CD3L1 (CD3 ligand 1), also known as ITPRIPL1, is the first identified ligand of CD3 and plays a crucial role in tumor immune evasion and testicular immune privilege. CD3L1 inhibits T-cell activation by directly binding to CD3ε, a process that involves the sustained binding of Nck to the intracellular domain of CD3ε, competitively inhibiting the recruitment and phosphorylation of Zap70, thus suppressing T-cell activation at the initial stage. This discovery reveals the existence of a natural ligand for CD3, suggesting that the TCR/CD3 complex may not be regulated in a TCR-dominant "monopolar" manner but rather in a "bipolar" mode where both TCR and CD3 have natural regulatory ligands. The identification of CD3L1 offers a new target for cancer immunotherapy and promises to bring new breakthroughs in the field.