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Background <p>Emerging evidence has underscored the significance of antitumor humoral immunity, which is associated with the development of T follicular helper (Tfh) cell. However, the molecular mechanisms underlying Tfh differentiation in antitumor immunity remains poorly understood.</p> Methods <p>We analyzed publicly available RNA-seq data across various representative immune models to identify signature pathways of Tfh cells. Subsequently, we generated T-cell-specific <i>Mek</i>1/2 knockout mice and investigated the functional phenotypes through Tfh cell polarization, adoptive transfer, and flow cytometry assays. Next, we employed multi-omics sequencing and overexpression experiments to delineate the underlying mechanisms of cellular phenotypes. Finally, by integrated analysis of scRNA-seq datasets combined with MEK inhibitor intervention studies, we elucidated the anti-tumor humoral responses of MEK inhibitors in both murine tumor models and TCGA-SKCM patient cohort.</p> Results <p>Mitogen-activated protein kinase kinase 1/2 (MEK1/2) signaling was identified as a potential regulator of Tfh cells and antitumor humoral response. Codeletion or pharmacological inhibition of MEK1/2 effectively promoted Tfh cell development in vitro and in vivo. Mechanistically, ATAC-seq and RNA-seq integrative analysis revealed interferon regulatory factor 4 (IRF4)-dependent epigenetic modulation of characteristic Tfh cell genes, thereby driving Tfh differentiation. Overexpression of <i>Irf4</i> counteracted <i>Mek</i>1/2 ablation-mediated Tfh cell generation. Moreover, MEK1/2 inhibitor therapy enhanced Tfh infiltration coupled with humoral immune responses in murine melanoma model and was correlated with favorable clinical prognosis in melanoma patients.</p> Conclusions <p>Our study revealed the MEK1/2-IRF4 axis potentiates Tfh development to enhance the antitumor humoral response. These findings may provide an unprecedented strategy to improve antitumor immunotherapy efficacy by harnessing humoral immune responses.</p>

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The MEK1/2-IRF4 axis fosters T follicular helper cell differentiationand antitumor humoral immune response

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月16日

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  • Shuan Ran,
  • Song Wang,
  • Ran Li,
  • Longyong Lai,
  • Jizhang Yu,
  • Xi Zhang,
  • Yuan Li,
  • Weicong Ye,
  • Junjie Zong,
  • Xiaohan Li,
  • Yanglin Hao,
  • Jiulu Zhao,
  • Zilong Luo,
  • Han Zhang,
  • Kexiao Zheng,
  • Pinyan Huang,
  • Wang Zhan,
  • Zifeng Zou,
  • Yanqiang Zou,
  • Jikai Cui,
  • Jie Wu,
  • Jiahong Xia

摘要

Background

Emerging evidence has underscored the significance of antitumor humoral immunity, which is associated with the development of T follicular helper (Tfh) cell. However, the molecular mechanisms underlying Tfh differentiation in antitumor immunity remains poorly understood.

Methods

We analyzed publicly available RNA-seq data across various representative immune models to identify signature pathways of Tfh cells. Subsequently, we generated T-cell-specific Mek1/2 knockout mice and investigated the functional phenotypes through Tfh cell polarization, adoptive transfer, and flow cytometry assays. Next, we employed multi-omics sequencing and overexpression experiments to delineate the underlying mechanisms of cellular phenotypes. Finally, by integrated analysis of scRNA-seq datasets combined with MEK inhibitor intervention studies, we elucidated the anti-tumor humoral responses of MEK inhibitors in both murine tumor models and TCGA-SKCM patient cohort.

Results

Mitogen-activated protein kinase kinase 1/2 (MEK1/2) signaling was identified as a potential regulator of Tfh cells and antitumor humoral response. Codeletion or pharmacological inhibition of MEK1/2 effectively promoted Tfh cell development in vitro and in vivo. Mechanistically, ATAC-seq and RNA-seq integrative analysis revealed interferon regulatory factor 4 (IRF4)-dependent epigenetic modulation of characteristic Tfh cell genes, thereby driving Tfh differentiation. Overexpression of Irf4 counteracted Mek1/2 ablation-mediated Tfh cell generation. Moreover, MEK1/2 inhibitor therapy enhanced Tfh infiltration coupled with humoral immune responses in murine melanoma model and was correlated with favorable clinical prognosis in melanoma patients.

Conclusions

Our study revealed the MEK1/2-IRF4 axis potentiates Tfh development to enhance the antitumor humoral response. These findings may provide an unprecedented strategy to improve antitumor immunotherapy efficacy by harnessing humoral immune responses.