In this study, we show that resveratrol down-regulates CRC cell survival, colony formation, invasion and activation of CSC cells by targeting T-lymphocytes/fibroblasts and NF-κB signaling induced by TNF-β- or multicellular-TME, but not by Sirt1-ASO, pointing to the central role of this enzyme in the anti-tumor function of resveratrol in the suppression of cross-talk in pro-inflammatory multicellular-TME. The gene discussed is SIRT1; the disease is colorectal carcinoma.