Dihydroartemisinin (DHA) exhibits a direct antitumor effect in various tumor models. However, the mechanism of DHA inducing ferroptosis and activating antitumor immunity remains obscure. Therefore, our study was dedicated to investigate the effect of DHA on ferroptosis and tumor microenvironment and elucidate the underlying molecular mechanism. PDAC orthotopic tumor model was used to investigate tumor proliferation and the population of immune cell in vivo, including M2-type macrophages (M2), myeloid-derived suppressor cells (MDSCs), CD4+T cells, CD8+T cells, NK cells and NKT cells. Levels of GPX4, SLC7A11, P53 and ALOX12 were determined by Real-time PCR and Western blot. CCK8 assay was performed to detect cell viability, and the ferroptosis was distinguished by flow cytometry. Our results showed that DHA inhibited pancreatic cancer cell proliferation. In addition, DHA induced cell ferroptosis by up-regulating the expression of P53 and ALOX12, which was blocked by baicalein (a selective ALOX12 inhibitor). However, DHA also up-regulated the expression of GPX4 and SLC7A11. On the other hand, DHA significantly decreased the suppressive expansion of M2 and MDSCs. Moreover, DHA increased the immune cell population of CD8+T cells, NK cells and NKT cells in the tumor tissues of the tumor-bearing mice. Whereas, the DHA treatment did not affect the frequencies of M2, MDSCs, CD4+T, CD8+T, NK and NKT cells in the spleen. Our research provided experimental evidences on the activity and mechanism of ferroptosis induced by DHA and revealed that DHA regulated tumor local immunosuppressive microenvironment.
Keywords: Dihydroartemisinin; Ferroptosis; M2; MDSCs; NK; NKT; Pancreatic cancer.
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