasis by interacting with ligands such as galectin-9. phosphatidylserine, and HMGB1. These interactions modulate T cell exhaustion, apoptosis, and cytokine secretion, thereby dampening excessive immune responses.
In pathological contexts, HAVCR2 is often overexpressed in tumor-infiltrating lymphocytes (TILs) and exhausted T cells in chronic infections (e.g., HIV, hepatitis) or cancers, contributing to immune evasion. Targeting HAVCR2 with blocking antibodies has emerged as a therapeutic strategy to rejuvenate anti-tumor or anti-viral immunity. Preclinical studies show that HAVCR2 antibodies enhance T cell activation, reduce immunosuppression, and synergize with PD-1/PD-L1 inhibitors. Clinical trials are evaluating HAVCR2 antibodies in cancers like melanoma, non-small cell lung cancer, and renal cell carcinoma. However, its dual role in promoting or suppressing immunity depending on context underscores the need for precise targeting to avoid autoimmune adverse effects. Research continues to unravel its complex signaling networks and ligand diversity.