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<p>Colorectal cancer (CRC) is one of the most prevalent malignancies worldwide, and liver metastases stands as a leading contributor to its high mortality rate in advanced stages. Regorafenib plus anti-PD-1 is a new therapeutic option for patients with colorectal cancer liver metastases (CRCLM). However, a considerable number of patients have not benefited from it. In this study, <i>KRAS</i> mutation was identified associated with resistance to regorafenib plus anti-PD-1 in CRCLM. Dihydroartemisinin (DHA), a clinically approved anti-malaria agent, was verified to selectively downregulate KRAS<sup>G12D</sup> mutant with no discernible influences on wild-type KRAS, which is consistent with the higher sensitivity of <i>KRAS</i>-mutant CRC cells and organoids to DHA treatment. In preclinical <i>KRAS</i><sup>G12D</sup> CRCLM models, DHA substantially potentiated the therapeutic efficacy of regorafenib plus anti-PD-1 by remodeling the tumor immune microenvironment, including enhancing the cytotoxicity of CD8<sup>+</sup> effector T cells and promoting pro-inflammatory macrophage polarization. Mechanically, DHA could restore interferon response that was impaired by oncogenic <i>KRAS</i> mutations, and inhibit ERBB signaling activation induced by regorafenib. Collectively, these findings support DHA as a potential adjunct to regorafenib plus anti-PD-1 for <i>KRAS</i><sup>G12D</sup> CRCLM and suggest a therapeutic strategy with translational potential for <i>KRAS</i>-driven malignancies.</p><p></p>

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Dihydroartemisinin inhibits mutant KRAS to potentiate regorafenib plus anti-PD-1 in KRAS-mutant colorectal cancer liver metastases

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月6日

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  • Ning Huang,
  • Liming Wang,
  • Hongming Deng,
  • Chenyang Nan,
  • Zhenbang Ye,
  • Changchun Zhou,
  • Jiajun Zhang,
  • Ruoyu Zhang,
  • Ke Xu,
  • Jianxiong Wu,
  • Rui Liu,
  • Mei Liu

摘要

Colorectal cancer (CRC) is one of the most prevalent malignancies worldwide, and liver metastases stands as a leading contributor to its high mortality rate in advanced stages. Regorafenib plus anti-PD-1 is a new therapeutic option for patients with colorectal cancer liver metastases (CRCLM). However, a considerable number of patients have not benefited from it. In this study, KRAS mutation was identified associated with resistance to regorafenib plus anti-PD-1 in CRCLM. Dihydroartemisinin (DHA), a clinically approved anti-malaria agent, was verified to selectively downregulate KRASG12D mutant with no discernible influences on wild-type KRAS, which is consistent with the higher sensitivity of KRAS-mutant CRC cells and organoids to DHA treatment. In preclinical KRASG12D CRCLM models, DHA substantially potentiated the therapeutic efficacy of regorafenib plus anti-PD-1 by remodeling the tumor immune microenvironment, including enhancing the cytotoxicity of CD8+ effector T cells and promoting pro-inflammatory macrophage polarization. Mechanically, DHA could restore interferon response that was impaired by oncogenic KRAS mutations, and inhibit ERBB signaling activation induced by regorafenib. Collectively, these findings support DHA as a potential adjunct to regorafenib plus anti-PD-1 for KRASG12D CRCLM and suggest a therapeutic strategy with translational potential for KRAS-driven malignancies.