Farnesyl diphosphate synthase inhibition remodels the tumor immune microenvironment by activating endogenous retroviruses

Farnesyl diphosphate synthase (FDPS) is a crucial enzyme in isoprenoid and cholesterol biosynthesis and the target for nitrogen-containing bisphosphonate (N-BP) drugs widely used for osteoporosis treatment. Here we show that FDPS inhibition overcomes tumor resistance to immune checkpoint blockade (ICB) therapy by activating endogenous retroviruses (ERVs) and promoting a potent type I interferon response. FDPS inhibition, either by genetic knockout or alendronate, enhances the efficacy of ICB therapy substantially in multiple murine tumors by remodeling the immune microenvironment and enhancing lymphocyte infiltration, which is caused by increased type I interferon upregulation. Mechanistically, FDPS inhibition attenuates mitochondrial membrane potential (MtMP), enabling endonuclease G (EndoG) migration from the mitochondria into the nucleus, increasing DNA double-strand breaks and degradation of the heterochromatin maintenance protein TRIM28(KAP1), promoting enhanced ERV transcription and activation of the MDA5/MAVS pathway. The ensuing type I interferon upregulation is responsible for enhanced antigen presentation and sensitization to ICB therapy. Because of the synergy observed between FDPS deficiency and ICB treatment, we next sought to characterize the tumor immune microenvironment (TIME) in FDPS-deficient tumors. For this purpose, we sorted CD45+ live immune cells from subcutaneously engrafted control and FDPSKO B16F10 tumors and conducted single-cell RNA sequencing (scRNA-seq).