Tumor-Targeted Delivery of PD-1-Displaying Bacteriophages by Escherichia coli for Adjuvant Treatment of Colorectal Cancer.

Abstract

Bacteriophages, leveraging phage display and chemical modification, have the potential to deliver large payloads of antitumor agents with precision and to advance vaccine development. However, systemic phage administration often induces neutralizing antibodies, which accelerate phage clearance and reduce accumulation at the target site. To address this limitation, we propose a genetically modified nonpathogenic bacterial strain that specifically targets tumors and releases programmed death ligand 1 (PD-L1)-specific M13 bacteriophage within tumor tissue. We assessed the antitumor efficacy of this phage-expressing strain as an adjunctive therapeutic strategy along with a therapeutic bacterial strain engineered for the controlled release of an immunotoxin. The combination of these strains demonstrated synergistic effects in eliciting antitumor immune responses and inhibiting tumor growth in a murine model of colorectal cancer (CRC). Moreover, when combined with Folfox, the phage-expressing strain significantly extended the survival. This strategy of in vivo expression and tumor-specific release mediated by nonpathogenic bacterial strains provides an effective and safe method for targeted therapeutic phage delivery to tumors.