T-cell immunoglobulin and mucin domain-containing molecule 3 (TIM-3) (TIM-3)

T-cell immunoglobulin and mucin domain-containing molecule 3 (TIM-3) is a type I transmembrane protein and a key immune checkpoint receptor primarily expressed on Th1, Th17, and CD8+ T cells, as well as innate immune cells like dendritic cells and macrophages [2, 7, 13]. It functions as a negative regulator of immune responses, where its interaction with ligands such as Galectin-9, phosphatidylserine (PtdSer), HMGB1, and CEACAM1 leads to T-cell inhibition, exhaustion, or apoptosis [1, 3, 5, 8]. In the context of cancer, TIM-3 is often upregulated on tumor-infiltrating lymphocytes and leukemic stem cells, contributing to immune evasion and disease progression [10, 12, 14]. Therapeutic strategies focus on using monoclonal antibodies to block TIM-3 signaling, often in combination with PD-1/PD-L1 inhibitors, to reinvigorate exhausted T cells and enhance anti-tumor immunity [9, 11, 19]. Beyond oncology, TIM-3 is implicated in chronic viral infections and autoimmune disorders, making it a versatile target for immunomodulatory therapies [11, 15, 17]. Clinical development of TIM-3 inhibitors, such as sabatolimab and cobolimab, aims to overcome resistance to existing immunotherapies and provide new options for patients with advanced malignancies [10, 16, 19].

Other names

HAVCR2CD366TIM3TIMD3T-cell immunoglobulin mucin receptor 3Hepatitis A virus cellular receptor 2

TIM-3 inhibitors are monoclonal antibodies that block the interaction between the TIM-3 receptor and its ligands (Galectin-9, PtdSer, HMGB1, and CEACAM1). This blockade prevents the phosphorylation of conserved tyrosine residues in the cytoplasmic tail of TIM-3, which would otherwise lead to the release of the adaptor protein Bat3 and the recruitment of inhibitory kinases like Fyn. By maintaining Bat3 binding, the receptor can recruit activating kinases such as Lck, thereby restoring T-cell signaling and reversing the exhausted phenotype. In the myeloid compartment, TIM-3 inhibition enhances antigen presentation and promotes pro-inflammatory cytokine production, further supporting the anti-tumor immune response [1, 3, 6, 10].