Leveraging bacteria for cancer immunotherapy has gradually attracted wide attention since the discovery of "Cloey's toxin." However, one of the persistent challenges for bacteria-based therapy is striking a balance between safety and immunogenicity. Genetically engineered bacteria with virulence factors removed could further enhance antitumor ability by integrating genetic elements. In addition, bacterial derivatives, including outer membrane vesicles (OMVs) produced by bacterial secretion and nanovesicles synthesized by modification of OMVs, could enhance antitumor immunity while improving safety. This perspective discusses the unique advantages of engineered bacteria and their derivatives for immunotherapy, as well as the challenges that need to be overcome to achieve clinical translation.