Light-promoted engineered bacterial DNase I therapeutic intervention to enable potent cancer photoimmunotherapy

Bacteria are emerging as a promising tool for targeted cancer therapy due to their innate tumor-homing ability, high mobility, and capacity to rapidly colonize in the tumor microenvironment (TME). However, bacterial cancer therapy (BCT) alone has not proven fully effective. Herein, we present an innovative bio-therapeutic system, TEPy@VNP-D, which integrates genetically engineered Salmonella typhimurium VNP20009 carrying humanized DNase I toxin plasmids (VNP-D) with an aggregation-induced emission photosensitizer (TEPy), enabling photoimmunotherapy for melanoma. Leveraging the tumor-targeting properties of VNP20009, TEPy@VNP-D ensures effective delivery of both TEPy and DNase I to tumor sites, promoting the intratumoral accumulation of cytotoxic agents. Upon light activation, TEPy@VNP-D not only disrupts bacterial structures, facilitating plasmid release but also directly kills cancer cells through the generation of cytotoxic reactive oxygen species. Accordingly, the synergistic effects of photodynamic therapy (PDT) from TEPy and tumor lysis by VNP-D result in significant tumor suppression. Furthermore, TEPy@VNP-D enhances both innate and adaptive immune responses by triggering immunogenic cell death and remodeling the immunosuppressive TME. When combined with anti-PD-L1 antibody, TEPy@VNP-D elicits remarkable synergistic effects under light irradiation, effectively eliminating distant abscopal tumors and establishing robust immune memory to prevent recurrence and rechallenge. Together, the TEPy@VNP-D-mediated BCT synergized photoimmunotherapy strategy offers a powerful, tailored approach to cancer treatment, achieving cooperative antitumor activity with reduced toxicity. This promising approach holds great potential for advancing combination cancer therapies.