Tumor-associated carbohydrate antigens (TACAs) are attractive targets for vaccine development. In this context, we described a strategy combining artificial TACA and glycoengineering for cancer vaccine devel-opment. A 2,4-ditrophenyl (DNP)-modified GM3 intermediate was synthesized chemoenzymatically and conjugated to keyhole limpet hemocyanin (KLH), and the resulting bioconjugate was tested for its po-tential as a vaccine candidate. Mice immunological studies revealed that the DNP-modified GM3 (GM3-NHDNP) analog elicited strong and rapid immune responses by recruiting anti-DNP antibodies to facilitate the targeted delivery of the vaccine construct to antigen processing cells (APCs). Moreover, the endoge-nously produced anti-DNP antibodies, together with the elicited antibodies against GM3-NHDNP, may synergistically promote tumor binding and cancer cell death when the cancer cell surfaces are glycoengi-neered to express the GM3-NHDNP antigen.