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<p>Immunotherapy has become a promising treatment for various cancers, including colorectal cancer (CRC). Despite significant progress, identifying immune cell-specific therapeutic targets remains challenging, especially for CD4<sup>+</sup> T cells, whose activation influences both anti-tumor and pro-tumor immune responses. This study aims to identify potential immunotherapy targets for CRC by exploring the causal relationships between CD4<sup>+</sup> T cell activation-associated genes and CRC through Mendelian randomization (MR) and single-cell RNA sequencing (scRNA-seq). We used transcriptome-wide MR, summary-based MR (SMR), and colocalization analysis, along with validation through multi-omics approaches, to identify 28 dynamic CD4<sup>+</sup> T cell-related genes as therapeutic targets. Notably, PARP14 and ORMDL3 emerged as key targets, with strong associations to immune therapy resistance and CRC. This research highlights the critical role of CD4<sup>+</sup> T cell activation in CRC progression and identifies novel potential targets for immunotherapy.</p>

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Transcriptome-wide Mendelian randomization and single-cell analysis during CD4+ T cell activation deciphers immunotherapeutic targets for colorectal cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月29日

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  • Kai Cui,
  • Qiuming Zou,
  • Xinyi Qu,
  • Yu Yan,
  • Meishan Lu,
  • Xiaofeng Zhou,
  • Lili Liu,
  • Yitong Shen,
  • Shihan Wang,
  • Xiaosong Zhuang,
  • Jinxuan Su,
  • Baifu Qin,
  • Wencai Ye,
  • Qi Qi

摘要

Immunotherapy has become a promising treatment for various cancers, including colorectal cancer (CRC). Despite significant progress, identifying immune cell-specific therapeutic targets remains challenging, especially for CD4+ T cells, whose activation influences both anti-tumor and pro-tumor immune responses. This study aims to identify potential immunotherapy targets for CRC by exploring the causal relationships between CD4+ T cell activation-associated genes and CRC through Mendelian randomization (MR) and single-cell RNA sequencing (scRNA-seq). We used transcriptome-wide MR, summary-based MR (SMR), and colocalization analysis, along with validation through multi-omics approaches, to identify 28 dynamic CD4+ T cell-related genes as therapeutic targets. Notably, PARP14 and ORMDL3 emerged as key targets, with strong associations to immune therapy resistance and CRC. This research highlights the critical role of CD4+ T cell activation in CRC progression and identifies novel potential targets for immunotherapy.