Mechanistic analysis and clinical translation strategies of m6A erasers in the metabolism-immunity axis of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a malignant tumor with high heterogeneity and immunotherapeutic resistance worldwide, presenting a severe challenge in clinical prevention and treatment. N6-methyladenosine (m6A) is the most common reversible post-transcriptional modification on eukaryotic mRNA, whose dynamic balance is precisely regulated by "demethylases" (Erasers). Recent studies have confirmed that the two core m6A Erasers (FTO and ALKBH5) exhibit significant expression imbalance in HCC, which strongly drives malignant tumor progression. Erasers enhance the ferroptosis resistance of HCC cells by regulating the stability of lipid metabolism-related RNAs such as GPNMB and FLAD1, helping them adapt to adverse metabolic microenvironments such as hypoxia and nutrient deprivation. Meanwhile, FTO can promote exosome release, inhibit the antigen-presenting function of dendritic cells (DCs), and further induce CD8⁺ T cells into an exhausted state. These processes synergistically construct an immunosuppressive tumor microenvironment (TIME), facilitating HCC to escape immune attack. Small-molecule inhibitors targeting core targets such as FTO and the emerging PROTAC technology have shown potential in preclinical models for reversing immunosuppression and enhancing the efficacy of systemic therapy. This review systematically synthesizes the regulatory mechanisms of Erasers in the HCC "metabolism-immunity" axis, comprehensively summarizes Eraser intervention strategies based on different etiological backgrounds for the first time, and concludes the clinical translation progress of related targeted drugs, providing new ideas and targets at the epitranscriptomic level for overcoming HCC immunotherapeutic resistance.