KRAS mutations reprogram RNA m6A modification to drive CD73-dependent immune evasion in colorectal cancer [MeRIP-seq]

Here, we show that KRAS mutations remodel the m6A epitranscriptome to promote immune evasion. Methylated RNA-immunoprecipitation sequencing of isogenic CRC cells revealed that KRAS-mutant cells exhibit increased N6-methyladenosine (m6A) deposition on CD73 mRNAs, enhancing the stability of the transcripts by promoting interaction with IGF2BP3.

This m6A modification was driven by TEAD4-dependent recruitment of the METTL3 methyltransferase complex, 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 natural killer (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.