Abstract
Bacteria-based therapies hold great promise for cancer treatment due to their selective tumor colonization and proliferation. However, clinical application is hindered by the need for safe, precise control systems to regulate local therapeutic payload expression and release. Here we developed a near-infrared (NIR) light-mediated PadC-based photoswitch (NETMAP) system based on a chimeric phytochrome-activated diguanylyl cyclase (PadC) and a cyclic diguanylate monophosphate-dependent transcriptional activator (MrkH). The NETMAP-engineered bacteria exhibited antitumor performance in mouse tumor models with different levels of immunogenicity. Specifically, in immunogenic lymphoma tumors, NIR-induced PD-L1 and CTLA-4 nanobodies enhanced the activation of adaptive immunity. In low-immunogenic tumors-including mouse-derived colon cancer models, an orthotopic human breast cancer cell line-derived xenograft model and a colorectal cancer patient-derived xenograft model-NIR-induced azurin and cytolysin A predominantly led to tumor inhibition. Our study identifies an NIR light-mediated therapeutic platform for engineered bacteria-based therapies with customizable outputs and precise dosage control.
Overview
- The study develops a near-infrared (NIR) light-mediated PadC-based photoswitch (NETMAP) system for safe and precise control of local therapeutic payload expression and release in bacteria-based therapies.
- The system is engineered with a chimeric phytochrome-activated diguanylyl cyclase (PadC) and a cyclic diguanylate monophosphate-dependent transcriptional activator (MrkH) to regulate the expression of different proteins in response to NIR light.
- The study aims to overcome the limitations of current bacteria-based therapies by providing a customizable platform with precise dosage control and tunable therapeutic output.
Comparative Analysis & Findings
- The study demonstrates the antitumor performance of NETMAP-engineered bacteria in mouse tumor models with different levels of immunogenicity.
- In immunogenic lymphoma tumors, NIR-induced PD-L1 and CTLA-4 nanobodies enhanced the activation of adaptive immunity, whereas in low-immunogenic tumors, NIR-induced azurin and cytolysin A primarily led to tumor inhibition.
- The study shows that the NETMAP system can be fine-tuned to produce different therapeutic outcomes depending on the specific biological context and target.
Implications and Future Directions
- The NIR light-mediated therapeutic platform for engineered bacteria-based therapies has the potential to revolutionize cancer treatment by providing a safe, precise, and customizable approach.
- Future studies can investigate the mechanisms underlying the therapeutic effects of NETMAP-engineered bacteria and explore their potential applications in various cancer types and treatment settings.
- The development of new photoswitches and protein engineering strategies could further enhance the capabilities of the NETMAP system and expand its therapeutic potential.