Abstract
Bacterial therapeutics hold great promise for cancer treatment by targeting oxygen-poor tumor regions and complementing existing therapies. However, current approaches often struggle with safety concerns and complex engineering. Developing a safe, effective delivery platform relying entirely on natural bacterial biosynthesis remains a challenge. Here we show that attenuated Serratia marcescens serves as a powerful biohybrid platform for cancer therapy by leveraging its natural biosynthesis of prodigiosin, a photosensitive pigment. We engineer S. marcescens to yield high prodigiosin levels, which exhibit strong intrinsic anti-cancer activity and near-infrared photosensitivity. In female mouse models of melanoma and colorectal cancer, this platform triggers robust systemic immune responses, including enhanced T cell recruitment and long-term memory against tumor recurrence. Furthermore, the bacteria induces tumor cell death via mitophagy, while photothermal properties of prodigiosin enables rapid, light-controlled bacterial clearance post-treatment. These findings establish S. marcescens as a versatile, self-regulating biosynthetic platform for precise and safe cancer immunotherapy.
Data availability
The mass spectrometry-based proteomics data generated in this study have been deposited in the ProteomeXchange Consortium via the PRIDE partner repository under accession code PXD074961. The differentially expressed gene data generated in this study are provided in Supplementary Data 1. All other data supporting the findings of this study are available within the paper and its Supplementary Information. Source data for all corresponding main text and Supplementary Figures (including the uncropped and unprocessed scans of blots) are provided with this paper. Source data are provided with this paper.
References
Gurbatri, C. R., Arpaia, N. & Danino, T. Engineering bacteria as interactive cancer therapies. Science 378, 858–864 (2022).
Redenti, A. et al. Probiotic neoantigen delivery vectors for precision cancer immunotherapy. Nature 635, 453–461 (2024).
Feng, Z. et al. Recent advances in bacterial therapeutics based on sense and response. Acta Pharm. Sin. B 13, 1014–1027 (2023).
Makabenta, J. M. V. et al. Nanomaterial-based therapeutics for antibiotic-resistant bacterial infections. Nat. Rev. Microbiol 19, 23–36 (2021).
Wang, W. et al. Systemic immune responses to irradiated tumours via the transport of antigens to the tumour periphery by injected flagellate bacteria. Nat. Biomed. Eng. 6, 44 (2022).
Xiao, Y. et al. Aptamer-drug conjugates-loaded bacteria for pancreatic cancer synergistic therapy. Signal Transduct. Target. Ther. 9, 272 (2024).
Clairmont, C. et al. Genetically modified Salmonella typhimurium, VNP20009, a novel anticancer agent:: bio-distribution, genetic stability, selective tumor accumulation, and antitumor efficacy. Cancer Gene Ther. 6, S11–S12 (1999).
Clairmont, C. et al. VNP20009, a genetically modified Salmonella typhimurium: anti-tumor efficacy, toxicology, and biodistribution in preclinical models. Clin. Cancer Res. 5, 3830S–3830S (1999).
Low, K. B. et al. VNP20009, a genetically modified Salmonella typhimurium for treatment of solid tumors. Proc. Am. Assoc. Cancer Res. Annu. Meet. 40, 87–88 (1999).
Chang, Z. et al. Bacterial immunotherapy leveraging IL-10R hysteresis for both phagocytosis evasion and tumor immunity revitalization. Cell https://doi.org/10.1016/j.cell.2025.02.002 (2025).
Roberts, N. J. et al. Intratumoral injection of Clostridium novyi-NT spores induces antitumor responses. Sci. Transl. Med. https://doi.org/10.1126/scitranslmed.3008982 (2014).
Agrawal, N. et al. Bacteriolytic therapy can generate a potent immune response against experimental tumors. Proc. Natl. Acad. Sci. USA 101, 15172–15177 (2004).
Zhou, S., Gravekamp, C., Bermudes, D. & Liu, K. Tumour-targeting bacteria engineered to fight cancer. Nat. Rev. Cancer 18, 727–743 (2018).
Bettegowda, C. et al. The genome and transcriptomes of the anti-tumor agent Clostridium novyi-NT. Nat. Biotechnol. 24, 1573–1580 (2006).
Liu, Y. et al. Dressing bacteria with a hybrid immunoactive nanosurface to elicit dual anticancer and antiviral immunity. Adv. Mater. https://doi.org/10.1002/adma.202210949 (2023).
Li, J. J. et al. Decorating bacteria with triple immune nanoactivators generates tumor-resident living immunotherapeutics. Angew. Chem. Int. Ed. https://doi.org/10.1002/anie.202202409 (2022).
Brockstedt, D. G. et al. Listeria-based cancer vaccines that segregate immunogenicity from toxicity. Proc. Natl. Acad. Sci. USA 101, 13832–13837 (2004).
Le, D. T. et al. A live-attenuated listeria vaccine (ANZ-100) and a live-attenuated listeria vaccine expressing mesothelin (CRS-207) for advanced cancers: phase I studies of safety and immune induction. Clin. Cancer Res. 18, 858–868 (2012).
Le, D. T. et al. Safety and survival With GVAX pancreas prime and listeria monocytogenes-expressing mesothelin (CRS-207) boost vaccines for metastatic pancreatic cancer. J. Clin. Oncol. 33, 1325 (2015).
Toso, J. F. et al. Phase I study of the intravenous administration of attenuated Salmonella typhimurium to patients with metastatic melanoma. J. Clin. Oncol. 20, 142–152 (2002).
Thamm, D. H. et al. Systemic administration of an attenuated, tumor-targeting Salmonella typhimurium to dogs with spontaneous neoplasia:: phase I evaluation. Clin. Cancer Res. 11, 4827–4834 (2005).
Janku, F. et al. Phase I clinical study of intratumoral injection of oncolytic Clostridium novyi-NT spores in patients with advanced cancers. Eur. J. Cancer 69, S94–S94 (2016).
Costerton, J. W., Stewart, P. S. & Greenberg, E. P. Bacterial biofilms: a common cause of persistent infections. Science 284, 1318–1322 (1999).
Hemmi, H. et al. A Toll-like receptor recognizes bacterial DNA. Nature 408, 740–745 (2000).
Wang, Y. et al. In situ production and precise release of bioactive GM-CSF and siRNA by engineered bacteria for macrophage reprogramming in cancer immunotherapy. Biomaterials https://doi.org/10.1016/j.biomaterials.2024.123037 (2025).
Mabesoone, M. F. J. et al. Evolution-guided engineering of trans-acyltransferase polyketide synthases. Science 383, 1312–1317 (2024).
Pistofidis, A. et al. Structures and mechanism of condensation in non-ribosomal peptide synthesis. Nature 638, 270–278 (2025).
Jang, M. S. et al. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science 275, 218–220 (1997).
Baur, J. A. & Sinclair, D. A. Therapeutic potential of resveratrol:: the in vivo evidence. Nat. Rev. Drug Discov. 5, 493–506 (2006).
Newman, D. J. & Cragg, G. M. Natural products as sources of new drugs from 1981 to 2014. J. Nat. Products 79, 629–661 (2016).
Xu, S., Gao, S. & An, Y. Research progress of engineering microbial cell factories for pigment production. Biotechnol. Adv. 65, 108150 (2023).
Williamson, N. R. et al. Biosynthesis of the red antibiotic, prodigiosin, in Serratia: identification of a novel 2-methyl-3-n-amyl-pyrrole (MAP) assembly pathway, definition of the terminal condensing enzyme, and implications for undecylprodigiosin biosynthesis in Streptomyces. Mol. Microbiol. 56, 971–989 (2005).
Tuli, H. S., Chaudhary, P., Beniwal, V. & Sharma, A. K. Microbial pigments as natural color sources: current trends and future perspectives. J. Food Sci. Technol. 52, 4669–4678 (2015).
Darshan, N. & Manonmani, H. K. Prodigiosin and its potential applications. J. Food Sci. Technol. 52, 5393–5407 (2015).
Wang, Z. et al. Prodigiosin inhibits Wnt/β-catenin signaling and exerts anticancer activity in breast cancer cells. Proc. Natl. Acad. Sci. USA 113, 13150–13155 (2016).
Liu, S. et al. Preparation, characterization, formation mechanism, and stability studies of zein/pectin nanoparticles for the delivery of prodigiosin. Int. J. Biol. Macromol. https://doi.org/10.1016/j.ijbiomac.2024.138915 (2025).
Pan, X. et al. Improving prodigiosin production by transcription factor engineering and promoter engineering in Serratia marcescens. Front. Microbiol. 13, 977337 (2022).
Romanowski, E. G. et al. Thermoregulation of prodigiosin biosynthesis by Serratia marcescens is controlled at the transcriptional level and requires HexS. Pol. J. Microbiol. 68, 43–50 (2019).
Shanks, R. M. et al. A Serratia marcescens PigP homolog controls prodigiosin biosynthesis, swarming motility and hemolysis and is regulated by cAMP-CRP and HexS. PLoS ONE 8, e57634 (2013).
Gristwood, T., McNeil, M. B., Clulow, J. S., Salmond, G. P. & Fineran, P. C. PigS and PigP regulate prodigiosin biosynthesis in Serratia via differential control of divergent operons, which include predicted transporters of sulfur-containing molecules. J. Bacteriol. 193, 1076–1085 (2011).
Magiera-Mularz, K. et al. Macrocyclic peptide inhibitor of PD-1/PD-L1 immune checkpoint. Adv. Therap. https://doi.org/10.1002/adtp.202000195 (2020).
Elsinghorst, E. A. Measurement of invasion by gentamicin resistance. Methods Enzymol. 236, 405–420 (1994).
Haas, L. et al. Acquired resistance to anti-MAPK targeted therapy confers an immune-evasive tumour microenvironment and cross-resistance to immunotherapy in melanoma. Nat. Cancer 2, 693–708 (2021).
Grierson, P. M. et al. The MK2/Hsp27 axis is a major survival mechanism for pancreatic ductal adenocarcinoma under genotoxic stress. Sci. Transl. Med. 13, eabb5445 (2021).
Rada, C. C. et al. Heat shock protein 27 activity is linked to endothelial barrier recovery after proinflammatory GPCR-induced disruption. Sci. Signal 14, eabc1044 (2021).
Bertheloot, D., Latz, E. & Franklin, B. S. Necroptosis, pyroptosis and apoptosis: an intricate game of cell death. Cell. Mol. Immunol. 18, 1106–1121 (2021).
Yuan, J. & Ofengeim, D. A guide to cell death pathways. Nat. Rev. Mol. Cell Biol. 25, 379–395 (2023).
Xu, C. & Pu, K. Second near-infrared photothermal materials for combinational nanotheranostics. Chem. Soc. Rev. 50, 1111–1137 (2021).
Li, N., Wang, Y., Li, Y., Zhang, C. & Fang, G. Recent advances in photothermal therapy at near-infrared-II based on 2D MXenes. Small 20, e2305645 (2024).
Liu, Y. et al. A triple enhanced permeable gold nanoraspberry designed for positive feedback interventional therapy. J. Control Release 345, 120–137 (2022).
Hu, D., Zha, M., Zheng, H., Gao, D. & Sheng, Z. Recent advances in indocyanine green-based probes for second near-infrared fluorescence imaging and therapy. Research https://doi.org/10.34133/research.0583 (2025).
Ji, L. et al. Enhancing L-malate production of Aspergillus oryzae by nitrogen regulation strategy. Appl. Microbiol. Biotechnol. 105, 3101–3113 (2021).
Xiang, T. et al. Transcriptomic analysis reveals competitive growth advantage of non-pigmented Serratia marcescens mutants. Front. Microbiol. https://doi.org/10.3389/fmicb.2021.793202 (2022).
He, Q. et al. A novel alternative for pyrogen detection based on a transgenic cell line. Signal Transduct. Target Ther. 9, 33 (2024).
Wang, J. et al. Biocompatible aggregation-induced emission active polyphosphate-manganese nanosheets with glutamine synthetase-like activity in excitotoxic nerve cells. Nat. Commun. 15, 3534 (2024).
Guenther, C. et al. β2-integrin adhesion regulates dendritic cell epigenetic and transcriptional landscapes to restrict dendritic cell maturation and tumor rejection. Cancer Immunol. Res. 9, 1354–1369 (2021).
Nguyen, D. H. et al. Reprogramming the tumor immune microenvironment using engineered dual-drug loaded Salmonella. Nat. Commun. 15, 6680 (2024).
Zhao, X. et al. A ferroptosis-inducing arsenene-iridium nanoplatform for synergistic immunotherapy in pancreatic cancer. Angew. Chem. Int. Ed. Engl. 63, e202400829 (2024).
Wang, J. et al. Hierarchical assembly of flexible biopolymer polyphosphate-manganese into nanosheets. Small 18, e2203200 (2022).
Chen, S., Li, S. & Wang, H. Remodeling tumor-associated macrophages in the tumor microenvironment. Oncol. Transl. Med. 10, 281–285 (2024).
Acknowledgements
This work was supported by the National Natural Science Foundation of China (22293052, 22025701, and 92353301 to J.Z.; 22477057 to X.X.W.; 22177048 to W.W.), the National Key R&D Program of China (2023YFA1508900 to X.X.W.), the Natural Science Foundation of Jiangsu Province (BK20232020 to J.Z.), the Jiangsu Provincial Science and Technology Plan Special Fund (BM2023008 to W.W.), the Nanjing Science and Technology Program (202305003 to J.Z.), the Fundamental and Interdisciplinary Disciplines Breakthrough Plan of the Ministry of Education of China (JYB2025XDXM507 to J.Z.), the Fundamental Research Funds for the Central Universities (KG202510 to W.W., 2024300401 to X.X.W.), and the Yachen Foundation of Nanjing University (to J.Z.).
Author information
Authors and Affiliations
Contributions
Conceptualization, J.L.H., Z.T.Z., W.L. and W.W.; Methodology, J.L.H., Z.J.Y., W.J. and W.X.X.; Experimental execution, J.L.H., J.T.Q., Q.Z.H., G.S.Q., W.Y.Q. and H.H.M.; Investigation, J.L.H., J.T.Q., G.S.Q., Q.Z.H., H.H.M., W.Y.Q. and W.L.; Writing–original draft, J.L.H.; Writing–review & editing, W.X.X., L.C. and W.W.; Funding acquisition, M.Y.L., Z.J., and W.W.; Resources, W.X.X., Z.J. and W.W.; Supervision, Z.J. and W.W.
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing interests.
Peer review
Peer review information
Nature Communications thanks Desheng Lu, Dinh-Huy Nguyen, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. A peer review file is available.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Source data
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Ji, L., Zhu, T., Jiang, T. et al. A live biohybrid bacterial therapy based on engineered Serratia marcescens. Nat Commun (2026). https://doi.org/10.1038/s41467-026-70949-4
Received:
Accepted:
Published:
DOI: https://doi.org/10.1038/s41467-026-70949-4
