Targeting T cell exhaustion in colorectal cancer: emerging roles of LAG-3, TIM-3, and TIGIT signaling in overcoming immunotherapy resistance

Exhaustion of T cells, characterized by their compromised function and cytokine production, was first discovered in chronic infections and later redefined in the context of immunosuppressed tumor microenvironment (TME). Exhaustion markers include the immune checkpoints PD-1, TIM-3, LAG-3, and TIGIT. Colorectal cancer (CRC), which ranks among the highest in global prevalence, has been associated with exhaustion of T cells. While many trials have focused on anti-PD1 therapeutics in clinical trials, results indicate suboptimal efficacy. A robust approach involved dual blockade of other immune checkpoints together with PD-1. Interestingly, novel exhaustion markers could be used as prognostic markers for the development and progression of CRC. The present work discusses the basics of T cell exhaustion markers and their signaling in CRC. Also, novel combination therapy approaches and challenges in the field are discussed.