Novel therapies for TP53-mutated MDS and AML. Cell-extrinsic immunotherapeutic approaches include targeting cell-surface markers including LSC markers, macrophage and T-cell checkpoints, bispecific engagers, and adoptive cellular therapies including unmodified and chimeric antigen receptor–modified cells. Cell-intrinsic approaches include mutant p53 reactivators, mutant p53 degraders, metabolism-targeting agents, GSPT1 degraders, and others. Ab, antibody; ADCC, antibody-dependent cell-mediated cytotoxicity; BiTE, bispecific T-cell engager; NK, natural killer; TCR, T-cell receptor; Treg, regulatory T cell; TriKE, trispecific killer cell engager.