Pharmacological modulation of nucleic acid sensors — therapeutic potential and persisting obstacles

Nucleic acid sensors, primarily TLR and RLR family members, as well as cGAS–STING signalling, play a critical role in the preservation of cellular and organismal homeostasis. Accordingly, deregulated nucleic acid sensing contributes to the origin of a diverse range of disorders, including infectious diseases, as well as cardiovascular, autoimmune and neoplastic conditions. Accumulating evidence indicates that normalizing aberrant nucleic acid sensing can mediate robust therapeutic effects. However, targeting nucleic acid sensors with pharmacological agents, such as STING agonists, presents multiple obstacles, including drug-, target-, disease- and host-related issues. Here, we discuss preclinical and clinical data supporting the potential of this therapeutic paradigm and highlight key limitations and possible strategies to overcome them. Nucleic acid sensors (NASs) are essential for the preservation of cellular and organismal homeostasis, with dysregulated NAS signalling contributing to the pathology of a variety of conditions, including infectious diseases, autoimmune disorders and malignancy. Here, Galluzzi and colleagues discuss recent progress in the development of therapeutic NAS modulators and highlight obstacles faced in their clinical development.