Mechanistically, we show that IL-17R–ACT1 and IL-22R–STAT3 signaling pathways converge to the key negative regulator C/EBPβ to inhibit chemokine expression in colon epithelial cells, which prevents the pathologic breakdown of epithelial barrier in inflammatory colitis and colon cancer development. Here, STAT3 is linked to malignant colon neoplasm.