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<p>Serine arginine-rich splicing factor 1 (SRSF1) is a key oncogenic splicing factor in various cancers, promoting abnormal gene expression through post-translational regulation. Although the protumoral function of SRSF1 is well-established, the effects of inhibiting tumor-intrinsic SRSF1 on the tumor microenvironment and its impact on CD8<sup>+</sup> T cell-mediated antitumor immunity remain unclear. Our findings indicate that depleting SRSF1 in CD8<sup>+</sup> T cells improve antitumor immune function, glycolytic metabolism, and the efficacy of adoptive T cell therapy. The inactivation of SRSF1 in tumor cells reduces transcription factors, including c-Jun, c-myc, and JunB, facilitating glycolytic metabolism reprogramming, which restores CD8<sup>+</sup> T cell function and inhibits tumor growth. The small-molecule inhibitor TN2008 targets SRSF1, boosting antitumor immune responses and improving immunotherapy effectiveness in mouse models. We therefore introduce a paradigm targeting SRSF1 that simultaneously disrupts tumor cell metabolism and enhances the antitumor immunity of CD8<sup>+</sup> T cells.</p>

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Targeting SRSF1 improves cancer immunotherapy by dually acting on CD8+T and tumor cells

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年1月22日

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  • Gui-Qi Zhu,
  • Zheng Tang,
  • Tian-Hao Chu,
  • Biao Wang,
  • Shi-Ping Chen,
  • Chen-Yang Tao,
  • Jia-Liang Cai,
  • Rui Yang,
  • Wei-Feng Qu,
  • Yi Wang,
  • Qian-Fu Zhao,
  • Run Huang,
  • Meng-Xin Tian,
  • Yuan Fang,
  • Jun Gao,
  • Xiao-Ling Wu,
  • Jian Zhou,
  • Wei-Ren Liu,
  • Zhi Dai,
  • Ying-Hong Shi,
  • Jia Fan

摘要

Serine arginine-rich splicing factor 1 (SRSF1) is a key oncogenic splicing factor in various cancers, promoting abnormal gene expression through post-translational regulation. Although the protumoral function of SRSF1 is well-established, the effects of inhibiting tumor-intrinsic SRSF1 on the tumor microenvironment and its impact on CD8+ T cell-mediated antitumor immunity remain unclear. Our findings indicate that depleting SRSF1 in CD8+ T cells improve antitumor immune function, glycolytic metabolism, and the efficacy of adoptive T cell therapy. The inactivation of SRSF1 in tumor cells reduces transcription factors, including c-Jun, c-myc, and JunB, facilitating glycolytic metabolism reprogramming, which restores CD8+ T cell function and inhibits tumor growth. The small-molecule inhibitor TN2008 targets SRSF1, boosting antitumor immune responses and improving immunotherapy effectiveness in mouse models. We therefore introduce a paradigm targeting SRSF1 that simultaneously disrupts tumor cell metabolism and enhances the antitumor immunity of CD8+ T cells.