Effects of RNA modifications on innate and adaptive immunity (see text for references). RNA modifications impart various effects on innate immune pathways. (A) A-to-I editing of dsRNA regions by ADAR prevents IFIH1 (also known as MDA5) sensing and subsequent activation of the type I IFN signaling pathway. ADAR also binds Z-RNA, thus inhibiting ZBP1 activation. (B) m⁶A modifications in circRNAs can function as markers of “self,” preventing RIGI sensing. (C) The presence of pseudouridine and m⁵C can repress TLR signaling. Pseudouridine has also been shown to inhibit 5-triphosphate mediated RIGI sensing. (D) Depletion of m⁵C modifications results in increased transcription of Pol III transcripts, including RPPH1. RPPH1 itself facilitates transcription of 7SL RNAs, which are RIGI ligands. RNA modifications play roles in adaptive immunity: (E) Deletion of ADAR results in excessive ISG expression, thus impairing T cell receptor (TCR) signaling. (F) Loss of m⁶A leads to destabilization of Tcf7 transcripts, consequently impairing naïve T cell differentiation into T follicular helper (T_fh) cells. On the other hand, the absence of m⁶A stabilizes JAK-STAT signaling inhibitors (SOCS family), leading to subsequent inhibition of T cell homeostatic proliferation and differentiation. (G) An A-to-I editing site in cyclin I (CCNI R75G) leads to the production of an altered peptide (CCNI-ED). When presented by tumor cells, this peptide could be recognized by tumor-infiltrating lymphocytes. Created with BioRender (https://www.biorender.com).