This study explores the use of prodrugs as an alternative to conventional chemotherapy for targeted cancer therapy. The researchers identified a strain of *Lactobacillus plantarum* (Lp) that specifically binds to nasopharyngeal carcinoma (NPC) cells through heparan sulfate recognition mediated by its OppA protein. The engineered Lp strain was modified to display streptavidin on its surface, enabling the loading of biotinylated prodrugs, which can be activated by tumor-associated biosignals to release the chemotherapy agent SN-38 near NPC cells. In vitro experiments showed that the prodrug-loaded microbes significantly increased the potency of SN-38 against NPC cell lines, up to 10-fold. In a mouse xenograft model, intravenous injection of the engineered Lp led to bacterial colonization in NPC tumors and a 67% inhibition in tumor growth, enhancing the efficacy of SN-38 by 54%. This approach leverages the inherent interactions between bacteria and cancer cells within the tumor microbiome, providing a precise and targeted delivery system for prodrugs, with potential applications in various cancers.This study explores the use of prodrugs as an alternative to conventional chemotherapy for targeted cancer therapy. The researchers identified a strain of *Lactobacillus plantarum* (Lp) that specifically binds to nasopharyngeal carcinoma (NPC) cells through heparan sulfate recognition mediated by its OppA protein. The engineered Lp strain was modified to display streptavidin on its surface, enabling the loading of biotinylated prodrugs, which can be activated by tumor-associated biosignals to release the chemotherapy agent SN-38 near NPC cells. In vitro experiments showed that the prodrug-loaded microbes significantly increased the potency of SN-38 against NPC cell lines, up to 10-fold. In a mouse xenograft model, intravenous injection of the engineered Lp led to bacterial colonization in NPC tumors and a 67% inhibition in tumor growth, enhancing the efficacy of SN-38 by 54%. This approach leverages the inherent interactions between bacteria and cancer cells within the tumor microbiome, providing a precise and targeted delivery system for prodrugs, with potential applications in various cancers.