2. Academic Validation
  3. The tumor-intrinsic role of the m6A reader YTHDF2 in regulating immune evasion

The tumor-intrinsic role of the m6A reader YTHDF2 in regulating immune evasion

  • Sci Immunol. 2024 May 31;9(95):eadl2171. doi: 10.1126/sciimmunol.adl2171.
Sai Xiao 1 2,  Shoubao Ma 1 2 3,  Baofa Sun 4,  Wenchen Pu 5,  Songqi Duan 6,  Jingjing Han 1 2,  Yaqun Hong 1 2,  Jianying Zhang 7,  Yong Peng 5,  Chuan He 8,  Ping Yi 9,  Michael A Caligiuri 1 2 3,  Jianhua Yu 1 2 3 10
Affiliations

Affiliations

  • 1 Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA 91010, USA.
  • 2 Hematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, CA 91010, USA.
  • 3 Comprehensive Cancer Center, City of Hope, Los Angeles, CA 91010, USA.
  • 4 State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for Cell Responses, College of Life Sciences, Nankai University, Tianjin 300071, China.
  • 5 Laboratory of Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Chengdu, China.
  • 6 College of Food Science, Sichuan Agricultural University, Ya'an, Sichuan 625014, China.
  • 7 Department of Computational and Quantitative Medicine, City of Hope National Medical Center, Los Angeles, CA 91010, USA.
  • 8 Department of Chemistry, Department of Biochemistry and Molecular Biology, and Institute for Biophysical Dynamics, University of Chicago, Chicago, IL 60637, USA.
  • 9 Third Affiliated Hospital of Chongqing Medical University, Chongqing 401120, China.
  • 10 Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Los Angeles, CA 91010, USA.
PMID: 38820140 DOI: 10.1126/sciimmunol.adl2171
Abstract

Tumors evade attacks from the immune system through various mechanisms. Here, we identify a component of tumor immune evasion mediated by YTH domain-containing family protein 2 (YTHDF2), a reader protein that usually destabilizes m6A-modified mRNA. Loss of tumoral YTHDF2 inhibits tumor growth and prolongs survival in immunocompetent tumor models. Mechanistically, tumoral YTHDF2 deficiency promotes the recruitment of macrophages via CX3CL1 and enhances mitochondrial respiration of CD8+ T cells by impairing tumor glycolysis metabolism. Tumoral YTHDF2 deficiency promotes inflammatory macrophage polarization and antigen presentation in the presence of IFN-γ. In addition, IFN-γ induces autophagic degradation of tumoral YTHDF2, thereby sensitizing tumor cells to CD8+ T cell-mediated cytotoxicity. Last, we identified a small molecule compound that preferentially induces YTHDF2 degradation, which shows a potent antitumor effect alone but a better effect when combined with anti-PD-L1 or anti-PD-1 Antibodies. Collectively, YTHDF2 appears to be a tumor-intrinsic regulator that orchestrates immune evasion, representing a promising target for enhancing Cancer Immunotherapy.

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