In this context, we have recently reported that blocking the interaction between CTLA-4 and its ligands CD80 and CD86 is neither necessary nor sufficient for CITE of anti-CTLA-4 antibodies.29 In contrast, studies from several laboratories, including ours, established that selective depletion of regulatory T cells in the tumor microenvironment (TME) but not in the normal tissues as the primary mechanism of action of CITE.29–33 The new understanding of regulatory T cell depletion explained why it is possible to uncouple irAE from CITE.33,34. The gene discussed is CTLA4; the disease is neoplasm.