Unravelling T cell exhaustion through co‐inhibitory receptors and its transformative role in cancer immunotherapy

Abstract

Abstract Persistent stimulation from cancer antigens leads to T lymphocytes (T cells) exhaustion, with up‐regulated expression of co‐inhibitory receptors, including programmed death‐1 (PD‐1), cytotoxic T lymphocyte‐associated antigen‐4 (CTLA‐4), lymphocyte‐activation gene 3 (LAG‐3), T cell immunoglobulin and mucin domain 3 (TIM‐3) and T cell immunoreceptor with Ig and ITIM domains (TIGIT). These receptors collectively impair T cell function via distinct molecular pathways, contributing to immune evasion and cancer progression. This review highlights the therapeutic promise of immune checkpoint inhibitors (ICIs) in reversing T cell exhaustion while delving into the complex molecular processes and functional works of these important co‐inhibitory receptors in tumourigenesis. Additionally, we examine the synergistic effects of combining ICIs with other therapeutic strategies, which can enhance anti‐tumour efficacy. Finally, the clinical implications of bispecific antibodies are highlighted, representing a promising frontier in cancer immunotherapy, that could revolutionise treatment paradigms while improving patient outcomes. Highlights This review discusses five major co‐inhibitory receptors (PD‐1, CTLA‐4, LAG‐3, TIM‐3 and TIGIT) and their related mechanisms of T cell exhaustion in the tumour environment. We also discuss the clinical application of checkpoint inhibitors (ICIs) in cancer immunotherapy. The potential of bispecific antibodies (BsAbs) in cancer immunotherapy is highlighted.

Keywords

• co‐inhibitory receptors
• exhaustion
• immune checkpoint inhibitors
• immunotherapy
• T cell
• tumour immunity