Fig. 1.

(A) Direct inhibitory effects of TIGIT. Firstly, TIGIT can directly inhibit the cytotoxic activity of T cells and NK cells by competitively antagonizing the stimulatory action of CD226. CD226 activation occurs upon binding with CD155 or CD112, which activates LFA-1, alters the conformation of ICAM-1, recruits Fyn, and drives the activation of the Akt signaling pathway, leading to the release of IFN-γ. Secondly, TIGIT can bind to CD155, and its ITT-like motif interacts with Grb2, which recruits SHIP1, thereby inhibiting PI3K, MAPK, and NF-κB signaling pathways. In addition, TIGIT also participates in the downregulation of the TCR complex itself and the central regulatory factors of TCR signaling cascades, such as PLCγ. TIGIT can also alter T cell metabolism by inhibiting glycolysis and synergizing with HIF1-α to enhance tumor cell invasion, colony formation, and angiogenesis. (B) Indirect inhibitory effects of TIGIT. Firstly, TIGIT exerts indirect inhibitory effects by triggering CD155 to induce DC acquisition of an immature tolerogenic phenotype, increasing IL-10 secretion, and decreasing IL-12 production. TIGIT can promote naive T cell differentiation into Treg cells more frequently and upregulate Foxp3 expression, which confers superior suppressive function to Treg cells. Finally, activation of the TIGIT/CD155 pathway can promote IL-10 transcription and induce macrophage polarization toward an anti-inflammatory M2 cytokine profile