2. Academic Validation
  3. Tumor-intrinsic YTHDF1 drives immune evasion and resistance to immune checkpoint inhibitors via promoting MHC-I degradation

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

  • Nat Commun. 2023 Jan 17;14(1):265. doi: 10.1038/s41467-022-35710-7.
Wanzun Lin 1 2 3,  Li Chen 1 2 3,  Haojiong Zhang 2 3 4,  Xianxin Qiu 2 3 4,  Qingting Huang 2 3 4,  Fangzhu Wan 1 2 3,  Ziyu Le 1 2 3,  Shikai Geng 1 2 3,  Anlan Zhang 1 2 3,  Sufang Qiu 5,  Long Chen 6,  Lin Kong 7 8 9,  Jiade J Lu 10 11 12
Affiliations

Affiliations

  • 1 Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Fudan University Cancer Hospital, Shanghai, 201321, China.
  • 2 Shanghai Key Laboratory of Radiation Oncology (20dz2261000), Shanghai, 201321, China.
  • 3 Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai, 201321, China.
  • 4 Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Shanghai, China.
  • 5 Department of Radiation Oncology, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fuzhou, 35005, China.
  • 6 Department of Neurosurgery & Neurocritical care, Huashan Hospital, Fudan University, Shanghai, China.
  • 7 Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Fudan University Cancer Hospital, Shanghai, 201321, China. lin.kong@sphic.org.cn.
  • 8 Shanghai Key Laboratory of Radiation Oncology (20dz2261000), Shanghai, 201321, China. lin.kong@sphic.org.cn.
  • 9 Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai, 201321, China. lin.kong@sphic.org.cn.
  • 10 Shanghai Key Laboratory of Radiation Oncology (20dz2261000), Shanghai, 201321, China. jiade.lu@sphic.org.cn.
  • 11 Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai, 201321, China. jiade.lu@sphic.org.cn.
  • 12 Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Shanghai, China. jiade.lu@sphic.org.cn.
PMID: 36650153 DOI: 10.1038/s41467-022-35710-7
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.

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