BACKGROUND: Interleukin 13 receptor alpha2 (IL13Ralpha2) is overexpressed in metastatic colorectal cancer. Here, we have developed novel strategies to block IL-13 binding to IL13Ralpha2 in order to reduce metastatic spread. METHODS: Synthetic IL13Ralpha2 D1 peptide (GSETWKTIITKN) was tested for the inhibition of IL-13 binding to IL13Ralpha2 using ELISA and different cellular assays. Peptide blocking effects on different cell signalling mediators were determined by western blot. An enantiomer version of the peptide (D-D1) was prepared to avoid proteolytic digestion. Nude mice were used for tumour growth and survival analysis after treatment with IL13Ralpha2 peptides. RESULTS: IL13Ralpha2 D1 peptide inhibited migration, invasion, and proliferation in metastatic colorectal and glioblastoma cancer cells treated with IL-13. Residues (82)K, (83)T, (85)I and (86)T were essential for blocking IL-13. IL13Ralpha2 peptide abolished ligand-mediated receptor internalisation and degradation, and substantially decreased IL-13 signalling capacity through IL13Ralpha2 to activate the FAK, PI3K/AKT and Src pathways as well as MT1-MMP expression. In addition, D1 significantly inhibited IL-13-mediated STAT6 activation through IL13Ralpha1. Nude mice treated with the enantiomer D-D1 peptide showed a remarkable survival increase. CONCLUSIONS: We propose that the D-D1 peptide from IL13Ralpha2 represents a promising therapeutic agent to inhibit metastatic progression in colorectal cancer and, likely, other solid tumours.