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<p>Emerging evidence underscores the pivotal role of CD4<sup>+</sup> effector T cells in antitumor immunity, yet their full therapeutic potential remains underexplored. This study investigates the impact of targeting the Wnt coactivators B-cell lymphoma 9 and B-cell lymphoma 9-like (BCL9/BCL9L) on CD4<sup>+</sup> T cell-mediated antitumor immunity. We demonstrate that either genetic deletion or pharmacological inhibition of BCL9/BCL9L suppresses tumor progression and increases CD4<sup>+</sup> T cell activation in the tumor microenvironment (TME). Critically, loss of <i>Bcl9/Bcl9l</i> skews CD4<sup>+</sup> T cell differentiation toward a Th1 phenotype at the expense of Th2, Th17, and Treg lineages, thereby establishing a Th1-dominant TME and unleashing a direct cytotoxic program in these Th1 cells. Mechanistically, BCL9/BCL9L inhibition promotes Th1 polarization by suppressing TCF4-mediated regulation of PIAS family genes and enhancing STAT1/STAT4 activation, thereby driving a potent Th1-mediated antitumor response. Collectively, our findings identify BCL9/BCL9L as critical negative regulators of CD4<sup>+</sup> T cell antitumor immunity and establish them as promising therapeutic targets for reprogramming the TME toward a Th1-supportive state.</p>

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Targeting BCL9/BCL9L enhances CD4+ T cell-mediated Th1 antitumor immunity through activation of STAT1/STAT4 signaling

  • 期刊论文

  • 发表日期：

    2026年6月29日

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  • Yuan-yuan Zhu,
  • An-qi Li,
  • Fan Yang,
  • Yu-xuan Dong,
  • Ya-si Huang,
  • Xiang-jing Meng,
  • Dai-zhou Zhang,
  • Ye Li,
  • Yan-fang Xian,
  • Di Zhu,
  • Mei Feng

摘要

Emerging evidence underscores the pivotal role of CD4+ effector T cells in antitumor immunity, yet their full therapeutic potential remains underexplored. This study investigates the impact of targeting the Wnt coactivators B-cell lymphoma 9 and B-cell lymphoma 9-like (BCL9/BCL9L) on CD4+ T cell-mediated antitumor immunity. We demonstrate that either genetic deletion or pharmacological inhibition of BCL9/BCL9L suppresses tumor progression and increases CD4+ T cell activation in the tumor microenvironment (TME). Critically, loss of Bcl9/Bcl9l skews CD4+ T cell differentiation toward a Th1 phenotype at the expense of Th2, Th17, and Treg lineages, thereby establishing a Th1-dominant TME and unleashing a direct cytotoxic program in these Th1 cells. Mechanistically, BCL9/BCL9L inhibition promotes Th1 polarization by suppressing TCF4-mediated regulation of PIAS family genes and enhancing STAT1/STAT4 activation, thereby driving a potent Th1-mediated antitumor response. Collectively, our findings identify BCL9/BCL9L as critical negative regulators of CD4+ T cell antitumor immunity and establish them as promising therapeutic targets for reprogramming the TME toward a Th1-supportive state.