Anti-TIGIT therapies in digestive cancers: from immune evasion to precision immunotherapy

Immune checkpoint inhibitors, particularly anti-PD-1 and anti-PD-L1 therapies, have transformed cancer treatment, yet their effectiveness in gastrointestinal cancers remains limited due to tumor complexity, immunosuppressive microenvironments, and resistance mechanisms. TIGIT, an emerging immune checkpoint receptor expressed on T cells and natural killer cells, plays a central role in suppressing antitumor immunity by promoting T-cell exhaustion and facilitating tumor immune evasion.

We performed a comprehensive review of preclinical and clinical evidence evaluating anti-TIGIT strategies in GI cancers. Databases and clinical trial registries were searched for studies investigating anti-TIGIT agents as monotherapy or combined with ICIs, chemotherapy, or radiotherapy.

Preclinical studies demonstrate that TIGIT blockade restores antitumor immune responses, improves tumor control, and shows clear synergy when combined with PD-1/PD-L1 inhibitors or radiotherapy. Clinical trials have reported mixed outcomes, with meaningful responses observed in selected settings but limited benefit in others. Biomarkers such as TIGIT and CD155 expression, tumor molecular features, and immune landscape characteristics emerged as relevant predictors of response.

Anti-TIGIT therapies represent a promising approach for overcoming resistance to ICIs in GI cancers. Nevertheless, biological heterogeneity underscores the need for better patient stratification, predictive biomarkers, and evaluation of safety and toxicity to fully realize the therapeutic potential of TIGIT-targeted strategies.