TIGIT in cancer: from mechanism of action to promising immunotherapeutic strategies

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.