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

Yuan-Yuan Zhu1, An-Qi Li1, Fan Yang1

  • 1School of Pharmacy, Fudan University, and School of Basic Medical Sciences, Fudan University, Shanghai, 201203, China.

Acta Pharmacologica Sinica
|June 28, 2026
PubMed

Insights

Targeting B-cell lymphoma 9 and B-cell lymphoma 9-like (BCL9/BCL9L) enhances CD4+ T cell antitumor immunity. Inhibiting BCL9/BCL9L promotes a Th1-dominant tumor microenvironment (TME) for potent anti-cancer responses.

Area of Science:

  • Immunology
  • Cancer Biology
  • Molecular Biology

Background:

  • CD4+ effector T cells are crucial for antitumor immunity.
  • The therapeutic potential of CD4+ T cells is not fully realized.
  • Wnt coactivators B-cell lymphoma 9 and B-cell lymphoma 9-like (BCL9/BCL9L) role in immunity is unclear.

Purpose of the Study:

  • To investigate the impact of targeting BCL9/BCL9L on CD4+ T cell-mediated antitumor immunity.
  • To explore BCL9/BCL9L as potential therapeutic targets for cancer immunotherapy.

Main Methods:

  • Genetic deletion and pharmacological inhibition of BCL9/BCL9L.
  • Analysis of CD4+ T cell activation and differentiation in the tumor microenvironment (TME).
  • Investigated molecular mechanisms involving TCF4, PIAS genes, STAT1/STAT4.

Main Results:

  • BCL9/BCL9L suppression hinders tumor progression and boosts CD4+ T cell activation.
  • Loss of Bcl9/Bcl9l promotes Th1 differentiation, creating a Th1-dominant TME.
  • Inhibition of BCL9/BCL9L unleashes a direct cytotoxic program in Th1 cells.
  • Mechanism involves suppression of TCF4-mediated PIAS gene regulation and enhanced STAT1/STAT4 activation.

Conclusions:

  • BCL9/BCL9L are negative regulators of CD4+ T cell antitumor immunity.
  • Targeting BCL9/BCL9L can reprogram the TME towards a Th1-supportive state.
  • BCL9/BCL9L inhibition represents a promising strategy for enhancing cancer immunotherapy.
Keywords:
BCL9/BCL9LCD4+ T cellsSTAT1/STAT4Th1 cellstumor microenvironment

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