AML immune interplay and potential avenues for clinical translation. Current understanding of T-cell functional states and their effect on AML response to chemotherapy, bispecific molecules, and CPIs. Immune gene expression profiling (bulk and/or scRNA-seq) should be integrated with clinically validated prognosticators, including ELN risk category, LSC17 score, and molecular lesions (TP53, RUNX1, IDH1/2, and TET2 mutational status), to accurately stratify patients with AML into subgroups with substantially different survival probabilities. Patients with an IFN-γ–dominant, immune-enriched TME could be allocated immunotherapies that target AML-induced T-cell dysfunctional states, including T-cell engagers and CPIs. TP53-mutated AML have been shown to respond to a CD123-targeting bispecific molecule. Conversely, patients with a “cold,” immune-depleted profile could benefit from increasing T-cell trafficking to the TME and/or from priming therapies such as vaccines, adoptive T-cell transfer, or allogeneic HSCT. Interventions that balance type I (tumor-cell intrinsic) and type II (immune-cell intrinsic) IFN signaling could be instrumental to overcoming resistance to CPIs and other T-cell–based immunotherapies. In this respect, IFN-I hyporesponsiveness in tumor cells before anti-PD1 treatment has been correlated with long-term survival, as discussed in the main text. Furthermore, abrogating cancer cell IFN-I signaling increases IFN-II signaling in immune cells, thereby expanding T cells toward effector-like functional states. Red arrows denote inhibition; green arrows denote stimulation. GEP, gene expression profiling; LSC17, 17-gene leukemia stem cell; mAbs, monoclonal antibodies; TAM, tumor-associated macrophage.