RNA m6A Modification in Immunometabolism: Context-Dependent Mechanisms and Therapeutic Perspectives
Qiong Fang, Wei Li, Yongqing Cai, Shuyi Zhang, Xinzhi Tang, Chu Chu, Miaomiao Zhou, Fang Li, Zhen Zhang, Xia LiN6-methyladenosine (m6A) regulates RNA fate and has been linked to immune cell function and metabolic adaptation. This narrative review examines selected studies across innate, adaptive, and tissue-resident immune populations, focusing on the cellular origin, target transcript, and experimental evidence supporting each mechanism. Metabolic inputs, including α-ketoglutarate, lactate, and D-2-hydroxyglutarate, can influence m6A regulatory pathways, while m6A-dependent RNA regulation can alter metabolic enzymes, transporters, and immune responses. We discuss these findings within a proposed metabolite–m6A–immune framework; reciprocal relationships demonstrated in separate settings do not establish a closed feedback circuit in every cell population or disease model. We distinguish direct metabolic measurements from changes in signaling, survival, differentiation, and inferred pathway activity, and consider how tissue context and target selection may account for contrasting effects of the same regulator. Representative pharmacological studies of METTL3, FTO, and YTH domain readers are considered alongside interventions with less well-defined target specificity and early clinical development of METTL3 inhibition. The available evidence supports context-dependent mechanisms and therapeutic hypotheses, while clinical benefit, cellular selectivity, and long-term safety remain unresolved for the applications discussed.