JP1 normalizes tumor vasculature to suppress metastasis and facilitate drug delivery by inhibiting IL8.

Tumor vascular normalization prevents tumor cells from breaking through the basement membrane and entering the vasculature, and then inhibiting metastasis initiation. In this study, we reported that the anti-tumor peptide JP1 regulates the mitochondria metabolic reprogramming through AMPK/FOXO3a/UQCRC2 signaling, which improves the tumor microenvironment hypoxia. The oxygen-rich tumor microenvironment inhibits the secretion of interleukin-8 (IL8) by tumor cells, thereby promoting tumor vascular normalization. The normalized vasculature results in mature and regular blood vessels, which makes the tumor microenvironment form benign feedback of vascular normalization, sufficient perfusion, and oxygen-rich microenvironment, prevents tumor cells from entering the vasculature and inhibits metastasis initiation. Moreover, the combined therapy of JP1 and paclitaxel (PTX) maintain a certain vascular density in the tumor, as well as promoting tumor vascular normalization, increasing the delivery of oxygen and drugs, and enhancing the anti-tumor effect. Collectively, our work highlighted a novel anti-tumor peptide JP1 to inhibit metastasis initiation and its mechanism of action.