Role of TIGIT in tumor progression and immune evasion

Immune checkpoint inhibitors targeting programmed death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) encounter significant clinical hurdles, primarily stemming from the high incidence of acquired resistance. To address these challenges, researchers have investigated second-generation targets like lymphocyte activation gene 3 (LAG-3) and T-cell immunoglobulin and mucin domain-containing protein 3 (TIM-3). However, these alternatives face limitations: LAG-3 necessitates PD-1 co-blockade for optimal efficacy, while TIM-3 inhibitors face delays in clinical translation due to restricted cellular expression patterns. In contrast, T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) emerges as a promising option by bridging these gaps through its wide cellular distribution and synergistic mechanisms. This is attributed to its prevalent expression in T cells and natural killer (NK) cells, its ability to inhibit CD226 phosphorylation via the CD155/CD112 pathway, its synergistic reversal of T-cell exhaustion with PD-1, and its capacity to overcome drug resistance. Recent clinical trials have shown that TIGIT monotherapy yields modest responses, while combinations with PD-1 inhibitors exhibit enhanced tumor control in conventional malignancies, surpassing standard PD-1/CTLA-4 or PD-1/chemotherapy protocols. Future research priorities include validating predictive biomarkers, optimizing dosing schedules to prevent resistance development, and devising multi-checkpoint strategies. This review systematically assesses the therapeutic synergy centered on TIGIT, offering a translational framework for surmounting tumor diversity and immunotherapy resistance through advanced combinatorial approaches.