Tumor EVs Use Endogenous dsRNA to Degrade Platelet Ribosomal Protein mRNAs

Recently, a study published in the Journal of Extracellular Vesicles unraveled a previously unknown intercellular communication axis spanning tumors, extracellular vesicles, and platelets. The researchers showed that tumor cells selectively package endogenous double-stranded RNA (dsRNA) into extracellular vesicles (EVs), which then activate the innate immune OAS–RNASEL pathway in blood platelets, triggering targeted degradation of ribosomal protein mRNAs (RP mRNAs).

Intercellular communication is paramount in multicellular organisms. Extracellular vesicles (EVs) carry nucleic acids, proteins, and other bioactive molecules, mediating critical cross-talk across cell types. Long viewed merely as cellular "trash bags" for discarding metabolic waste, EVs have gained immense research momentum over the past two decades as a body of evidence revealed their pivotal roles in regulating fundamental physiological and pathological processes.

Tumor EVs Function as Vectors for Stable Endogenous dsRNA

The research team discovered for the first time that colorectal cancer-derived EVs are highly enriched in endogenous dsRNAs. Compared to those in parent cells, these EV-bound dsRNAs exhibit lower minimum free energy (MFE) values, indicating a far more stable double-stranded secondary structure.

Tumor cells undergo hyperactive transcription. The intracellular accumulation of abundant endogenous dsRNA risks activating RNA-sensing innate immune receptors and unleashing unwanted inflammatory cascades. Acting akin to specialized "waste disposal units," tumor cells package and enrich these endogenous dsRNAs into EVs, which are then released into systemic circulation.

Platelets as Receptors: The OAS–RNASEL Activation Paradigm

Platelets are exceptionally abundant in human blood, ranging from 150,000 to 400,000 platelets per microliter. Because mature platelets lack a nucleus, they cannot alter their transcriptome via novel transcription in response to external cues. This unique characteristic makes them an ideal model system for studying the direct impact of exogenous nucleic acids on transcriptomic landscapes.

Capitalizing on this feature, the team observed that upon entering platelets, tumor EV-derived dsRNA activates the OAS–RNASEL innate immune pathway. This activation triggers a pronounced decline in abundant ribosomal protein mRNAs (RP mRNAs) within the platelet transcriptome, alongside functional alterations in platelets. Although this degradation process proceeds slowly, the anucleate nature of platelets prevents transcriptional replenishment, resulting in a marked drop in RP mRNA representation within the platelet transcriptome, inversely accompanied by a relative surge in mitochondrial RNA content.

Figure 1. Link between the platelet RNASEL/ABCE1/PELO axis and RP-mRNA. (Sun G, et al., 2026)

Mechanistically, PELO (a protein involved in ribosomal quality control) and ABCE1 (an inhibitor of RNASEL) play decisive roles in this dsRNA-sensing cascade:

• Upon activation of the OAS–RNASEL pathway by EVs, ABCE1 disengages from inhibiting RNASEL.
• Instead, ABCE1 acts synergistically with PELO to dissociate target mRNAs from platelet ribosomes.
• The liberated mRNAs are subsequently degraded by activated RNASEL.

Crucially, this enzymatic cleavage operates in a sequence-independent manner, meaning the structural double-stranded nature of the EV-encapsulated dsRNA—rather than its specific sequence—is what drives transcriptomic remodeling in platelets.

Clinical Relevance: A Cross-Cancer Biomarker for Liquid Biopsy

This breakthrough carries profound clinical translation potential. While RP mRNA levels are conspicuously elevated in tumor tissues to accelerate oncogenic protein synthesis, the study revealed that RP mRNA content in both platelets and plasma cell-free RNA (cfRNA) is significantly depleted in cancer patients.

Because platelets represent a major source of plasma EVs and circulating cfRNA, the researchers analyzed platelet transcriptomes and plasma cfRNA across multiple cancer types—including colorectal cancer, gastric adenocarcinoma, esophageal cancer, hepatocellular carcinoma, and lung adenocarcinoma. Their findings confirmed that the reduction in both quantity and integrity of RP mRNAs in platelets and released cfRNA represents a universal, pan-cancer biomarker feature. ROC curve analyses based on RP mRNA depletion yielded area under the curve (AUC) values ranging from 0.87 to 0.92, underscoring its exceptional promise for non-invasive liquid biopsy platforms.