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<p>Microsatellite-stable/proficient mismatch repair (MSS/pMMR) colorectal cancer (CRC) is characterized by a cold tumor microenvironment, with limited CD8⁺ T cell infiltration and poor responsiveness to immune checkpoint inhibitors (ICIs). Here, using an in vivo CRISPR/Cas9 screen in a CMT93 cell-derived murine tumor model, we identify <i>Arid3b</i> as a key negative regulator of CD8⁺ T cell infiltration and antitumor activity. Genetic ablation of <i>Arid3b</i> in CD8⁺ T cells significantly enhances their intratumoral accumulation and promotes robust tumor control. Mechanistically, <i>Arid3b</i> deficiency upregulates <i>Runx3</i>, driving a tissue-resident memory-like phenotype and effector function. Notably, the benefits conferred by <i>Arid3b</i> deficiency are abrogated upon <i>Runx3</i> deletion, indicating a RUNX3-dependent mechanism. Together, targeting ARID3B could offer a promising strategy to reshape the tumor microenvironment and sensitize MSS CRC to immunotherapy.</p>

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Arid3b suppresses CD8 + T cell infiltration and function in microsatellite-stable colorectal cancer via Runx3

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月15日

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  • Shuo Wang,
  • Sen Hou,
  • Ce Luo,
  • Haorui Zhang,
  • Yiteng Jin,
  • Rui Zhang,
  • Yanping Zhao,
  • Xiaoyu Xiong,
  • Rui Guo,
  • Chao Wang,
  • Yudi Bao,
  • Liang Wen,
  • Deng Pan,
  • Yingjiang Ye,
  • Zexian Zeng,
  • Zhidong Gao

摘要

Microsatellite-stable/proficient mismatch repair (MSS/pMMR) colorectal cancer (CRC) is characterized by a cold tumor microenvironment, with limited CD8⁺ T cell infiltration and poor responsiveness to immune checkpoint inhibitors (ICIs). Here, using an in vivo CRISPR/Cas9 screen in a CMT93 cell-derived murine tumor model, we identify Arid3b as a key negative regulator of CD8⁺ T cell infiltration and antitumor activity. Genetic ablation of Arid3b in CD8⁺ T cells significantly enhances their intratumoral accumulation and promotes robust tumor control. Mechanistically, Arid3b deficiency upregulates Runx3, driving a tissue-resident memory-like phenotype and effector function. Notably, the benefits conferred by Arid3b deficiency are abrogated upon Runx3 deletion, indicating a RUNX3-dependent mechanism. Together, targeting ARID3B could offer a promising strategy to reshape the tumor microenvironment and sensitize MSS CRC to immunotherapy.