Hepatitis A virus cellular receptor 2 (TIM-3) and Leukocyte immunoglobulin-like receptor subfamily B member 1 (ILT2) signaling pathway (TIM-3/ILT2)

The TIM-3/ILT2 pathway is a dual inhibitory signaling axis involving the T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) and the Immunoglobulin-like transcript 2 (ILT2, also known as LILRB1). These receptors are members of the immunoglobulin superfamily and are co-expressed on exhausted T cells, natural killer (NK) cells, and various myeloid cells, where they function as critical immune checkpoints that limit the intensity and duration of immune responses. TIM-3 interacts with multiple ligands, including Galectin-9, CEACAM1, and HMGB1, while ILT2 primarily binds to classical and non-classical MHC class I molecules, most notably HLA-G. In the context of malignancy, the over-activation of this pathway facilitates immune evasion by inducing T-cell senescence and impairing the cytotoxic activity of NK cells. Therapeutic strategies targeting the TIM-3/ILT2 pathway involve monoclonal antibodies or bispecific agents designed to block these inhibitory signals, thereby reinvigorating anti-tumor immunity and potentially overcoming resistance to existing PD-1/PD-L1 therapies.

Other names

HAVCR2/LILRB1 pathwayCD366/CD85j pathwayTIM-3 and ILT2 inhibitory axisT-cell immunoglobulin and mucin-domain containing-3 and Immunoglobulin-like transcript 2 pathway

Dual blockade of the TIM-3 and ILT2 inhibitory receptors to prevent their interaction with ligands (such as Galectin-9 and HLA-G), thereby restoring the effector functions of exhausted T cells and NK cells and enhancing the pro-inflammatory activity of myeloid cells in the tumor microenvironment.