Tumor-intrinsic YTHDF1 drives immune evasion and resistance to immune checkpoint inhibitors via promoting MHC-I degradation

Wanzun Lin, Li Chen, Haojiong Zhang, Xianxin Qiu, Qingting Huang, Fangzhu Wan, Ziyu Le, Shikai Geng, Anlan Zhang, Sufang Qiu, Long Chen, Lin Kong () and Jiade J. Lu ()
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Wanzun Lin: Fudan University Cancer Hospital
Li Chen: Fudan University Cancer Hospital
Haojiong Zhang: Shanghai Key Laboratory of Radiation Oncology (20dz2261000)
Xianxin Qiu: Shanghai Key Laboratory of Radiation Oncology (20dz2261000)
Qingting Huang: Shanghai Key Laboratory of Radiation Oncology (20dz2261000)
Fangzhu Wan: Fudan University Cancer Hospital
Ziyu Le: Fudan University Cancer Hospital
Shikai Geng: Fudan University Cancer Hospital
Anlan Zhang: Fudan University Cancer Hospital
Sufang Qiu: Fujian Cancer Hospital & Fujian Medical University Cancer Hospital
Long Chen: Huashan Hospital, Fudan University
Lin Kong: Fudan University Cancer Hospital
Jiade J. Lu: Shanghai Key Laboratory of Radiation Oncology (20dz2261000)

Nature Communications, 2023, vol. 14, issue 1, 1-22

Abstract: Abstract The recently described role of RNA methylation in regulating immune cell infiltration into tumors has attracted interest, given its potential impact on immunotherapy response. YTHDF1 is a versatile and powerful m6A reader, but the understanding of its impact on immune evasion is limited. Here, we reveal that tumor-intrinsic YTHDF1 drives immune evasion and immune checkpoint inhibitor (ICI) resistance. Additionally, YTHDF1 deficiency converts cold tumors into responsive hot tumors, which improves ICI efficacy. Mechanistically, YTHDF1 deficiency inhibits the translation of lysosomal genes and limits lysosomal proteolysis of the major histocompatibility complex class I (MHC-I) and antigens, ultimately restoring tumor immune surveillance. In addition, we design a system for exosome-mediated CRISPR/Cas9 delivery to target YTHDF1 in vivo, resulting in YTHDF1 depletion and antitumor activity. Our findings elucidate the role of tumor-intrinsic YTHDF1 in driving immune evasion and its underlying mechanism.

Date: 2023
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DOI: 10.1038/s41467-022-35710-7

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