Review highlights TIGIT as a promising second-generation immunotherapy target

Malignant tumors remain a major threat to human health, with conventional therapies and first-generation immune checkpoint inhibitors (ICIs) facing limitations like drug resistance and low response rates. Now, a comprehensive review made available online on September 22, 2025 and was published in Volume 9, Issue 1 of the Journal of Pancreatology on March 30, 2026, highlights T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) as a promising second-generation target to address these challenges.

Unlike LAG-3, TIM-3, and other emerging checkpoints, TIGIT boasts wide expression in T cells, natural killer (NK) cells, and regulatory T cells (Tregs), exerting immunosuppressive effects through multiple pathways-primarily by competitively binding CD155/CD112 ligands to block CD226 signaling, inhibiting T and NK cell function and promoting a hypoxic, immunosuppressive tumor microenvironment (TIME).

Clinical evidence links elevated TIGIT expression to poor prognosis in multiple cancers, including breast, colorectal, and pancreatic cancer. For instance, TCGA data shows that higher TIGIT levels in breast cancer tissues correlate with shorter overall survival and progression-free intervals. Notably, TIGIT outperforms PD-1 in defining tumor CD8⁺ T-cell phenotypes, underscoring its potential as a prognostic and therapeutic marker.

While TIGIT monotherapy yields modest results, combination with PD-1 inhibitors has shown remarkable promise. Clinical trials, such as the phase II CITYSCAPE trial, demonstrate that tiragolumab (anti-TIGIT) plus atezolizumab (anti-PD-1) significantly improves objective remission rates and progression-free survival compared to PD-1 monotherapy, with manageable safety profiles. This synergy arises from TIGIT's ability to reverse T-cell exhaustion and prevent NK cell depletion, addressing PD-1 resistance.

Current TIGIT inhibitors, including vibostolimab, tiragolumab, and ociperlimab, are in phase III trials, with dual-target agents like candonilimab (TIGIT/CTLA-4) under development. Future research will focus on validating biomarkers, optimizing dosing, and combining TIGIT blockade with metabolic or epigenetic interventions to enhance efficacy.

"TIGIT-centered immunotherapy offers a translational framework to surmount tumor diversity and immunotherapy resistance," the review authors note, highlighting its potential to revolutionize treatment for solid tumors and hematologic malignancies.

Source:

Chinese Medical Journals Publishing House Co., Ltd.

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