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서울대학교 의과대학
Cancer Res., Jul 29 2026, | https://doi.org/10.1158/0008-5472.CAN-26-0403
KRAS Mutations Reprogram RNA m6A Modifications to Drive CD73-Dependent Immune Evasion in Colorectal Cancer
Seungjae Shin1,#, Seung-Pyo Hong1,3,#, Seoho Lee1, Yeonseo Jang6, Jisoo Yang1, Jaeik Oh2, Dongjun Jang1, Soo-Jin Lee1, Jiwon Kim1, Sang Eun Lee1, Yoojin Yang1, Dohee Kim1, Eunjeong Yang1, Seohyeon Park1, Sabeen Hwang1, Ae Jin Choi3, Hae Rim Jung3, Yumi Oh3, Chang-Han Lee1,4,7, Joo-Youn Cho1,6, Kyungho Choi1, Jeong Mo Bae4,5*, Jong-Il Kim1,3,4*, Sung-Yup Cho1,2,3,4*
1Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.
2Department of Translational Medicine, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.
3Medical Research Center, Genomic Medicine Institute, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.
4Cancer Research Institute, Seoul National University, Seoul 03080, Republic of Korea.
5Department of Pathology, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
6Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul 03080, Republic of Korea
7BK21 FOUR Biomedical Science Project, Seoul National University College of Medicine, Seoul, Republic of Korea
#These authors contributed equally
*Corresponding Authors: Jeong Mo Bae, Jong-Il Kim, Sung-Yup Cho
1Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.
2Department of Translational Medicine, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.
3Medical Research Center, Genomic Medicine Institute, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.
4Cancer Research Institute, Seoul National University, Seoul 03080, Republic of Korea.
5Department of Pathology, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
6Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul 03080, Republic of Korea
7BK21 FOUR Biomedical Science Project, Seoul National University College of Medicine, Seoul, Republic of Korea
#These authors contributed equally
*Corresponding Authors: Jeong Mo Bae, Jong-Il Kim, Sung-Yup Cho
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.
논문정보
- Research article
- 2026년 07월 (BRIC 등록일 2026-08-03)
- 국내 연구진
- 의약학 > 종양의학
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