Abstract
ABSTRACT
Extracellular vesicles (EVs) mediate intercellular communication within the tumour microenvironment by carrying cargoes from paracrine parent cells. EVs have attracted great research interest for their ability to carry nucleic acids into recipient cells and modulate cellular functions. However, previous studies have largely focused on RNA sequence information rather than RNA structure features. Here, we observed that EVs derived from colorectal cancer cells are enriched with endogenous double‑stranded RNA (dsRNA), a danger‑associated molecular pattern (DAMP) that leads to the activation of dsRNA‑sensing pathways in recipient cells. Crucially, we investigated the specific crosstalk between tumour‐derived EVs and circulating platelets. As anucleate cells, platelets are uniquely suited models for isolating the effects of exogenous nucleic acids. Our analysis reveals that endogenous dsRNA from tumour EVs activates the platelet OAS–RNASEL innate immune ribonuclease cascade and the RNASEL/ABCE1/PELO axis, resulting in the decay of ribosomal protein mRNAs. This study, spanning from clinical observation to mechanistic validation, uncovers a novel pathway of tumour–platelet communication. We identify EV‐enriched endogenous dsRNA as a functional mediator that enables tumour cells to directly reprogram platelet transcriptomes, revealing a new dimension of tumour–immune modulation.