Cellular endogenous double-stranded RNA: From pathophysiology to therapeutic implications

Through co-evolution with pathogens, eukaryotic cells have developed sophisticated pattern recognition receptors (PRRs) that detect conserved structures of pathogen-derived nucleic acids, triggering innate immune responses against microbial invasion. While these mechanisms effectively identify pathogen-derived nucleic acids, such as viral double-stranded RNA (dsRNA) produced during infection or replication, emerging evidence reveals that stress or pathological conditions can also generate cellular endogenous dsRNA, which activates the same defense systems. Endogenous dsRNA originates through multiple pathways, including mitochondrial damage, epigenetic dysregulation, and aberrant RNA processing or modification. When detected by cytosolic dsRNA sensors, endogenous dsRNA elicits "viral mimicry"—a phenomenon where cells trigger antiviral-like responses despite the absence of viral infections. This process manifests as a double-edged sword: uncontrolled activation contributes to immune-related disorders, while targeted induction offers promising strategies for cancer immunotherapy by stimulating anti-tumor immunity. This review provides a brief overview of recent advances in endogenous dsRNA, from its biogenesis pathways and sensor recognition mechanisms to its emerging roles as critical regulators of immune homeostasis. We identify four distinct functional modes of endogenous dsRNA and discuss how it contributes to the physiology of development and regeneration and pathophysiology of autoimmune and neurodegenerative diseases, while highlighting innovative strategies to exploit for cancer immunotherapy.