TIGIT immune checkpoint (IC) has attracted great interest in recent years. It belongs to the PVR-like protein family, and it inhibits T and NK cell cytotoxic activities. TIGIT mediates its inhibitory effect by direct signaling through the cytoplasmic tail, CD155-mediated inhibition, or competition with the immune-activating receptor CD226. Preclinical observations from studies involving TIGIT-specific blocking monoclonal antibodies (mAbs) are promising, but the results of the clinical trials using anti-TIGIT mAb monotherapy were not favorable, which prompted a focus on combinational therapies. Some alternative approaches have the potential to avoid limitations, including low penetration, immunogenicity and safety of mAbs. This review addresses the mechanisms underlying TIGIT-mediated immune suppression. Additionally, promising immunotherapeutic approaches against TIGIT, including co-inhibition of TIGIT with other ICs, using small molecule inhibitors, blocking the TIGIT/PVR pathway using CAR-T cells and the current state of clinical trials as well as future directions, are discussed.

The discovery of immune checkpoints (ICs) has pushed cancer treatment into the next era. As an emerging immune checkpoint, the TIGIT/CD155 axis inhibits the cytotoxicity of T and NK cells through multiple pathways. Immune checkpoint inhibitors (ICIs) targeting TIGIT are hopefully expected to address the issue of unresponsiveness to anti-PD-(L)1 monoclonal antibodies (mAbs) by combination therapy. This paper presents insights on the expression, structure and mechanism of action of TIGIT, as well as the principles and methods of designing mAbs targeting TIGIT and their clinical data. The advantages and disadvantages of targeting TIGIT using mAbs, bispecific and tri-specific antibodies (bsAbs and tsAbs), peptides, and compounds, in addition to potential combination therapies of anti-TIGIT with anti-PD-1 or cancer vaccines, are addressed. Finally, perspectives on current immunotherapies targeting TIGIT are discussed.