Inositol 1,4,5-triphosphate receptor interacting protein like 1 (ITPRIPL1) is a single transmembrane protein，exhibits normal testis-enriched expression and widespread overexpression in various human cancers. ITPRIPL1 is commonly found in tumors with low PD-L1 expression. ITPRIPL1 acts as a natural ligand for CD3 ε, evading immune surveillance, leading to decreased T cell activity and promoting tumor growth. Research has shown that inducing stable CD3E-NCK1 binding prevents CD3E-ZAP70 interaction, subsequently inhibiting downstream ERK-NFkB signaling cascade and calcium influx activation.