Uncovering cantharidin's mechanism for cholangiocarcinoma treatment using patient-derived tumor organoids.

This study investigates the antitumor efficacy of cantharidin against cholangiocarcinoma (CCA) using patient-derived organoids (PDOs) that faithfully replicate the histological and genomic features of original tumors. Results demonstrate that cantharidin effectively inhibits CCA PDO growth, showing comparable or superior efficacy to conventional chemotherapeutics such as cisplatin, though slightly less potent than gemcitabine or Adriamycin. Critically, drug sensitivity in PDOs correlated perfectly with clinical responses in five patients, validating the model's predictive relevance. Mechanistic studies revealed that cantharidin suppresses proliferation and induces apoptosis primarily through downregulation of the p-ERK1/2-c-Fos signaling pathway, both in vitro and in patient-derived organoids-based xenografts. These effects were reversible upon treatment with a p-ERK agonist, confirming pathway specificity. The study highlights cantharidin's potential as a targeted therapeutic agent in CCA and underscores the utility of PDOs in personalized drug screening and mechanistic investigation.