Among bacteria used as anticancer vaccines, attenuated Listeria monocytogenes (Lmat) stands out because it spreads from one infected cancer cell to the next, induces a strong adaptive immune response, and is suitable for repeated injection cycles. Here we use click chemistry to functionalize the Lmat cell wall and turn the bacterium into an “intelligent carrier” of the chemotherapeutic drug doxorubicin. Doxorubicin-loaded Lmat retains most of its biological properties and has enhanced cytotoxicity against melanoma cells compared to the control fluorophore-functionalized bacteria. Our results provide the first demonstration of a two-in-one therapeutic approach that in principle combines immunotherapy with chemotherapy through the covalent loading of Lmat cell wall with the drug of interest.