Orchestrating innate immunity through RNA editing and helicase activity: ADAR1, dsRNA sensors, and tumor immune evasion

Dysregulated dsRNA editing and RNA metabolism in cancer contribute to immune evasion, highlighting the critical role of RNA structural regulation in disease. Intracellular RNA structures regulate gene expression, innate immunity, genome stability, and cell fate. Among these, double-stranded RNA (dsRNA) is particularly important; exogenous dsRNA typically originates from viral infection, whereas endogenous dsRNA arises from repetitive elements or transcriptional errors, allowing cells to distinguish "self" from "non-self." The RNA-editing enzyme Adenosine Deaminase Acting on RNA 1 (ADAR1) prevents inappropriate innate immune activation by catalyzing adenosine-to-inosine (A-to-I) editing of endogenous dsRNA. RNA helicases complement this function by remodeling RNA structures and resolving nucleic acid hybrids, maintaining RNA homeostasis and immune surveillance. Recent studies have revealed an interplay between ADAR1 and RNA helicases that regulate dsRNA immunogenicity and R-loop dynamics, establishing this network as a key determinant of tumor immunity. Dysregulated RNA editing and structural regulation in cancer further underscore the potential of targeting these pathways therapeutically, providing strategies beyond conventional gene- or protein-centered approaches. In this review, we summarize current insights into how ADAR1 and RNA helicases control RNA structure, emphasize their roles in innate immune sensing, and discuss emerging approaches to modulate RNA editing and RNA architecture for therapeutic benefit. Taken together, research in this area positions RNA structural control as a central determinant of immune homeostasis and a promising frontier in cancer therapy.