Finally, we present data indicating that “normalization” of the tumor microenvironment by vitamin D3, a potent chemopreventive agent, restores the sensitivity of colon cancer cells to TRAIL, suggesting that the therapeutic efficiency of TRAIL may be greatly improved by agents that inhibit the crosstalk between tumor cells and the tumor microenvironment. The gene discussed is TNFSF10; the disease is malignant colon neoplasm.