As it is increasingly clear that only a minority of solid tumor patients respond to current immunotherapy approaches such as checkpoint inhibitors, and some tumor types do not respond at all, a deeper understanding of the specific mechanisms and functional regulation of these cytotoxic CD4+ T cells may lead to more innovative and effective immunotherapies that are targeted to this effector population independent of or in combination with conventional CD8+ T cells. The gene discussed is CD8A; the disease is neoplasm.