Enhanced antitumoral activity of TLR7 agonists via activation of human endogenous retroviruses by HDAC inhibitors

Abstract In this work, we are reporting that “Shock and Kill”, a therapeutic approach designed to eliminate latent HIV from cell reservoirs, is extrapolatable cancer therapy. This based on the observation malignant cells express spectrum of human endogenous retroviral elements (HERVs) which can be transcriptionally boosted by HDAC inhibitors. The endoretroviral gene HERV-V2 codes for an envelope protein, resembles syncytins. It significantly overexpressed upon exposure inhibitors effectively targeted simultaneous application TLR7/8 agonists, triggering intrinsic apoptosis. We demonstrated synergistic cytotoxic effect was accompanied functional disruption TLR7/8-NF?B, Akt/PKB, Ras-MEK-ERK signalling pathways. CRISPR/Cas9 ablation TLR7 HERV-V1/V2 curtailed apoptosis significantly, proving pivotal role these in driving death. effectiveness new confirmed ovarian tumour xenograft studies, revealing promising avenue future therapies.