T cell inhibition is a major obstacle to the success of adoptive T cell immunotherapies. Mechanistic insights indicate that ligand-dependent activation of various inhibitory receptors coupled to different but synergistic intracellular pathways are associated to this ineffective state, creating an opportunity for novel therapeutic strategies. Genome editing has been used to selectively inactivate genes encoding for inhibitory receptors with encouraging results. However, when scaled up to address multiple targets simultaneously, side effects tend to be magnified due to the increase in genotoxicity related to multiple DNA breaks within the cell. Epigenome editing may be more suitable for multiplexing, as it allows to control gene expression by changing epigenetic marks needless of DNA sequence disruption. Despite this remarkable advantage, genome and epigenome editing share the risk for unspecific interactions that could cause off-target effects. Here, we performed a thorough specificity study of designer epigenome modifiers (DEMs) used to silence two genes encoding key T cell inhibitory receptors (PDCD1 and LAG3) with a multiplexed hit-and-run approach in T cells. Importantly, co-delivery of the two DEMs did not affect their silencing capabilities, resulting in a stable loss of expression of both PD-1 and LAG-3. A comparative transcriptome analysis confirmed the absence of DEM-mediated off-target silencing. Considering that the few significantly deregulated genes can be attributed to the engineering procedure itself and the in silico predicted DEM off-target binding sites were not within cis-regulatory regions. Our study confirms the safety of epigenome editing and encourages its exploitation to modulate multiple T cell inhibitory pathways.