Beyond m6A: The Expanding Landscape of mRNA Modifications in Renal Cell Carcinoma.

Renal cell carcinoma (RCC) comprises molecularly diverse tumor subtypes. This diversity is reflected in distinct and adaptable gene-expression programs that enable tumor cells to reprogram metabolism and survive therapeutic pressure. By regulating RNA processing, export, stability, decay, and translation, messenger RNA (mRNA) modifications may help shape these programs. Examining mRNA modifications is therefore important for understanding metabolic adaptation and treatment resistance in RCC. This narrative review focuses on RCC studies of N6-methyladenosine (m6A), 5-methylcytosine (m5C), N7-methylguanosine (m7G), and N4-acetylcytidine (ac4C). We focus on protein-coding transcripts and mRNA-centered mechanisms. Transcript-level studies are most extensive for m6A, while selected m5C and ac4C studies have identified defined regulator-mRNA axes. By comparison, RCC data for specific internal m7G sites in mRNA remain largely indirect. Many reported links with immune features or treatment response are based on retrospective analyses rather than treatment-specific clinical validation. Different modification pathways converge on PI3K/AKT, Hippo/YAP, metabolism, and treatment resistance, although direct molecular crosstalk has not been shown in RCC. No RNA-modification biomarker or targeted agent is used in routine RCC care. Further progress will require orthogonal site validation, broader coverage of RCC subtypes, and prospective studies conducted within contemporary treatment settings.