Dihydroartemisinin restrains angiogenesis through the TNF-α pathway to enhance the efficacy of anti-PD-1 immunotherapy in breast cancer

Tumor vascular abnormality promotes the formation of immunosuppressive microenvironment, thus limiting the efficacy of tumor immunotherapy and promoting tumor development. Dihydroartemisinin (DHA) has shown potential as an anti-tumor agent. The potential role of its anti-angiogenic effect has not yet been discovered. This research investigates whether DHA inhibits tumor-induced angiogenesis, promotes immunotherapy and explored the underlying mechanism. The promoting effect of 4T-1 cell-conditioned media (CM) on SVEC4-10 activity and tube formation can be reversed by DHA-treated with CM. Consistently, following DHA administration in a breast cancer mouse model, the number of transplanted tumor vessels was markedly reduced and perivascular cells increased. Subsequently, in vivo administration of DHA evidently promoted inhibitory effect of anti-PD-1 in tumor and reversed the infiltration of T cells and the phenotypes of macrophages. Network pharmacology and RNA-seq analysis revealed that DHA inhibit tumor growth by angiogenesis through the TNF-α pathway. Besides, TNF-α cytokine replenishment experiment and the expression of key molecules involved signaling pathway confirmed the above mechanism. In conclusion, DHA alleviates tumor cell-induced abnormal blood vessels through TNF-α pathway, which contributes to the anti-PD-1 efficacy of tumors.