Since the CTLA-4 mAbs were comparable in tumor rejection, but yet vary greatly in inducing peripheral T cell activation, our data are inconsistent with the notion that anti-CTLA-4 antibodies promote tumor rejection by stimulating naive T cell activation in the periphery.1 The distinct mechanism and locality associated with irAE and CITE provide new insights on ways to produce more effective and safer CTLA-4-targeting reagents that favor Treg depletion within the tumor microenvironment while avoiding general T cell activation in the peripheral lymphoid organs. This evidence concerns the gene CTLA4 and neoplasm.