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Peer-reviewedCC BY 4.0Cell Death Discovery

Calreticulin-targeting L-asparaginase-flagellin conjugate enhances Salmonella-mediated antitumor efficacy

  • Dinh-Huy Nguyen1,2,3
  • Aqeel Rana Afzal1
  • Phuong Thi-Minh Nguyen1
  • Quoc-Thai Do-Ba4
  • Khuynh Van Nguyen1,4
  • Wan-Sik Lee5
  • Jung-Joon Min1,2,3,4,6
  • Yeongjin Hong1,4,6,7
7 affiliations
  1. 1Institute for Molecular Imaging and Theranostics, Chonnam National University, Jeonnam, Republic of Korea
  2. 2Department of Nuclear Medicine, Chonnam National University Medical School and Hwasun Hospital, Jeonnam, Republic of Korea
  3. 3Institute of Biomedical Science, Chonnam National University Hwasun Hospital, Jeonnam, Republic of Korea
  4. 4Department of Biomedical Science (BrainKorea21 Plus) Chonnam National University Graduate School, Jeonnam, Republic of Korea
  5. 5Division of Gastroenterology, Department of Internal Medicine, Chonnam National University Medical School and Hwasun Hospital, Jeonnam, Republic of Korea
  6. 6CNCure Co. Ltd., Jeonnam, Republic of Korea
  7. 7Department of Microbiology and Immunology, Chonnam National University Medical School, Jeonnam, Republic of Korea
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Abstract

Targeted therapeutics have transformed cancer treatment by selectively eliminating malignant cells while limiting systemic toxicity. L-asparaginase (L-ASNase), which induces metabolic stress by depleting asparagine (Asn), is clinically used for hematological malignancies but shows limited activity against solid tumors due to poor delivery and an immunosuppressive microenvironment. We previously developed CRT3LP, a calreticulin (CRT)-targeting monobody-L-ASNase fusion protein, designed to exploit immunogenic cell death (ICD); however, its therapeutic potential is constrained by insufficient immune activation. Here, we show that CRT3LFP, a multifunctional fusion protein incorporating the flagellin B subunit (FlaB) into the CRT3LP scaffold, effectively promotes M2-to-M1 macrophage polarization while maintaining tumor-selective metabolic disruption. In combination with the tumor-colonizing bacterial strain CNC018, which induces surface-exposed CRT, CRT3LFP achieves precise tumor localization. This synergistic approach significantly inhibits tumor growth and reshapes the tumor microenvironment, characterized by enhanced macrophage polarization, dendritic cell maturation, and CD8+ T-cell expansion. Additionally, CD47 blockade further potentiates this effect, fostering the formation of durable immune memory. Together, our findings establish CRT3LFP as a tumor-targeted immunometabolic platform that integrates metabolic deprivation with coordinated innate and adaptive immune activation to overcome resistance in solid tumors.

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Cite

BibTeXRIS
BibTeX
@article{nguyen2026calreticulintargeting,
  title = {{Calreticulin-targeting L-asparaginase-flagellin conjugate enhances Salmonella-mediated antitumor efficacy}},
  author = {Dinh-Huy Nguyen and Aqeel Rana Afzal and Phuong Thi-Minh Nguyen and Quoc-Thai Do-Ba and Khuynh Van Nguyen and Wan-Sik Lee and Jung-Joon Min and Yeongjin Hong},
  journal = {Cell Death Discovery},
  year = {2026},
  month = aug,
  doi = {10.1038/s41420-026-03300-x},
  url = {https://doi.org/10.1038/s41420-026-03300-x},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Calreticulin-targeting L-asparaginase-flagellin conjugate enhances Salmonella-mediated antitumor efficacy
AU  - Dinh-Huy Nguyen
AU  - Aqeel Rana Afzal
AU  - Phuong Thi-Minh Nguyen
AU  - Quoc-Thai Do-Ba
AU  - Khuynh Van Nguyen
AU  - Wan-Sik Lee
AU  - Jung-Joon Min
AU  - Yeongjin Hong
PY  - 2026
DA  - 2026/08/09
JO  - Cell Death Discovery
DO  - 10.1038/s41420-026-03300-x
UR  - https://doi.org/10.1038/s41420-026-03300-x
AB  - Targeted therapeutics have transformed cancer treatment by selectively eliminating malignant cells while limiting systemic toxicity. L-asparaginase (L-ASNase), which induces metabolic stress by depleting asparagine (Asn), is clinically used for hematological malignancies but shows limited activity against solid tumors due to poor delivery and an immunosuppressive microenvironment. We previously developed CRT3LP, a calreticulin (CRT)-targeting monobody-L-ASNase fusion protein, designed to exploit immunogenic cell death (ICD); however, its therapeutic potential is constrained by insufficient immune activation. Here, we show that CRT3LFP, a multifunctional fusion protein incorporating the flagellin B subunit (FlaB) into the CRT3LP scaffold, effectively promotes M2-to-M1 macrophage polarization while maintaining tumor-selective metabolic disruption. In combination with the tumor-colonizing bacterial strain CNC018, which induces surface-exposed CRT, CRT3LFP achieves precise tumor localization. This synergistic approach significantly inhibits tumor growth and reshapes the tumor microenvironment, characterized by enhanced macrophage polarization, dendritic cell maturation, and CD8+ T-cell expansion. Additionally, CD47 blockade further potentiates this effect, fostering the formation of durable immune memory. Together, our findings establish CRT3LFP as a tumor-targeted immunometabolic platform that integrates metabolic deprivation with coordinated innate and adaptive immune activation to overcome resistance in solid tumors.
SN  - 2058-7716
ER  -