Cancer immunotherapy has transformed treatment possibilities, but its effectiveness differs significantly among patients, indicating the presence of alternative pathways for immune evasion. Here, we show that ITPRIPL1 functions as an inhibitory ligand of CD3ε, and its expression inhibits T cells in the tumor microenvironment. 1,4,5-triphosphate receptor-interacting protein-like 1 (ITPRIPL1), a natural CD3 ligand, to evade immune surveillance and promote tumor growth. ITPRIPL1, is also a remarkable NSCLC biomarker. Detecting ITPRIPL1 in tumors can contribute to better diagnosis, CD8 positive T cell infiltration revelation, disease progression surveillance, and prognosis prediction.