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<p>CD4<sup>+</sup> T cells differentiate into various subsets, including T helper 1 (Th1), Th2, Th9, Th17 and regulatory T (T<sub>reg</sub>) cells, which are essential for immune responses and cancer immunotherapy. However, the role of RNA <i>N</i><sup>6</sup>-methyladenosine (m<sup>6</sup>A) modification in this differentiation is unclear. Here we show that YTHDF2, an important m<sup>6</sup>A reader protein known to destabilize m<sup>6</sup>A-modified mRNA, negatively regulates Th9 cell differentiation. Ablation of <i>Ythdf2</i> in both mouse and human naive CD4<sup>+</sup> T cells promotes Th9 differentiation by stabilizing <i>Gata3</i> and <i>Smad3</i> mRNA under interleukin-4 (IL-4) and transforming growth factor β (TGF-β) signaling, respectively. <i>Ythdf2</i>-deficient Th9 cells produce increased amounts of IL-9 and IL-21, leading to increased tumor infiltration and cytotoxicity by CD8<sup>+</sup> T cells and natural killer (NK) cells, thereby improving antitumor activity compared with wild-type Th9 cells. Moreover, YTHDF2 depletion in CAR-Th9 cells enhances their immune activation, reduces their terminal differentiation and augments their antitumor efficacy. Targeting YTHDF2 is thereby a promising strategy to enhance Th9 and CAR-Th9 cell-based cancer immunotherapies.</p>

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Loss of YTHDF2 enhances Th9 programming and CAR-Th9 cell antitumor efficacy

  • 期刊论文

  • 发表日期：

    2025年8月18日

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  • Sai Xiao,
  • Songqi Duan,
  • Yaqun Hong,
  • Jianying Zhang,
  • Shoubao Ma,
  • Michael A. Caligiuri,
  • Jianhua Yu

摘要

CD4+ T cells differentiate into various subsets, including T helper 1 (Th1), Th2, Th9, Th17 and regulatory T (Treg) cells, which are essential for immune responses and cancer immunotherapy. However, the role of RNA N6-methyladenosine (m6A) modification in this differentiation is unclear. Here we show that YTHDF2, an important m6A reader protein known to destabilize m6A-modified mRNA, negatively regulates Th9 cell differentiation. Ablation of Ythdf2 in both mouse and human naive CD4+ T cells promotes Th9 differentiation by stabilizing Gata3 and Smad3 mRNA under interleukin-4 (IL-4) and transforming growth factor β (TGF-β) signaling, respectively. Ythdf2-deficient Th9 cells produce increased amounts of IL-9 and IL-21, leading to increased tumor infiltration and cytotoxicity by CD8+ T cells and natural killer (NK) cells, thereby improving antitumor activity compared with wild-type Th9 cells. Moreover, YTHDF2 depletion in CAR-Th9 cells enhances their immune activation, reduces their terminal differentiation and augments their antitumor efficacy. Targeting YTHDF2 is thereby a promising strategy to enhance Th9 and CAR-Th9 cell-based cancer immunotherapies.