KRAS Mutations Reprogram RNA m6A Modifications to Drive CD73-Dependent Immune Evasion in Colorectal Cancer.

Abstract

KRAS mutations, present in about 40% of colorectal cancers (CRCs), are strongly associated with an immunosuppressive tumor microenvironment characterized by restricted immune infiltration and poor responses to immunotherapy. Here, we found that KRAS mutations remodel the N6-methyladenosine (m6A) epitranscriptome to promote immune evasion. Methylated RNA immunoprecipitation sequencing revealed that KRAS-mutant cells exhibit increased m6A deposition on CD73 mRNA, enhancing its stability through IGF2BP3. TEAD4-dependent recruitment of the METTL3 methyltransferase complex induced the m6A modification, identifying TEAD4 as a spatial regulator of m6A deposition. Functionally, METTL3 knockdown in KRAS-mutant syngeneic tumors suppressed tumor growth and restored antitumor immunity by increasing CD8⁺ T-cell and NK-cell infiltration in a CD73-dependent manner. Moreover, METTL3 inhibition synergized with anti-PD-1 therapy and a CD73 inhibitor to reduce tumor burden. Together, these findings demonstrate that KRAS-driven m6A remodeling is a key mechanism of immune suppression in CRC and highlight METTL3 as a promising therapeutic target.