The Potential Regulatory Roles of Circular RNAs in Tumor Immunology and Immunotherapy

Circular RNAs (circRNAs) are covalently closed RNA molecules in eukaryotes with features of high stability, tissue-specific and cell-specific expression. According to their biogenesis, circRNAs are mainly classified into five types, i.e. exonic circRNAs (EciRNAs), exon-intron circRNAs (EIciRNAs), intronic RNAs (CiRNAs), fusion circRNAs (f-circRNAs), and read-through circRNAs (rt-circRNAs). CircRNAs have been emerging as important non-coding regulatory RNAs in a variety of human cancers. CircRNA4s were revealed to exert regulatory function through multiple mechanisms, such as sponges/decoys of miRNAs and proteins, enhancers of protein functions, protein scaffolds, protein recruitment, or protein translation templates. Furthermore, some circRNAs are intensively associated with immune cells in tumor immune microenvironment (TIME), e.g. circARSP91 and natural killer cells. Through regulating immune checkpoint genes, circRNAs are demonstrated to modulate the immune checkpoint blockade immunotherapy, e.g. circCPA4 could up-regulate PD-L1 expression. In summary, we reviewed the molecular features of circRNAs and mechanisms how they exert functions. We further summarized functional implications of circRNA regulations in tumor immunology and immunotherapy. Further understanding of the regulatory roles of circRNAs in tumor immunology and immunotherapy will benefit tumor treatment.