We demonstrated a new pharmacological function of phytogalatolipids isolated from plant medicine Crassocephalum rabens on dominant anti-tumor humoral responses. Phytogalatolipids effectively inhibit tumor growth in colorectal tumor allograft mice and attract massive B cells into the tumor. Phytogalatolipids induce B cell differentiation in spleens and tumors, resulting in high titers of antitumor antibodies in serum. Galactolipids-induced antitumor antibodies specifically recognize surface antigens on the plasma membrane of cancer cells and trigger stronger antibody-dependent cytotoxicity, including antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC). We discovered that these galactolipids can interact with IL-6 receptors on T cells, activate STAT3 and cMaf, and cause T cells to secrete IL-21, which in turn induces B cell differentiation through the IL-21R/STAT3/Blimp-1 pathway. Therefore, galactolipids induce B cell activation in a T cell-dependent manner and trigger antitumor antibodies, thereby preventing the progression of colorectal cancer. This research suggests that galactolipid-induced humoral immunity may be a new and effective immunotherapy for colorectal cancer.