Background <p>The guanine nucleotide exchange factor RASGRF1 actively acts in a broad range of human cancers, including thyroid cancer (THCA). This study defined the activity of RASGRF1 in THCA progression and elucidated the m6A modification mechanism governing dysregulation of RASGRF1.</p> Methods <p>Expression analyses were performed by immunoblotting, immunohistochemistry (IHC) or quantitative PCR. Cell growth was evaluated by colony formation and EdU proliferation assays. Animal experiments tested the function of RASGRF1 in xenograft growth. The conditioned medium (CM) of THCA cells was used to treat THP-1-differentiated macrophages. Cell apoptosis and CD206⁺ macrophages were assessed by flow cytometry. Cell invasiveness and migratory ability were detected by transwell assays. The influence of FTO in RASGRF1 was evaluated by RNA immunoprecipitation (RIP) and MeRIP assays.</p> Results <p>RASGRF1 was upregulated in human THCA. RASGRF1 depletion retarded THCA cell growth, motility, invasiveness and promoted cell apoptosis and ferroptosis in vitro, as well as diminished the growth of TPC1 THCA xenograft tumors in vivo. Moreover, RASGRF1 depletion diminished M2 polarization and migration of THP-1-differentiated macrophages. Mechanistically, FTO reduced <i>RASGRF1</i> mRNA stability via an m6A-dependent mechanism. FTO upregulation suppressed THCA malignant behaviors, promoted cell ferroptosis and reduced macrophage M2 polarization and migration through repression of RASGRF1.</p> Conclusion <p>Our findings suggest that FTO-mediated the instability of <i>RASGRF1</i> mRNA diminishes THCA-related macrophage M2 polarization and THCA progression. Anti-RASGRF1 strategies may be useful for the treatment of THCA.</p> Graphical Abstract <p>In THCA cells, downregulated FTO leads to the enhanced stability and expression of RASGRF1 mRNA via an m6A-dependent manner and thus promotes THCA-related macrophage M2 polarization and THCA progression.</p> <p></p>