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

Abstract 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 KRAS G12D 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 KRAS G12D 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 KRAS G12D CRCLM and suggest a therapeutic strategy with translational potential for KRAS -driven malignancies.