TNF-α is up-regulated in a chronic inflammatory environment, including tumors, and has been recognized as a pro-tumor factor in many cancers. Applying the traditional TNF-α antibodies that neutralize the TNF-α activity, however, only exerts modest anti-tumor efficacy in the clinical studies. Here, we develop an innovative approach to target TNF-α that is distinct from the neutralization mechanism. We employed phage display and yeast display to select non-neutralizing antibodies that can piggyback on TNF-α and co-internalize into cells through the receptor ligation. When conjugating with toxins, the antibody exhibited cytotoxicity to cancer cells in a TNF-α-dependent manner. We further implemented the immunotoxin to an E. coli vehicle specially engineered for a high secretion level. In a syngeneic murine melanoma model, the bacteria stimulated the TNF-α expression that synergized with the secreted immunotoxin and greatly inhibited the tumor growth. The treatment also dramatically remodeled the tumor microenvironment in favor of several anti-tumor immune cells, including the N1 neutrophils, the M1 macrophages, and the activated CD4 and CD8 lymphocytes. We anticipate that our new piggyback strategy is generalizable to target other soluble ligands and/or conjugate with different drugs for managing a diverse set of diseases.