aspA promoter as a tumor microenvironment-responsive autoswitch for anticancer agent expression in Escherichia coli
- 1Division of Biomedical Convergence, College of Biomedical Science, Kangwon National University, Chuncheon, 24341 Republic of Korea
- 2Department of Bioscience and Biotechnology, Hankuk University of Foreign Studies, Yongin, 17035 Republic of Korea
Abstract
Bacterial cancer therapy has emerged as a promising strategy for the local delivery of anticancer agents to solid tumors because bacteria preferentially colonize the tumor microenvironment (TME). However, strategies for exploiting metabolic features of the TME to achieve tumor-selective expression of anticancer agents remain limited. Here, we present a tumor-responsive gene expression system in Escherichia coli for tumor-selective expression of the recombinant immunotoxin psp-TGFa-PE38 (TP), exploiting its intrinsic ability to sense metabolic cues in the TME. To identify such TME-associated metabolic cues, we examined tumor metabolites in CT26 tumor-bearing mice and confirmed that tumors contained > 3-fold lower glucose and > 5-fold higher fumarate levels than those in the liver. In response to this nutrient heterogeneity, E. coli upregulated genes involved in fumarate respiration, including frdA, dctA, dcuB, and aspA, in the DcuSR regulon. aspA was most upregulated (65-fold) in tumors, which is indicative of the strongest activity of its promoter in the TME. We used the aspA promoter (PaspA) as a tumor-specific switch to control TP expression, targeting secreted functional TP and inducing cytotoxicity in vitro. TP was specifically expressed by PaspA in tumors, reducing the tumor size by 2.8-fold and extending survival by 35 days in vivo. Overall, these results suggest that the potential of PaspA as a tumor-specific expression system.
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s13036-026-00743-9.
Related
- Ultrasound-responsive nanoplatforms for cancer immunotherapy: engineering spatiotemporal immune activation in the tumor microenvironment
- Pathological microenvironment-responsive nano-glycospheres restore disc homeostasis by combinatorial metabolic and genetic regulation.
- Cell cycle regulated expression of NCoR might control cyclic expression of androgen responsive genes in an immortalized prostate cell line
- Silicon Modulates the Expression of Copper-Responsive Transporters and Non-Coding RNAs in Cucumber Subjected to Copper Stress
- Genome-Wide Identification of the BhKCS Gene Family in Wax Gourd (Benincasa hispida) and Stress-Responsive Expression of BhKCS8/9/14/15
BibTeX
@article{lee2026aspa,
title = {{aspA promoter as a tumor microenvironment-responsive autoswitch for anticancer agent expression in Escherichia coli}},
author = {Dogeun Lee and Seyeon Hong and Jihyeon Kim and Miryoung Song and Daejin Lim},
journal = {Journal of Biological Engineering},
year = {2026},
month = jul,
doi = {10.1186/s13036-026-00743-9},
url = {https://doi.org/10.1186/s13036-026-00743-9},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - aspA promoter as a tumor microenvironment-responsive autoswitch for anticancer agent expression in Escherichia coli
AU - Dogeun Lee
AU - Seyeon Hong
AU - Jihyeon Kim
AU - Miryoung Song
AU - Daejin Lim
PY - 2026
DA - 2026/07/31
JO - Journal of Biological Engineering
DO - 10.1186/s13036-026-00743-9
UR - https://doi.org/10.1186/s13036-026-00743-9
AB - Bacterial cancer therapy has emerged as a promising strategy for the local delivery of anticancer agents to solid tumors because bacteria preferentially colonize the tumor microenvironment (TME). However, strategies for exploiting metabolic features of the TME to achieve tumor-selective expression of anticancer agents remain limited. Here, we present a tumor-responsive gene expression system in Escherichia coli for tumor-selective expression of the recombinant immunotoxin psp-TGFa-PE38 (TP), exploiting its intrinsic ability to sense metabolic cues in the TME. To identify such TME-associated metabolic cues, we examined tumor metabolites in CT26 tumor-bearing mice and confirmed that tumors contained > 3-fold lower glucose and > 5-fold higher fumarate levels than those in the liver. In response to this nutrient heterogeneity, E. coli upregulated genes involved in fumarate respiration, including frdA, dctA, dcuB, and aspA, in the DcuSR regulon. aspA was most upregulated (65-fold) in tumors, which is indicative of the strongest activity of its promoter in the TME. We used the aspA promoter (PaspA) as a tumor-specific switch to control TP expression, targeting secreted functional TP and inducing cytotoxicity in vitro. TP was specifically expressed by PaspA in tumors, reducing the tumor size by 2.8-fold and extending survival by 35 days in vivo. Overall, these results suggest that the potential of PaspA as a tumor-specific expression system. Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s13036-026-00743-9.
SN - 1754-1611
ER -