Abstract

ALKBH5 was positively correlated with macrophage infiltration in MM. • ALKBH5 silencing suppressed M2 TAMs polarization and invasion, and restored CD8 T cell cytotoxicity. • EIF4A3 directly interacted and stabilized ALKBH5 mRNA, thus upregulating TGF-β1 secretion in an m6A dependent manner. • EIF4A3 silence inhibited TAMs M2-like polarization, MM cell invasion and T cell resistance by repressing ALKBH5. • TGF-β1 abolished the regulatory effects of ALKBH5 silencing in TAMs M2-like polarization and malignant MM cell phenotypes. Meningioma (MM) is the most prevalent primary tumor in the central nervous system. This study sought to unveil the mechanism by which Alkylation repair homolog protein 5 (ALKBH5) regulates tumor-associated macrophages (TAMs) M2-like polarization and modulates the resistance of MM cells to CD8 + T cell-mediated cytotoxicity. The data showed that ALKBH5 upregulation was positively correlated with M2-like TAM polarization. ALKBH5 knockdown suppressed TAM M2-like polarization and the aggressive phenotypes of MM cells, thus inhibiting tumor growth. Additionally, EIF4A3 knockdown attenuated TAM M2-like polarization, suppressed invasive phenotypes of MM cells, and reduced MM cell resistance to CD8 + T cell-mediated cytotoxicity in vitro by inhibiting ALKBH5. ALKBH5 promoted TGF-β1 expression in an m6A-dependent manner. TGF-β1 reversed the ALKBH5 knockdown-mediated effects. In summary, EIF4A3-mediated upregulation of ALKBH5 elevated the malignant phenotypes of MM cells and their resistance to CD8 + T cell-mediated cytotoxicity in vitro by facilitating TAM M2-like polarization and TGF-β1 secretion.