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Reprogramming Disulfide Reduction in Endoplasmic Reticulum Uncouples Immune Evasion of Pancreatic Cancer
Zhongqiu Guo1,2, Yuting Lu2, Li Zhang2,3
1Department of Nuclear Medicine, The First Affiliated Hospital of Naval Medical University, Shanghai, P. R. China.
Abstract:
The modulation of immune checkpoint activity exerts profound impacts on tumor immunotherapy. However, the interfere of mature immune checkpoints encounter efficacy challenges in solid tumors, which underlies a critical barrier in clinical translation of multiple potential targets. Herein, we propose a biochemical immune modulation strategy for immunosuppression reversal by blocking the mature of CD47 within the endoplasmic reticulum (ER). Clinically used radionuclides iodine-131 (131I) is reengineered to encapsulate within microporous barium titanate nanoparticles, forming an immunoactive nanomodulator. Leveraging polarized and collisional relaxation, the electrons emitted from 131I mediate continuous disulfide bond reduction, blocking CD47 folding and surface translocation, resulting in a 93.6% reduction in CD47 expression. Together with the remarkable increase of tumor antigen presentation induced by ER reductive stress in pancreatic tumor-bearing mice, we realize a 93% tumor inhibition and a 3-fold prolongation of survival. This work underscores the role of organellar biochemistry in reshaping immunosuppression for tumor immunotherapy.
Insights
This study introduces a novel strategy to reverse tumor immunosuppression by blocking CD47 maturation in the endoplasmic reticulum (ER). This approach significantly inhibits tumor growth and improves survival in mice.
Area of Science:
- Biochemistry
- Immunology
- Nanotechnology
- Oncology
Background:
- Mature immune checkpoints present challenges for solid tumor immunotherapy.
- Blocking CD47 is a potential therapeutic target, but clinical translation faces barriers.
Purpose of the Study:
- To develop a biochemical strategy for reversing tumor immunosuppression.
- To block CD47 maturation within the endoplasmic reticulum (ER) for enhanced immunotherapy.
Main Methods:
- Engineered iodine-131 (131I) within barium titanate nanoparticles as an immunoactive nanomodulator.
- Utilized electrons from 131I to induce disulfide bond reduction and block CD47 folding and translocation.
- Induced ER reductive stress to enhance tumor antigen presentation.
Main Results:
- Achieved a 93.6% reduction in CD47 expression.
- Observed a 93% tumor inhibition in pancreatic tumor-bearing mice.
- Demonstrated a 3-fold prolongation of survival.
Conclusions:
- Biochemical modulation of organellar processes can overcome immunosuppression in cancer.
- Targeting CD47 maturation within the ER offers a promising avenue for tumor immunotherapy.
- This strategy enhances tumor antigen presentation and inhibits tumor growth effectively.
