Thiostrepton suppresses intrahepatic cholangiocarcinoma progression via FOXM1-mediated tumor-associated macrophages reprogramming

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• Thiostrepton (TST) effectively inhibited the proliferation and metastasis of intrahepatic cholangiocarcinoma (ICC) cells by targeting FOXM1. • TST reprogrammed tumor-associated macrophages (TAMs) towards the M1 phenotype, promoting anti-tumor immune responses in ICC. • Utilizing murine ICC cells innovatively for constructing a mouse tumor model, TST significantly reduced tumor burden in mouse models, highlighting its potential as a novel therapeutic strategy for ICC patients. Intrahepatic cholangiocarcinoma (ICC) is an aggressive cancer with an extremely poor prognosis, highlighting the urgent need for new treatment options. Recent studies increasingly suggest that the Forkhead box M1 (FOXM1) transcription factor may serve as a candidate target for cancer immunotherapy. However, its role and the underlying molecular mechanisms in ICC remain not fully understood. Here, we identify thiostrepton (TST) as a potent FOXM1 inhibitor, capable of exerting “dual anti-tumor” effects in ICC. On one hand, TST effectively suppresses tumor cell proliferation and metastasis. On the other hand, TST treatment improves the tumor immune microenvironment by reprogramming tumor-associated macrophages (TAMs), thereby enhancing anti-tumor immune responses. Mechanistically, TST directly alleviates ICC progression by arresting the cell cycle, promoting apoptosis, and inhibiting the epithelial-mesenchymal transition (EMT) process. Furthermore, TST-treated tumor cells secrete cytokines that drive TAMs repolarization toward the tumor-suppressive M1 phenotype. Overall, our results indicate that FOXM1 can serve as a novel target for ICC immunotherapy. By targeting FOXM1, TST exerts “dual anti-tumor” effects and has the potential to become a promising immunotherapy agent for ICC patients.