TIM-3 Inhibitor Development: Overcoming Immune Evasion in Cancer Therapy

Although immune checkpoint blockade therapies targeting PD-1/PD-L1 and CTLA-4 have achieved remarkable clinical success, limitations such as low response rates and acquired resistance remain significant challenges. TIM-3 has recently emerged as a key immunosuppressive receptor and a promising therapeutic target for augmenting antitumor immunity. However, the development of TIM-3 inhibitors is highly imbalanced: multiple antibody-based candidates have entered Phase III trials, whereas small-molecule inhibitors are still in the preclinical stage, with current research remaining fragmented and lacking systematic structure-activity relationship studies. This Account systematically summarizes the structural and functional mechanisms of TIM-3, with a focus on recent advances in the discovery and development of small-molecule TIM-3 inhibitors. We highlight representative lead compounds identified through virtual screening and rational design and discuss future directions to facilitate the development of novel TIM-3-targeted agents.