The RNA methylation modification as an immunometabolic regulatory hub in pancreatic cancer: from mechanistic insights to clinical translation perspectives

RNA methylation represents the most abundant post-transcriptional modification in RNA and has recently emerged as a central topic in molecular biology. It precisely regulates various biological functions by influencing key processes like RNA splicing, translation, transport, and stability. Pancreatic cancer remains one of the most aggressive and lethal malignancies, with its high mortality largely attributed to late diagnosis and limited therapeutic options. Recent research has shown that RNA methylation is intimately linked to tumor immunity and is vital in forming the tumor microenvironment (TME). Moreover, accumulating evidence indicates that reprogrammed metabolism is a critical driver of pancreatic tumorigenesis, progression, therapeutic response, and prognosis. RNA methylation, particularly N6-methyladenosine (m⁶A), regulates RNA translation and stability through the coordinated actions of methyltransferases (“writers”), demethylases (“erasers”), and binding proteins (“readers”), ultimately shaping immune and metabolic pathways in pancreatic cancer. By reprogramming tumor immunity and metabolism, RNA methylation critically governs key malignant behaviors such as cell proliferation, invasion, and metastasis. This review provides a comprehensive overview of the molecular mechanisms and biological functions of RNA methylation, emphasizing its dual roles in immune modulation and metabolic reprogramming in pancreatic cancer. Furthermore, we explore the intricate crosstalk between immune responses and metabolic networks mediated by m⁶A modifications. By integrating current advances, this review aims to establish a conceptual framework for understanding the immunometabolic regulation of pancreatic cancer and to highlight potential therapeutic strategies targeting RNA methylation for improved non-surgical treatment outcomes.