N6-methyladenosine Modifications in Pancreatic Cancer: Molecular Mechanisms and Therapeutic Implications

Abstract

Pancreatic cancer is one of the most aggressive malignancies with a high mortality rate and poor prognosis, characterized by low early diagnosis, resection, and survival rates. Recent studies have highlighted the role of N6-methyladenosine (m6A) RNA modification in the initiation, progression, and treatment of pancreatic cancer. This review explores the molecular mechanisms of m6A modification, focusing on the regulatory roles of m6A writers (e.g., METTL3, METTL14), erasers (e.g., FTO, ALKBH5), and readers (e.g., YTHDF2, YTHDC1) in pancreatic cancer. METTL14, a core component of the m6A methyltransferase complex, is overexpressed in pancreatic cancer tissues and correlates with poor patient survival. Its depletion reduces m6A levels and inhibits cancer cell growth, identifying PERP as a key target gene regulated by METTL14. Additionally, m6A modification impacts CAR-T cell therapy and immune checkpoint inhibitors (ICIs) by influencing T cell activation, expansion, and immune evasion. Targeting m6A regulators, such as METTL3 and YTHDF2, enhances the efficacy of CAR-T cells and ICIs, offering potential therapeutic strategies. Future research should validate the clinical relevance of the m6A-METTL14-PERP axis and develop selective inhibitors to improve pancreatic cancer treatment. Understanding m6A dynamics provides new insights into the molecular mechanisms underlying pancreatic cancer and highlights the potential for m6A-based therapies to overcome current treatment challenges.