Antibiotic-drug conjugates: Enhancing chemo-immunotherapy of gemcitabine for pancreatic cancer by eliminating intratumoral bacteria.

Abstract

Pancreatic cancer has a dismal five-year survival rate of only ∼13%, owing to its insidious onset, rapid progression, and frequent primary or acquired resistance to gemcitabine (Gm). Moreover, intratumoral bacteria capable of expressing cytidine deaminase (CDD) can undermine the therapeutic efficacy of Gm and contribute to chemoresistance. To address this challenge, antibiotic-drug conjugates (AiDCs, Tob-SS-Gm NPs) were developed by covalently linking tobramycin (Tob) and Gm via disulfide bonds. Tob-SS-Gm NPs retained antibacterial activity against E. coli and chemotherapeutic activity in Panc02 cells, indicating that the conjugation preserves the functional properties of both components. Meanwhile, disulfide linkage enables these AiDCs to remain stable under physiological conditions while undergoing cleavage in the high GSH tumor microenvironment, thereby releasing Tob and Gm for coordinated antibacterial and antitumor effects. In vivo evaluation demonstrated that Tob-SS-Gm NPs effectively reduced intratumoral bacterial burden and were associated with improved therapeutic response to Gm under bacteria-colonized tumor conditions. Furthermore, bacterial elimination and tumor cell damage were accompanied by modulation of the tumor immune microenvironment, including enhanced dendritic cell maturation and increased cytotoxic CD8⁺ T-cell infiltration. Collectively, this AiDCs strategy provides a promising approach for the treatment of intratumoral bacteria-associated, drug-resistant malignancies.