Azacitidine at low doses serves as an epigenetic modifier by regulating DNA methylation, whereas at higher doses it can be directly cytotoxic. Ruan et al administered oral azacitidine (CC-486) prior to each cycle of cytotoxic CHOP therapy in PTCL. When examining pharmacodynamic effects on 5 paired tumor samples, they observed differential gene expression before and after CC-486 administration in gene sets related to inflammatory response and hypoxia, suggesting a favorable change in the composition of the tumor microenvironment (TME) facilitated by CC-486. Furthermore, gene-based cell subtype deconvolution showed a trend towards lower TFH lymphoma cells and proliferation suggesting a possible directly antineoplastic effect on malignant T cells, particularly TFH cells. Although the exact mechanisms of the potentially chemosensitizing changes remain to be further elucidated, epigenetic priming may lead to a favorably disposed and likely more “inflammatory” TME and synergy with cytotoxic chemotherapy or other partners. Professional illustration by Patrick Lane, ScEYEnce Studios.