Tumour-associated dsRNA accumulation and innate immune activation: mechanistic basis and therapeutic strategies.

Abstract

Endogenous double-stranded RNA (dsRNA) links disrupted RNA homoeostasis in cancer to innate immunity. Tumour-associated dsRNA arises from complementary repeat transcripts, mitochondrial transcriptional imbalance, defective RNA processing and cellular stress. Its immunogenicity depends on ligand structure, editing, persistence, localisation, sensor access and pathway competence. ADAR1 and RNA-binding or decay factors buffer self-dsRNA, allowing tumour cells to tolerate potentially immunogenic RNA. Disruption of this control engages RIG-I-MAVS, MDA5-MAVS, TLR3-TRIF, PKR-eIF2α, and OAS-RNase L pathways; Z-conformation RNA can activate ZBP1. Outputs include interferon responses, translational arrest, RNA degradation, and regulated cell death, which can promote antigen presentation and immune-cell recruitment or drive chronic interferon adaptation, suppressive inflammation and treatment resistance. This Review examines critical-target and cumulative-burden models, methods for ligand identification, biomarker-guided patient selection and therapeutic strategies based on viral mimicry, ADAR1 targeting, engineered dsRNA agonists, and delivery platforms.