TIGIT is an inhibitory immune checkpoint receptor expressed on T cells, NK cells, and regulatory T cells that negatively regulates anti-tumor immunity 1. Upon binding to ligands CD155 (PVR) or CD112 (NECTIN2) on antigen-presenting cells and tumor cells, TIGIT transduces inhibitory signals through phosphorylation of its cytoplasmic ITIM domain by Src family kinases, recruiting adapters GRB2 and SHIP1 to suppress PI3K and MAPK signaling 2. TIGIT additionally suppresses dendritic cell maturation and promotes regulatory T cell differentiation, collectively dampening CD8+ T cell function and NK cell cytotoxicity 3. In cancer, TIGIT upregulation on exhausted T cells correlates with immune checkpoint inhibitor (ICI) resistance, independent of PD-L1 status 4. Mechanistically, TIGIT and PD-1 converge on CD226 signaling: PD-1 blocks CD226 phosphorylation while TIGIT competitively inhibits CD226-ligand interaction, necessitating dual blockade for optimal CD8+ T cell restoration 5. Preclinical studies demonstrate that combined TIGIT and PD-1/PD-L1 blockade synergistically enhances tumor rejection across solid and hematologic malignancies 6, including neuroblastoma where NECTIN2-TIGIT axis inhibition induces complete responses 7. Multiple clinical trials are evaluating TIGIT blockade monotherapy and combination strategies, positioning TIGIT as a promising second-wave immunotherapy target.