Cell-penetrating TIPE2 peptide effectively suppresses tumor migration and progression via targeting RAC1.

Metastasis is the leading cause of cancer-related death and a major challenge in clinical cancer therapy. Insufficient cell membrane permeability of therapeutic proteins severely hinders the clinical transformation of promising anti-tumor targets. As a native negative immune regulator, TIPE2 participates extensively in inflammatory immunity, cellular metabolism and tumor immunity, holding great potential for anti-tumor targeted therapy. Herein, we constructed a cell-penetrating fusion peptide 9R-TIPE2, composed of the 9R cell-penetrating sequence and the α0 domain of TIPE2 protein. 9R-TIPE2 efficiently penetrates cell membranes into the cytoplasm, with definite intracellular metabolic characteristics and no obvious cytotoxicity. It recapitulates the function of endogenous TIPE2 to promote nutrient deprivation-induced tumor cell death, and markedly inhibits the migration of HepG2 and A549 cells by suppressing RAC1-mediated F-actin polymerization and the mTOR signaling pathway. Furthermore, in vivo xenograft experiments confirmed that 9R-TIPE2 effectively inhibits the metastasis of A549 tumors in nude mice. Collectively, 9R-TIPE2 possesses favorable membrane permeability and biosafety, exerts intact biological functions to induce starvation-related tumor cell death and suppress tumor migration both in vitro and in vivo, and is a potent candidate for TIPE2-targeted therapy against hepatocellular carcinoma, lung cancer and other malignancies.