CD8A and neoplasm: T cell immunoreceptor with Ig and ITIM domains (TIGIT), V-domain Ig suppressor of T cell activation (VISTA) blockade, glucocorticoid-induced TNFR-related protein (GITR) agonism, Stimulator of Interferon Genes (STING) pathway activation, and T cell immunoglobulin and mucin-domain containing-3 (TIM-3) inhibition—has revealed strategies to both unleash CD8+ T-cell cytotoxicity and dismantle regulatory networks that foster tumor tolerance.