Although the success of immune-checkpoint blockade has revolutionized cancer treatment, a number of tumors do not respond or develop resistance, including acute myeloid leukemia (AML). Although the mechanisms of resistance can be multiple, we focus here on the impact of the immune microenvironment and the regulation of MHC-I antigen presentation. We present induction of inflammation as a mechanism of T cell dysfunction in AML and present data that implicate monocytic subpopulations in the regulation of immune response. Moreover, we perform peptide-MHC-I-guided CRISPR/Cas9 screens and identify factors that can modulate recognition of cancer cells by CD8 T cells and suppression of tumor progression.