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.