Inflammatory mitochondrial signalling and viral mimicry in cancer

Endogenous transposable elements (TEs) are receiving increasing attention as potential targets to develop novel immunostimulatory strategies against cancer. Indeed, the defective epigenetic suppression of TEs in malignant cells offers a therapeutic window to enable their re-activation with at least some degree of selectivity. In line with this notion, multiple clinically employed epigenetic modifiers such as DNA-demethylating agents have been shown to promote the re-expression of TEs in preclinical tumour models, hence driving powerful inflammatory responses that enables increased sensitivity of immunitary immune cells to immunotherapy with immune checkpoint inhibitors (ICIs). This phenomenon is commonly referred to as "viral mimicry" as (at least in part) it impinges on the activation of immunological pathways commonly driven by viral infection, notably the detection of cytosolic nucleic acids by pattern recognition receptors. Here, we critically discuss the molecular mechanisms through which the mitochondria-dependent cGAS-STING and MAVS pathways enable viral mimicry as elicited by the re-activation of TEs in neoplastic cells, as we comment on the therapeutic potential of using epigenetic modifiers to harness these mechanisms in support of restored ICIs sensitivity across cancer types.