Engineering bioluminescent bacteria to boost photodynamic therapy and systemic anti-tumor immunity for synergistic cancer treatment

The limited penetration depth of external excitation light would remarkably impair the therapeutic efficacy of photodynamic therapy (PDT) and its clinical utilization. Herein, we engineered bioluminescent bacteria by transforming attenuated Salmonella typhimurium strain delta ppGpp (S.T.(delta ppGpp)) with firefly-luciferase-expressing plasmid (Luc-S.T.(delta ppGpp)) as an internal light source to evenly illuminate whole tumors. Upon being fixed inside tumors with in-situ formed hydrogel, the colonized Luc-S.T.(delta ppGpp) together with D-luciferin could continuously generate light to excite photosensitizer chlorin e6 (Ce6), leading to effective suppression of different types of tumors including opaque melanoma and large rabbit tumors. Such bioluminescence-triggered PDT presented significant advantages over conventional PDT excited with an external 660-nm light, which at a much high light energy could only slightly retard the growth of small subcutaneous tumors. Furthermore, we uncovered that Luc-S.T.(delta ppGpp) boosted PDT could also elicit potent antitumor immunity post the treatment to inhibit tumor metastasis and prevent tumor challenge. Therefore, this work highlights that such bioluminescent bacteria boosted PDT is a general and highly effective therapeutic approach toward diverse cancers with varying light-absorbing capacities and tumor sizes, promising for potential clinical translation because of their acceptable safety profiles.

Automated summary

This study developed bioluminescent bacteria as an internal light source to enhance photodynamic therapy (PDT). The bioluminescence-triggered PDT showed significant advantages over conventional PDT and could also induce potent antitumor immunity. This research provides a general and highly effective therapeutic approach for diverse cancers with varying light-absorbing capacities and tumor sizes.