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

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 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. 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE311797 | GEO | 2026/07/25

REPOSITORIES: GEO

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

Project description: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 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. 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.

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