RNA modifications as a means of self-recognition and immune protection

More than 170 distinct RNA modifications have been identified, playing pivotal roles in regulating development, homeostasis, and adaptive evolution. A recent groundbreaking study in <i>Nature</i> revealed that glycoRNA prevents endogenous RNA from being misidentified as non-self, thereby averting autoimmune responses. This function is astonishingly parallel to that of A-to-I RNA editing, another prevalent RNA modification. Here, we synthesize current knowledge of RNA modifications linked to immune function and highlight an intriguing but intuitive principle: modifications that act within the cell, such as A-to-I editing, must be installed in the nucleus before reaching the cytoplasm where unmodified exogeneous RNAs also prevail. By contrast, glycoRNA, which functions at the cell surface, faces no such spatial constraint, as self/non-self-identity needs not be resolved in the cytoplasm. We also acknowledge the existence of modifications such as C-to-U editing that appear less related to immunity. Future investigations will determine whether immune-associated functions are a dominant property of a broader spectrum of RNA modifications. Overall, this work deepens our understanding of how RNA modifications shape immune homeostasis and self/non-self-discrimination, and prompts broader reflection on how multilayered molecular regulations allow organisms to balance stability with diversity across development, evolution, and adaptation.