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David Diaz-Carballo, Sahitya Saka, Ali Haydar Acikelli, Ekaterina Homp, Julia Erwes, Rebecca Demmig, Jacqueline Klein, Katrin Schröer, Sascha Malak, Flevy D’Souza, Adrien Noa-Bolaño, Saskia Menze, Emilio Pano, Swetlana Andrioff, Marc Teipel, Philip Dammann, Diana Klein, Amber Nasreen, Andrea Tannapfel, Nicole Grandi, Enzo Tramontano, Crista Ochsenfarth, Dirk Strumberg

• In this work, we are reporting that "Shock and Kill", a therapeutic approach designed to eliminate latent HIV from cell reservoirs, is extrapolatable to cancer therapy. 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 \(\it HERV-V2\) 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\(\kappa\)B, Akt/PKB, and Ras-MEK-ERK signalling pathways. CRISPR/Cas9 ablation of \(\it TLR7\) and \(\it HERV-V1/V2\) curtailed apoptosis significantly, proving the pivotal role of these elements in driving cell death. The effectiveness of this new approach was confirmed in ovarian tumour xenograft studies, revealing a promising avenue for future cancer therapies.