T-cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) - Galectin-9 (Gal-9) interaction axis (TIM-3 - Gal-9 axis)

The T-cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) - Galectin-9 (Gal-9) interaction axis is a pivotal immune checkpoint pathway involved in the regulation of adaptive and innate immune responses. TIM-3 (encoded by HAVCR2) is a type I transmembrane protein expressed on various immune cells, including Th1 cells, CD8+ cytotoxic T cells, and dendritic cells (UniProt Q8TDQ0). Its primary ligand, Galectin-9 (encoded by LGALS9), is a soluble or membrane-bound lectin that binds to the carbohydrate motifs on the TIM-3 mucin domain, leading to the suppression of T-cell activity and the induction of apoptosis (Zhu et al., 2005, Nature Immunology). In many malignancies, the over-activation of this axis facilitates immune evasion by promoting T-cell exhaustion, a state characterized by reduced cytokine production and proliferative capacity. Consequently, the TIM-3 - Gal-9 axis has emerged as a high-priority target in cancer immunotherapy, particularly for patients who are refractory to PD-1/PD-L1 blockade. Clinical development focuses on monoclonal antibodies like Sabatolimab and Cobolimab, which aim to disrupt this interaction to reinvigorate the immune system's ability to identify and eliminate cancer cells (Friedman et al., 2020, Cancer Discovery).

Other names

HAVCR2-LGALS9 axisCD366-Galectin-9 interactionTIM3-GAL9 pathwayT-cell immunoglobulin and mucin-domain containing-3 - galectin-9 pathwayTIM-3/Gal-9 axis

Therapeutic agents, primarily monoclonal antibodies, bind to the TIM-3 receptor to sterically hinder its interaction with Galectin-9. This blockade prevents the induction of T-cell apoptosis and exhaustion signals, thereby restoring the effector function of Th1 and CD8+ T cells and enhancing anti-tumor immunity (Wolf et al., 2020, Nature Reviews Cancer; He et al., 2018, Journal of Hematology & Oncology).