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This is based on the observation that malignant cells express a spectrum of human endogenous retroviral elements (HERVs) which can be transcriptionally boosted by HDAC inhibitors. The endoretroviral gene<jats:italic>HERV-V2<\/jats:italic>codes for an envelope protein, which resembles syncytins. It is significantly overexpressed upon exposure to HDAC inhibitors and can be effectively targeted by simultaneous application of TLR7\/8 agonists, triggering intrinsic apoptosis. We demonstrated that this synergistic cytotoxic effect was accompanied by the functional disruption of the TLR7\/8-NF\u03baB, Akt\/PKB, and Ras-MEK-ERK signalling pathways. CRISPR\/Cas9 ablation of<jats:italic>TLR7<\/jats:italic>and<jats:italic>HERV-V1\/V2<\/jats:italic>curtailed apoptosis significantly, proving the pivotal role of these elements in driving cell death. 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