Chimeric RNAs as Novel Neoantigens for Extracellular Vesicles-Based Vaccines Against Cancer.

Tumor vaccines largely depend on targetable tumor-specific neoantigens. However, in certain tumors, mutation-based neoantigens are exceptionally rare or even absent. To address this challenge, we developed an innovative strategy beyond genomic mutation events by utilizing tumor-specific chimeric RNAs and their encoded chimeric proteins. In this study, we demonstrated through flow cytometry and cell counting kit-8 (CCK-8) assays that aberrantly spliced tumor-specific chimeric RNAs (e.g., the ASTN2-PAPPA antisense chimeric RNA, A-PaschiRNA) can serve as tumor neoantigens. Furthermore, utilizing mouse tumorigenesis models, we have developed a novel therapeutic strategy involving extracellular vesicle (EV)-based vaccines loaded with chimeric RNAs to treat esophageal squamous cell carcinoma.