trans-Scirpusin A (TSA) is a resveratrol oligomer found in Borassus flabellifer L.. We found that TSA inhibited the growth of colorectal cancer Her2/CT26 cells in vivo in mice. There was a significant increase in the level of TNF-a mRNA in tumor tissue and Her2-specific Ab production. More importantly, we found that TSA overcomes the tumor-associated immunosuppressive microenvironment by reducing the number of CD25+FoxP3+regulatory T cells and myeloid-derived suppressor cells. We detected the induction of autophagy in TSA-treated Her2/CT26 cells, based on the increased level of the mammalian autophagy protein LC3 puncta, and increased conversion of LC3-I to LC3-II. Further, TSA induced 5' AMP-activated protein kinase (p-AMPK) and inhibited mammalian target of rapamycin complex 1 activity as estimated by phosphorylated ribosomal protein S6 kinase beta-1 levels, thereby suggesting that TSA-mediated AMPK activation and inhibition of mTORC1 pathway might be associated with autophagy induction. Activation of autophagy by TSA resulted in cell death of Her2/CT26 cells via apoptosis, as inferred by the increased sub-G1 mitotic phases in these cells, Annexin V/PI-double positive results, and TUNEL-positive cells. Therefore, we propose the use of TSA for supplementary anticancer therapy to support anti-neoplastic drugs, such as docetaxel, by inducing apoptosis in cancer cells and resulting in the induction of neighborhood anti-cancer immunity.