Fig. 1.

DNMT inhibitors support anti-tumor T-cell immunity through multiple mechanisms. DNMT inhibitors are among the most studied type of epigenetic drugs and their effects on tumor cells are well characterized. The depletion of DNMTs from tumor cells leads to extensive DNA hypomethylation and enhanced expression of hundreds of genes, including tumor antigens (i.e. CTAs and HERVs) and key components of the antigen processing and presentation pathways (e.g. HLA I). The induction of HERV RNA species further provokes a viral-mimicry response that triggers the production of multiple immune signaling molecules, including type I interferons and other cytokines and chemokines with autocrine and paracrine effects on tumor and immune cells. DNMT inhibitors also exert indirect effects on the tumor by reducing the presence of TAMs and MDSCs. The net result of these effects should be a TME that better supports anti-tumor T cell immunity, which advocates the combined use epigenetic drugs, such as DNMT inhibitors, in combination with genetically engineered T cells