Engineered Bacteriophage-Based In Situ Vaccine Remodels a Tumor Microenvironment and Elicits Potent Antitumor Immunity
Abstract
In situ vaccines (ISVs) utilize the localized delivery of chemotherapeutic agents or radiotherapy to stimulate the release of endogenous antigens from tumors, thereby eliciting systemic and persistent immune activation. Recently, a bioinspired ISV strategy has attracted tremendous attention due to its features such as an immune adjuvant effect and genetic plasticity. M13 bacteriophages are natural nanomaterials with intrinsic immunogenicity, genetic flexibility, and cost-effectiveness for large-scale production, demonstrating the potential for application in cancer vaccines. In this study, we propose an ISV based on the engineered M13 bacteriophage targeting CD40 (M13 CD40 ) for dendritic cell (DC)-targeted immune stimulation, named H-GM-M13 CD40 . We induce immunogenic cell death and release tumor antigens through local delivery of ( S )-10-hydroxycamptothecin (HCPT), followed by intratumoral injection of granulocyte-macrophage colony stimulating factor (GM-CSF) and M13 CD40 to enhance DC recruitment and activation. We demonstrate that this ISV strategy can result in significant accumulation and activation of DCs at the tumor site, reversing the immunosuppressive tumor microenvironment. In addition, H-GM-M13 CD40 can synergize with the PD-1 blockade and induce abscopal effects in cold tumor models. Overall, our study verifies the immunogenicity of the engineered M13 CD40 bacteriophage and provides a proof of concept that the engineered M13 CD40 phage can function as an adjuv…
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Phages can remodel the tumor microenvironment.
“Phages can eliminate cancer-associated bacteria, remodel the tumor microenvironment, enhance antitumor immunity, and deliver targeted therapeutic payloads.”
From Phage therapy in oncology: opportunities for cancer prevention and treatment (2026) · cites this paper as [49]
Directing phage display ligands toward CAF-enriched receptors may mitigate stromal remodeling and improve drug accessibility.
“By directing phage display ligands toward CAF-enriched receptors, these platforms may mitigate stromal remodeling and improve drug accessibility, thereby integrating stromal targeting into the broader framework of phage-mediated modulation of the TME [49]”
From Phage therapy in oncology: opportunities for cancer prevention and treatment (2026) · cites this paper as [49]
Engineered phages can be designed to selectively target key tumor microenvironment components, including tumor-associated macrophages, cancer-associated fibroblasts, and the tumor vasculature.
“Engineered phages can be designed to selectively target key TME components, including tumor-associated macrophages (TAMs), cancer-associated fibroblasts (CAFs), and the tumor vasculature (Box 3) [15,48–50]”
From Phage therapy in oncology: opportunities for cancer prevention and treatment (2026) · cites this paper as [49]
Phage platforms can function as standalone cancer vaccines or as adjuvants that enhance the efficacy of immune checkpoint blockade.
“Such platforms can function as standalone cancer vaccines or as adjuvants that enhance the efficacy of immune checkpoint blockade [49,76,78,79]”
From Phage therapy in oncology: opportunities for cancer prevention and treatment (2026) · cites this paper as [49]
Combination approaches integrating phage therapy with immune checkpoint inhibitors have yielded synergistic antitumor effects in preclinical models.
“Importantly, combination approaches integrating phage therapy with immune checkpoint inhibitors have yielded synergistic antitumor effects in preclinical models, suggesting a role for phages as immunotherapy adjuvants [49]”
From Phage therapy in oncology: opportunities for cancer prevention and treatment (2026) · cites this paper as [49]
Phages may serve as immunotherapy adjuvants.
“Importantly, combination approaches integrating phage therapy with immune checkpoint inhibitors have yielded synergistic antitumor effects in preclinical models, suggesting a role for phages as immunotherapy adjuvants [49]”
From Phage therapy in oncology: opportunities for cancer prevention and treatment (2026) · cites this paper as [49]
Cites
Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer
Sahin, U., Derhovanessian, E., Miller, M., Kloke, B.-P., Simon, P., Löwer, M., Bukur, V., Tadmor, A. D., Luxemburger, U., Schrörs, B., et al. (2017) · Nature · doi:10.1038/nature23003 · Cited by 2,488 · see citing works
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Phage therapy in oncology: opportunities for cancer prevention and treatment
Mutalik, V. K., Inman, J. L., Chang, H., Arkin, A., & Mao, J.-H. (2026) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2026.02.001 · Cited by 5 · see citing works
- Authors
- Lei, L., Yan, J., Xin, K., Li, L., Sun, Q., Wang, Y., Chen, T., Wu, S., Shao, J., Liu, B., & Chen, X.
- Affiliations
- Nanjing Drum Tower Hospital (CN)
- Nanjing University of Chinese Medicine (CN)
- Corresponding author
- Liu, Baorui
- Chen, Xiaotong
- Venue
- ACS Nano
- Publisher
- American Chemical Society (ACS)
- Published
- 2024-05-01
- Volume
- 18
- Issue
- 19
- Pages
- 12194-12209
- ISSN
- 1936-0851 (ISSN-L)
- 1936-086X
- OpenAlex
- W4396561242
- Cited by
- 33
- References
- 1
- Citations by year
- 2026: 10 · 2025: 16 · 2024: 6 · 2022: 1
- FWCI
- 5.37
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- ACS Nano (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81930080)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Cancer Research and Treatments
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- in situ vaccine, M13 bacteriophage, dendritic cell recruitment, tumor microenvironment remodeling, immunogenic cell death, 10-hydroxycamptothecin, GM-CSF, anti-PD-1 therapy, abscopal effect, cold tumors, antitumor immunity
- MeSH terms
- Animals, Antigens, Neoplasm, Dendritic Cells, Female, Humans, Mice, Inbred C57BL, Granulocyte-Macrophage Colony-Stimulating Factor, Bacteriophage M13, CD40 Antigens, Cancer Vaccines, Cell Line, Tumor, Mice, Tumor Microenvironment
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