Various stimuli (e.g., hypoxia, soluble factors, metabolites, and therapeutic interventions) trigger epigenetic alterations in tumor-infiltrating immune cells. These global epigenetic changes upregulate the expression of cytokines or functional molecules (e.g., IFN-γ and TNF-α) in immune cells directly suppressing cancer cell growth. Additional epigenomic changes in innate immune cells regulate cancer cell biology through modulating T cell function. Epigenetic modifications in macrophages, MDSCs, and neutrophils are essential for regulating the expression of genes that encode immunosuppressive factors (e.g., IL10 and ARG1) or proinflammatory cytokines (e.g., IL1B). These innate immune cell–derived molecules further induce T cell activation or dampen T cell antitumor function. ARG1, arginase 1; HIF-1α, hypoxia-inducible factor α; IFNAR1, IFN α and β receptor subunit 1; IRAKM, IL-1 receptor–associated kinase 3; IRF4, IFN regulatory factor 4; MGL2, macrophage galactose N-acetyl-galactosamine–specific lectin 2; NFC1/2, neutrophil cytosolic factor 1/2; PERK, protein kinase RNA-like ER kinase; PRC2, polycomb-repressive complex 2; SLC43A2, solute carrier family 43 member 2.