Dihydroartemisinin inhibits mutant KRAS to potentiate regorafenib plus anti-PD-1 in KRAS-mutant colorectal cancer liver metastases.
An inexpensive antimalarial drug restores immune activity in hard-to-treat colon cancers, opening doors for combination therapy approaches.
This study demonstrated that dihydroartemisinin (DHA) specifically degrades KRASG12D mutant protein via autophagy-lysosome pathway, thereby restoring interferon response and enhancing anti-PD-1 immunotherapy efficacy in KRAS-mutant colorectal cancer liver metastases. Combining DHA with regorafenib plus anti-PD-1 remodeled the tumor immune microenvironment in preclinical KRASG12D CRCLM models, providing mechanistic rationale for clinical translation of this approved antimalarial.
What the study was
- Study design
- preclinical
- Category
- targeted therapy / drug repurposing
- Maturity
- Exploratory
- Journal
- Cell Death and Disease
Why it surfaced
Drug repurposing with strong mechanistic basis: DHA selectively targets KRASG12D (most common KRAS mutation in CRC, ~40%) and overcomes key resistance mechanism to PD-1 blockade. Patient-derived organoids and mouse models provide translational support. Combination includes two clinically approved drugs.
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