RNA modifications and metabolism in cancer: mechanisms, cross-talk and therapeutic implications.

RNA modifications, particularly in the realm of epitranscriptomics, have emerged as crucial regulatory factors in cancer progression, influencing cancer cell behavior by reprogramming metabolic pathways. These modifications, such as N⁶-methyladenosine (m⁶A), 5-methylcytosine (m⁵C), N¹-methyladenosine (m¹A), N⁷-methylguanosine (m⁷G), N⁴-acetylcytidine (ac⁴C) and pseudouridine (Ψ), modulate mRNA stability, splicing, translation efficiency, and non-coding RNA function, thereby fine-tuning the expression of metabolic enzymes and transporters. Importantly, these marks converge on shared metabolic enzymes, engage common effector proteins, and exhibit synergistic, antagonistic or hierarchical relationships that collectively shape the metabolic landscape of tumors. This review synthesizes current knowledge on how RNA modifications coordinate glucose, lipid, glutamine and nucleotide metabolism, with emphasis on cross-talk and functional integration among different marks. We further discuss tumor-type-specific wiring of these networks, the challenges of multi-modification detection, and the therapeutic potential of targeting the epitranscriptomic-metabolic axis in precision oncology.